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Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 0 Date: 17 Oct 2024 Reviewer's report: I read with interest the descriptive study, "Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups" by Zhang et al. The research team performed ITS1 sequencing of pharyngeal swab samples from PH Groups 1, 3, and 4 along with a group with lung disease without PH. They also distinguished patients based on whether they had recent corticosteroid and/or antibiotic exposure. They identified a distinct mycobiome profile between control and PH patients (and controlled for corticosteroid/antibiotic exposure) and between Group 3 PH and lung disease patients. The novelty of the study is that the mycobiome in understudied in pulmonary hypertension and all disease states. I recommend completion of the following additional analyses and modifications to improve the impact of the study: 1. The authors should complete ROC analysis to determine whether the pharyngeal mycobiome can distinguish the PH Group types as the pathophysiology of each of these PH types is different (Group 1 vs 3, Group 1 vs 4, Group 3 vs 4). 2. Ideally, the authors should have integrated metagenomic/microbiome data with the mycobiome data as alterations in the microbiome would have changed the entire micro/ mycobiome. 3. Additional transparency regarding the characteristics of the PH patients by PH type should be included in the characteristics table such has the average hemodynamics (mPAP, PVR, CO/ CI) and all therapies that each of the PH groups were on (pulmonary vasodilators, inhaled treprostinil, cortisteroid/antibiotics, anticoagulation, etc.) - not just clustering all data within all of PH. 4. It is unclear to me why any Group 1 or 4 PH patients would have taken corticosteroids and/ or antibiotics (recent infection?). Including the reasons why each of the Group 1 and 4 patients are on corticosteroids/antibiotics in the supplement would be beneficial. 5. Please discuss in the discussion why Group 2 PH patients were not included in the study as it is a more prevalent PH type. 6. Why was the mPAP subgroup analysis/breakdown not based on typical cutoffs for mild (mPAP 20-34), moderate (mPAP 35-44), and severe (mPAP >/= 45 mmHg).	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 0 Date: 17 Oct 2024 Reviewer's report: I read with interest the descriptive study, "Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups" by Zhang et al. The research team performed ITS1 sequencing of pharyngeal swab samples from PH Groups 1, 3, and 4 along with a group with lung disease without PH. They also distinguished patients based on whether they had recent corticosteroid and/or antibiotic exposure. They identified a distinct mycobiome profile between control and PH patients (and controlled for corticosteroid/antibiotic exposure) and between Group 3 PH and lung disease patients. The novelty of the study is that the mycobiome in understudied in pulmonary hypertension and all disease states. I recommend completion of the following additional analyses and modifications to improve the impact of the study: 1. The authors should complete ROC analysis to determine whether the pharyngeal mycobiome can distinguish the PH Group types as the pathophysiology of each of these PH types is different (Group 1 vs 3, Group 1 vs 4, Group 3 vs 4). 2. Ideally, the authors should have integrated metagenomic/microbiome data with the mycobiome data as alterations in the microbiome would have changed the entire micro/ mycobiome. 3. Additional transparency regarding the characteristics of the PH patients by PH type should be included in the characteristics table such has the average hemodynamics (mPAP, PVR, CO/ CI) and all therapies that each of the PH groups were on (pulmonary vasodilators, inhaled treprostinil, cortisteroid/antibiotics, anticoagulation, etc.) - not just clustering all data within all of PH. 4. It is unclear to me why any Group 1 or 4 PH patients would have taken corticosteroids and/ or antibiotics (recent infection?). Including the reasons why each of the Group 1 and 4 patients are on corticosteroids/antibiotics in the supplement would be beneficial. 5. Please discuss in the discussion why Group 2 PH patients were not included in the study as it is a more prevalent PH type. 6. Why was the mPAP subgroup analysis/breakdown not based on typical cutoffs for mild (mPAP 20-34), moderate (mPAP 35-44), and severe (mPAP >/= 45 mmHg).	BMC	12916_2025_3982_ReviewerReport_V0_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 12, "praise": 0, "presentation_and_reporting": 2, "results_and_discussion": 1, "suggestion_and_solution": 6, "total": 19 }	{ "criticism": 0.05263157894736842, "example": 0, "importance_and_relevance": 0.05263157894736842, "materials_and_methods": 0.631578947368421, "praise": 0, "presentation_and_reporting": 0.10526315789473684, "results_and_discussion": 0.05263157894736842, "suggestion_and_solution": 0.3157894736842105 }	1.210526	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 0 Date: 17 Oct 2024\nReviewer's report:\nI read with interest the descriptive study, \"Distinct Airway Mycobiome Signature in Patients\nwith Pulmonary Hypertension and Subgroups\" by Zhang et al. The research team performed\nITS1 sequencing of pharyngeal swab samples from PH Groups 1, 3, and 4 along with a group\nwith lung disease without PH. They also distinguished patients based on whether they had\nrecent corticosteroid and/or antibiotic exposure. They identified a distinct mycobiome profile\nbetween control and PH patients (and controlled for corticosteroid/antibiotic exposure) and\nbetween Group 3 PH and lung disease patients. The novelty of the study is that the mycobiome\nin understudied in pulmonary hypertension and all disease states. I recommend completion of\nthe following additional analyses and modifications to improve the impact of the study:\n1. The authors should complete ROC analysis to determine whether the pharyngeal mycobiome\ncan distinguish the PH Group types as the pathophysiology of each of these PH types is different\n(Group 1 vs 3, Group 1 vs 4, Group 3 vs 4).