Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study asks whether the HRG genotype changes the link between baseline blood selenium and later risk of death or cancer in women from a familial breast‑cancer registry. The prospective design, ICP‑MS selenium measurements, and genotype‑adjusted survival analyses are strengths, but a few important improvements are needed before the findings can be interpreted with confidence.
1. Relying on a single baseline selenium measurement makes exposure assessment fragile because selenium can vary with supplements, diet, season, and health events; adding repeat selenium measurements during follow‑up—or at least regular, structured questionnaires on diet and supplement use—plus sensitivity analyses would help show how much a one‑time measure might bias the results.
2. Running many subgroup and interaction tests without a pre‑specified plan and without correcting for multiple comparisons increases the chance of false positives, and small subgroups give unstable estimates; the authors should pre‑register primary and secondary hypotheses, limit exploratory subgroup tests, apply multiple‑comparison corrections (e.g., FDR or Bonferroni), report power and confidence intervals, and clearly label small‑n findings as exploratory or stabilize estimates by combining groups or using alternative models.
3. Because the cohort is drawn from a familial breast‑cancer registry, the results may not generalize to the broader population and the reported HRG×selenium interaction needs external validation; the authors should try to replicate the finding in independent, population‑based and more diverse cohorts, explain how candidate genes were chosen, share analysis code or summary data for meta‑analysis, and be explicit about the study’s population‑specific limits when discussing implications.
4. Key confounders that can affect both selenium and outcomes—such as BMI, chronic diseases (e.g., diabetes, CVD), medication or supplement use, dietary patterns, and socioeconomic status—are not clearly handled; the manuscript should collect and adjust for these variables where possible, use multiple imputation for missing covariates, and run sensitivity checks (e.g., propensity scores, E‑value or negative‑control analyses) to assess robustness to residual confounding.

It is not intended to ask the authors to undertake new investigations for all of these items; if further research or additional data collection is not feasible, please state this limitation clearly in the manuscript and explain how it will be addressed.

Author Response

 

This study asks whether the HRG genotype changes the link between baseline blood selenium and later risk of death or cancer in women from a familial breast‑cancer registry. The prospective design, ICP‑MS selenium measurements, and genotype‑adjusted survival analyses are strengths, but a few important improvements are needed before the findings can be interpreted with confidence.
1. Relying on a single baseline selenium measurement makes exposure assessment fragile because selenium can vary with supplements, diet, season, and health events; adding repeat selenium measurements during follow‑up—or at least regular, structured questionnaires on diet and supplement use—plus sensitivity analyses would help show how much a one‑time measure might bias the results.

In the current study, we planned to conduct only a single measurement of selenium levels. However, we have selective data regarding a subgroup of 299 patients whose selenium levels were measured based on two separate sample collection. For 233 patients (75%), the quarter assignment remained the same for both samples, whereas 76 patients (25%) showed shifts in quarters (e.g., from Q1 to Q2 etc.) [Table].We are fully aware of the potential limitations associated with single selenium measurements, as evidenced by the inclusion of a corresponding statement in the 'Limitations' section (“…blood Se concentration was determined from a single sample obtained at baseline, which may not fully reflect long-term exposure’’.)

 

      Table. Differences in blood Se level between first and second measurement

Characteristic	N = 2991
Se_first_measurement	57.15 - 199.59 (103.49/101.47)
Se_second_measurement	57.97 - 193.74 (105.08/104.24)
Quarters_match_vector
Different	76 (25%)
Matched	223 (75%)
1Min - Max (Mean/Median); n (%)

 

 

2. 
   Running many subgroup and interaction tests without a pre‑specified plan and without correcting for multiple comparisons increases the chance of false positives, and small subgroups give unstable estimates; the authors should pre‑register primary and secondary hypotheses, limit exploratory subgroup tests, apply multiple‑comparison corrections (e.g., FDR or Bonferroni), report power and confidence intervals, and clearly label small‑n findings as exploratory or stabilize estimates by combining groups or using alternative models.

We agree that extensive subgroup and interaction testing may increase the risk of false-positive findings, particularly in the presence of small subgroup sizes. To address this concern, we implemented several measures to improve the robustness and interpretability of our analyses .First, we restricted the number of subgroup analyses by excluding strata with very small numbers of events, which yielded unstable estimates. Analyses presented in the revised manuscript are therefore limited to subgroups with sufficient event counts to support Cox regression modeling.Second, the primary hypothesis of the study was defined as the association between blood selenium levels, HRG genotype, and all-cause mortality, while analyses of cancer incidence and age-stratified effects are now explicitly described as secondary or exploratory. Third, all effect estimates are presented together with 95% confidence intervals, allowing assessment of statistical precision. Fourth, while formal pre-registration was not performed due to the long-term observational nature of the cohort and the use of pre-existing data, the study design, inclusion criteria, exposure assessment, and primary outcomes were defined a priori and remained unchanged throughout the analysis. Nevertheless, we clearly state that subgroup-specific results should be interpreted as hypothesis-generating and warrant confirmation in independent cohorts.

 

3. 
   Because the cohort is drawn from a familial breast‑cancer registry, the results may not generalize to the broader population and the reported HRG×selenium interaction needs external validation; the authors should try to replicate the finding in independent, population‑based and more diverse cohorts, explain how candidate genes were chosen, share analysis code or summary data for meta‑analysis, and be explicit about the study’s population‑specific limits when discussing implications.

In the introduction was stated that the cohort is specific for familial breast cancer subgroup. In addition, in limitations section, there is a statement: “…validation in independent cohorts, including both Polish and other ethnic groups, is required.”

4. 
   Key confounders that can affect both selenium and outcomes—such as BMI, chronic diseases (e.g., diabetes, CVD), medication or supplement use, dietary patterns, and socioeconomic status—are not clearly handled; the manuscript should collect and adjust for these variables where possible, use multiple imputation for missing covariates, and run sensitivity checks (e.g., propensity scores, E‑value or negative‑control analyses) to assess robustness to residual confounding.

It is not intended to ask the authors to undertake new investigations for all of these items; if further research or additional data collection is not feasible, please state this limitation clearly in the manuscript and explain how it will be addressed.

 

Unfortunately, we do not have access to a complete set of information regarding the factors mentioned above. To maintain data integrity, we employed a complete-case approach excluding any individuals with missing data points from the final analysis.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents a prospective study investigating the interaction between blood selenium (Se) levels, the HRG rs10770 genotype, and risks of cancer incidence and all-cause mortality in a cohort of women from families with familial breast cancer. The research addresses a pertinent question regarding personalized risk assessment based on gene-nutrient interactions. The cohort is well-defined and the analytical plan is comprehensive. However, after a detailed review of the main text and supplementary materials, several fundamental methodological, statistical, and interpretational issues significantly undermine the validity and clarity of the reported findings. These concerns must be thoroughly addressed before the manuscript can be considered for publication.

1. The core of the analysis relies on quartile comparisons. A critical flaw is the inconsistent and seemingly post-hoc selection of reference groups. For instance, in Table 4 (any cancer, HRG TT), Q2 is the reference, and a significant HR is found for Q1 vs. Q2. Conversely, in Table 5 (death, whole group), Q4 is the reference for some comparisons, but the key result (Q4 vs. Q1-Q3) uses a collapsed reference group. Most problematically, for the HRG non-TT group, the analysis consistently compares the lowest quartile (Q1) against a combined group of the three higher quartiles (Q2-Q4). This analytical flexibility, especially when driven by low event counts, is a form of data dredging that dramatically increases the risk of false-positive findings. The analytical plan for defining reference and comparison groups must be pre-specified, justified, and applied consistently across all genotypes and outcomes to allow for fair comparison and valid inference.
2. The claims of strong effects, particularly for the HRG non-TT genotype, are based on analyses with extremely low event counts, rendering the estimates unstable and likely unreliable. Key examples illustrate this: The multivariate HR of 2.18 for Q1 in Table S.3 has a 95% CI of 1.025-4.63, where the lower bound is essentially 1.00. The critical finding of HR=7.93 in Table 6 is based on only 9 deaths in Q1 and 5 deaths in Q2-Q4 combined. The HR of 12.76 in Table 8 is derived from only 6 deaths in Q1 and 2 deaths in Q2-Q4. The authors must acknowledge that these hazard ratios, while statistically significant, are statistically unstable. They should discuss the implications of this instability and the high risk of overestimation.
3. The study performs a vast number of statistical tests. The analysis is stratified by outcome, age group, genotype, and Se quartile combinations, representing hundreds of comparisons. Without any adjustment for multiple testing, the probability of identifying statistically significant results by chance alone is very high. The reported p-values are likely overly optimistic. The manuscript must explicitly address the issue of multiple testing and consider applying appropriate corrections or, at minimum, interpreting the results with extreme caution.
4. The discussion attempts to link HRG, a protein involved in angiogenesis, coagulation, and immune modulation, to selenium biology and cancer risk. However, this link is highly speculative and not mechanistically explained. The authors propose that HRG genotype modifies the "reference range" for selenium, but they provide no biological hypothesis for how a polymorphism in the HRG gene alters the physiological impact of a specific blood concentration of selenium on the risk of death or cancer. The discussion of HRG's role in cancer biology, while informative, reads as a general review disconnected from the core gene-environment interaction question of the paper.
5. In several analyses for the HRG non-TT group (e.g., Tables S.20, S.25), there are zero events in all quartiles. The manuscript states the effect "could not be assessed." This is a serious limitation that should be highlighted in the results and discussion, not just mentioned in passing. The absence of events, particularly in the younger age group, prevents any meaningful analysis for that genotype stratum and severely limits the generalizability of conclusions about the "protective effect" of the non-TT genotype.
6. There are critical discrepancies that confuse the reader and undermine confidence in the data. The abstract states a finding for women over 50 "regardless of genotype" (HR=3.07, Q1 vs. Q4). The cited result in Table 9 is from a model adjusted for confounders excluding age. Is the abstract result from a different model? This must be clarified. The footnote for tables analyzing the "above 50 years" subgroup (e.g., Table 9) correctly states adjustment excludes age. However, the footnote for the analogous supplementary tables (e.g., Table S.11, S.15) incorrectly includes "age" in the adjustment list. This error needs to be corrected throughout. Table numbering is chaotic. The supplementary file contains two different tables labeled "S.25." This makes cross-referencing between the main text and supplements nearly impossible. Essential results should be in the main manuscript.
7. Based on statistically unstable findings from a single, unique cohort (BRCA1-negative, high-risk familial women from Poland), the authors make direct recommendations: "women carrying this genotype should maintain their selenium blood levels above 93.96 μg/L." This is premature and not supported by the evidence presented. The discussion should tone down these prescriptive statements and emphasize the need for replication and mechanistic understanding.
8. The measurement of selenium exposure as a single baseline blood level is a notable limitation. Selenium status can fluctuate over time due to dietary changes. A single measurement may not accurately represent long-term exposure, which is more relevant for chronic disease risk. This limitation should be explicitly acknowledged and its potential impact on the study's findings discussed in greater depth.
9. The cohort consists exclusively of women from high-risk familial breast cancer families who are BRCA1 mutation-negative. This limits the generalizability of the findings. The results may not be applicable to the general population, to men, or to individuals with different genetic risk profiles. The manuscript should clearly frame its conclusions within this specific population context.
10. The keywords include "familial breast cancers"; the text primarily uses "familial breast cancer." Consistency is preferred. Figure 1: The y-axis label "n" should be "Frequency" or "Number of participants." The phrase "strong- statistical significance" on page 15 should be corrected to "strong statistical significance." Ensure consistent formatting of confidence intervals.

The study explores a potentially interesting gene-environment interaction in a valuable cohort. However, the current analysis is compromised by an opportunistic and inconsistent statistical approach, severe issues with statistical power and data sparsity, a lack of correction for multiple testing, and unclear biological plausibility. The presentation contains significant errors and inconsistencies. The reported dramatic hazard ratios are likely artifacts of the analytical method and low event numbers rather than robust biological effects. For these reasons, I cannot recommend the manuscript for publication in its present form. Major revision is required. The authors must fundamentally reconsider their statistical methodology, provide a pre-specified and consistent analysis plan, fully acknowledge the severe limitations of their data, correct all inconsistencies, and substantially temper the clinical interpretations of their findings.

Author Response

This manuscript presents a prospective study investigating the interaction between blood selenium (Se) levels, the HRG rs10770 genotype, and risks of cancer incidence and all-cause mortality in a cohort of women from families with familial breast cancer. The research addresses a pertinent question regarding personalized risk assessment based on gene-nutrient interactions. The cohort is well-defined and the analytical plan is comprehensive. However, after a detailed review of the main text and supplementary materials, several fundamental methodological, statistical, and interpretational issues significantly undermine the validity and clarity of the reported findings. These concerns must be thoroughly addressed before the manuscript can be considered for publication.

1. The core of the analysis relies on quartile comparisons. A critical flaw is the inconsistent and seemingly post-hoc selection of reference groups. For instance, in Table 4 (any cancer, HRG TT), Q2 is the reference, and a significant HR is found for Q1 vs. Q2. Conversely, in Table 5 (death, whole group), Q4 is the reference for some comparisons, but the key result (Q4 vs. Q1-Q3) uses a collapsed reference group. Most problematically, for the HRG non-TT group, the analysis consistently compares the lowest quartile (Q1) against a combined group of the three higher quartiles (Q2-Q4). This analytical flexibility, especially when driven by low event counts, is a form of data dredging that dramatically increases the risk of false-positive findings. The analytical plan for defining reference and comparison groups must be pre-specified, justified, and applied consistently across all genotypes and outcomes to allow for fair comparison and valid inference.

In each regression model, the reference category was defined as the quartile with the lowest proportion of events in relation to the total number of individuals. This approach aimed to avoid HR values below one (1.0), improving the interpretability HRs between models. Due to the low frequency of events within individual quarters, we decided combine quartiles in such cases to enhance the stability of the results

 

2.The claims of strong effects, particularly for the HRG non-TT genotype, are based on analyses with extremely low event counts, rendering the estimates unstable and likely unreliable. Key examples illustrate this: The multivariate HR of 2.18 for Q1 in Table S.3 has a 95% CI of 1.025-4.63, where the lower bound is essentially 1.00. The critical finding of HR=7.93 in Table 6 is based on only 9 deaths in Q1 and 5 deaths in Q2-Q4 combined. The HR of 12.76 in Table 8 is derived from only 6 deaths in Q1 and 2 deaths in Q2-Q4. The authors must acknowledge that these hazard ratios, while statistically significant, are statistically unstable. They should discuss the implications of this instability and the high risk of overestimation.

We have added to manuscript ,,Since, some of presented results are based on a relatively small number of events, despite achieving statistical significance, can be unstable and should be interpreted with caution’’.

 

3.The study performs a vast number of statistical tests. The analysis is stratified by outcome, age group, genotype, and Se quartile combinations, representing hundreds of comparisons. Without any adjustment for multiple testing, the probability of identifying statistically significant results by chance alone is very high. The reported p-values are likely overly optimistic. The manuscript must explicitly address the issue of multiple testing and consider applying appropriate corrections or, at minimum, interpreting the results with extreme caution.

We acknowledge the issue of multiple testing; however, the analyses were hypothesis-driven and largely represent structured stratifications of the same exposure–genotype relationship rather than independent tests. Subgroup findings are therefore interpreted cautiously as exploratory.

 

4.The discussion attempts to link HRG, a protein involved in angiogenesis, coagulation, and immune modulation, to selenium biology and cancer risk. However, this link is highly speculative and not mechanistically explained. The authors propose that HRG genotype modifies the "reference range" for selenium, but they provide no biological hypothesis for how a polymorphism in the HRG gene alters the physiological impact of a specific blood concentration of selenium on the risk of death or cancer. The discussion of HRG's role in cancer biology, while informative, reads as a general review disconnected from the core gene-environment interaction question of the paper.

We agree with the reviewer that the initial version of the Discussion did not sufficiently articulate a biological hypothesis linking HRG genotype to selenium-related effects. In the revised manuscript, we have explicitly added a mechanistic, hypothesis-driven framework describing how HRG-dependent regulation of angiogenesis, immune responses, and tissue remodeling—processes that are highly sensitive to oxidative stress—may modify the cellular demand for selenium-dependent antioxidant defenses.

 

5.In several analyses for the HRG non-TT group (e.g., Tables S.20, S.25), there are zero events in all quartiles. The manuscript states the effect "could not be assessed." This is a serious limitation that should be highlighted in the results and discussion, not just mentioned in passing. The absence of events, particularly in the younger age group, prevents any meaningful analysis for that genotype stratum and severely limits the generalizability of conclusions about the "protective effect" of the non-TT genotype.

We agree with the reviewer that analyses with zero events across all selenium quartiles do not allow meaningful risk estimation and substantially limit interpretability. Accordingly, we have removed Tables S.20 and S.25 from the revised manuscript, as these analyses were uninformative.

In addition, we have strengthened the Results and Discussion sections to explicitly highlight the absence of events in younger HRG non-TT carriers as a key limitation, emphasizing that this precludes formal assessment of risk and limits generalizability. We now clearly state that any suggestion of a protective effect in this subgroup should be interpreted with caution.

 

6.There are critical discrepancies that confuse the reader and undermine confidence in the data. The abstract states a finding for women over 50 "regardless of genotype" (HR=3.07, Q1 vs. Q4). The cited result in Table 9 is from a model adjusted for confounders excluding age. Is the abstract result from a different model? This must be clarified. The footnote for tables analyzing the "above 50 years" subgroup (e.g., Table 9) correctly states adjustment excludes age. However, the footnote for the analogous supplementary tables (e.g., Table S.11, S.15) incorrectly includes "age" in the adjustment list. This error needs to be corrected throughout. Table numbering is chaotic. The supplementary file contains two different tables labeled "S.25." This makes cross-referencing between the main text and supplements nearly impossible. Essential results should be in the main manuscript.

We have made required corrections.

7.Based on statistically unstable findings from a single, unique cohort (BRCA1-negative, high-risk familial women from Poland), the authors make direct recommendations: "women carrying this genotype should maintain their selenium blood levels above 93.96 μg/L." This is premature and not supported by the evidence presented. The discussion should tone down these prescriptive statements and emphasize the need for replication and mechanistic understanding.

We agree with the reviewer that direct clinical recommendations based on findings from a single cohort are premature. In the revised manuscript, all prescriptive statements have been removed and rephrased in a hypothesis-driven, observational manner.The Discussion now emphasizes that the identified selenium thresholds represent data-driven cut-points within this specific cohort, do not constitute clinical recommendations, and require replication in independent populations and mechanistic validation. The language has been consistently toned down to reflect the exploratory and hypothesis-generating nature of the findings.

 

8.The measurement of selenium exposure as a single baseline blood level is a notable limitation. Selenium status can fluctuate over time due to dietary changes. A single measurement may not accurately represent long-term exposure, which is more relevant for chronic disease risk. This limitation should be explicitly acknowledged and its potential impact on the study's findings discussed in greater depth.

In the current study, we planned to conduct only a single measurement of selenium levels. However, we have selective data regarding a subgroup of 29 patients whose selenium levels were measured based on two separate sample collection. For 233 patients (75%), the quarter assignment remained the same for both samples, whereas 76 patients (25%) showed shifts in quarters (e.g., from Q1 to Q2 etc.)[Table].We are fully aware of the potential limitations associated with single selenium measurements, as evidenced by the inclusion of a corresponding statement in the 'Limitations' section (“…blood Se concentration was determined from a single sample obtained at baseline, which may not fully reflect long-term exposure.”).

 

Table. Differences in blood Se level between first and second measurement

Characteristic	N = 2991
Se_first_measurement	57.15 - 199.59 (103.49/101.47)
Se_second_measurement	57.97 - 193.74 (105.08/104.24)
Quarters_match_vector
Different	76 (25%)
Matched	223 (75%)
1Min - Max (Mean/Median); n (%)

 

9.The cohort consists exclusively of women from high-risk familial breast cancer families who are BRCA1 mutation-negative. This limits the generalizability of the findings. The results may not be applicable to the general population, to men, or to individuals with different genetic risk profiles. The manuscript should clearly frame its conclusions within this specific population context.

 

We agree with the reviewer that the study population represents a specific, high-risk subgroup of women from familial breast cancer families who are BRCA1-negative, which limits generalizability. In the revised manuscript, we have explicitly framed all conclusions within this population context and clarified that the findings may not be directly applicable to the general population.

 

10.The keywords include "familial breast cancers"; the text primarily uses "familial breast cancer." Consistency is preferred. Figure 1: The y-axis label "n" should be "Frequency" or "Number of participants." The phrase "strong- statistical significance" on page 15 should be corrected to "strong statistical significance." Ensure consistent formatting of confidence intervals.

We have made required corrections.

 

The study explores a potentially interesting gene-environment interaction in a valuable cohort. However, the current analysis is compromised by an opportunistic and inconsistent statistical approach, severe issues with statistical power and data sparsity, a lack of correction for multiple testing, and unclear biological plausibility. The presentation contains significant errors and inconsistencies. The reported dramatic hazard ratios are likely artifacts of the analytical method and low event numbers rather than robust biological effects. For these reasons, I cannot recommend the manuscript for publication in its present form. Major revision is required. The authors must fundamentally reconsider their statistical methodology, provide a pre-specified and consistent analysis plan, fully acknowledge the severe limitations of their data, correct all inconsistencies, and substantially temper the clinical interpretations of their findings.

 

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors noted that they incorporated all feasible improvements using the data available and acknowledged that collecting additional information is not possible at this stage. They also adopted a careful interpretive approach by distinguishing primary analyses from exploratory ones, limiting subgroup evaluations, and recognizing the need for external validation. Taken together, we believe these points adequately clarify the current constraints and how they were addressed.

Author Response

The authors noted that they incorporated all feasible improvements using the data available and acknowledged that collecting additional information is not possible at this stage. They also adopted a careful interpretive approach by distinguishing primary analyses from exploratory ones, limiting subgroup evaluations, and recognizing the need for external validation. Taken together, we believe these points adequately clarify the current constraints and how they were addressed.

 

We thank the reviewer for the constructive assessment and for acknowledging the revisions. We appreciate the reviewer’s careful evaluation of the revised manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

In their revised manuscript, the authors have addressed the reviewer comments in a comprehensive and constructive manner. The most significant improvement is the complete removal of prescriptive clinical recommendations, which have been replaced with appropriately descriptive language that frames the findings as observational and hypothesis-generating. The biological rationale linking HRG genotype to selenium status has been substantially strengthened through a more coherent hypothesis connecting HRG-mediated processes to oxidative stress and antioxidant defense. The authors have also improved the manuscript's scientific integrity by explicitly acknowledging the instability of estimates derived from small event numbers and by removing uninformative analyses with zero events. Technical errors in table numbering and formatting have been corrected. The only point where the authors' response was explanatory rather than corrective concerns multiple testing; they maintain that their hypothesis-driven, exploratory approach does not require correction for multiple comparisons, which is acceptable in this context given the explicitly stated exploratory nature of the analysis. Since the requested revisions primarily involved statistical re-interpretation, tempering of conclusions, and textual corrections rather than new data collection or experimental work, I recommend "Minor revision" to verify that all changes have been implemented consistently throughout the manuscript and that the language accurately reflects the exploratory nature of the findings.

Author Response

In their revised manuscript, the authors have addressed the reviewer comments in a comprehensive and constructive manner. The most significant improvement is the complete removal of prescriptive clinical recommendations, which have been replaced with appropriately descriptive language that frames the findings as observational and hypothesis-generating. The biological rationale linking HRG genotype to selenium status has been substantially strengthened through a more coherent hypothesis connecting HRG-mediated processes to oxidative stress and antioxidant defense. The authors have also improved the manuscript's scientific integrity by explicitly acknowledging the instability of estimates derived from small event numbers and by removing uninformative analyses with zero events. Technical errors in table numbering and formatting have been corrected. The only point where the authors' response was explanatory rather than corrective concerns multiple testing; they maintain that their hypothesis-driven, exploratory approach does not require correction for multiple comparisons, which is acceptable in this context given the explicitly stated exploratory nature of the analysis. Since the requested revisions primarily involved statistical re-interpretation, tempering of conclusions, and textual corrections rather than new data collection or experimental work, I recommend "Minor revision" to verify that all changes have been implemented consistently throughout the manuscript and that the language accurately reflects the exploratory nature of the findings.

We thank the reviewer for the positive and thoughtful evaluation of the revised manuscript. We appreciate the recognition of the improvements made, particularly regarding the interpretation of results, the strengthened biological rationale, and the clarification of analytical limitations.

In response to the recommendation for minor revision, we reviewed the manuscript to ensure that all changes have been implemented consistently throughout the text and that the language accurately reflects the exploratory and hypothesis-generating nature of the findings.