\n2. Ideally, the authors should have integrated metagenomic/microbiome data with the\nmycobiome data as alterations in the microbiome would have changed the entire micro/\nmycobiome.\n3. Additional transparency regarding the characteristics of the PH patients by PH type should\nbe included in the characteristics table such has the average hemodynamics (mPAP, PVR, CO/\nCI) and all therapies that each of the PH groups were on (pulmonary vasodilators, inhaled\ntreprostinil, cortisteroid/antibiotics, anticoagulation, etc.) - not just clustering all data within all\nof PH.\n4. It is unclear to me why any Group 1 or 4 PH patients would have taken corticosteroids and/\nor antibiotics (recent infection?). Including the reasons why each of the Group 1 and 4 patients\nare on corticosteroids/antibiotics in the supplement would be beneficial.\n5. Please discuss in the discussion why Group 2 PH patients were not included in the study as\nit is a more prevalent PH type.\n6. Why was the mPAP subgroup analysis/breakdown not based on typical cutoffs for mild\n(mPAP 20-34), moderate (mPAP 35-44), and severe (mPAP >/= 45 mmHg).", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 0 Date: 15 Nov 2024 Reviewer's report: I am reviewing a manuscript titled "Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups" submitted for publication by Dr. Zhang and colleagues. Overall, the manuscript is well written and well described. The authors put in detailed work in their publication. There are some issues I would like to see addressed: 1. There is a lot of information that is not clearly connected in the manuscript. The message and hypothesis needs to be tightened up and made more cohesive. As it stands, the manuscript has interesting conclusions and observations, but perhaps tying it to more cause would actually help the manuscript give more cohesion. For example, describing or using two different classifications in the manuscript between clinical groups and WHO classifications is difficult to understand the choice of authors. I suggest that the authors choose one and then put the other groups in the supplementary figure. 2. The details surrounding antibiotic use should be better described e.g, what antibiotics were the participants exposed to. And the authors should consider explaining in detail how the mycobiome may be affected by antibiotics which should not directly affect this form of -oMics. 3. Finally, One important aspect is that pulmonary hypertension is a symptom of larger diagnoses, for example, COPD and cor pulmonale - could the authors do subanalyses associated with diagnoses instead of classes and WHO groups? I will be using the word document page numbers and leftmost line numbers. Abstract: Page 2, Line 61 "Dramatically opposite patterns of the two major fungal phyla, Ascomycota and Basidiomycota..." I suggest tempering down this statement, which borders on being an over- statement. Background: Page 5, Line 96 "Although PH is mainly a cardiopulmonary disease, recent study has proposed that it could be considered a systemic disease affecting multiple organs, such as the lungs, heart, central nervous system, bone marrow, and gut. " I think there's some issues here is pulmonary hypertension is not a disease in it of itself, it is rather a symptom or a syndrome associated with multiple other diseased. I would carefully re-write this sentences to reflect this. Page 7 Line 123 "Extended recruitment procedure and methods are provided in the online Supplementary Material." In regards to the recruitment, can the authors provide a consort diagram of people screened for recruitment. I would like to see the number of patients who were excluded. Moreover, if all patients/participants received a RHC, could the authors also discuss if the RHC was to make the diagnosis or/and if it includes a table of the results from the RHC. Supplemental Material Page 2, Line 28 "The PH group was further divided into the subgroups of non-use of antibiotics and/or corticosteroids (non-ANT/CORT) and use of ANT, CORT, or ANT+CORT within 1 mont" Can the authors explain why this was done? This is a good category to analyze, but I would consider the PH WHO categories more clinical relevant. Supplemental Material Page 2, Line 30 "The patients were diagnosed with chronic obstructive pulmonary disease, bronchiectasis, interstitial lung disease, and other relevant conditions. All of the patients experienced dyspnea, but their echocardiographic probability of PH was low. " I'm surprised that the pH probability was low - can the authors also include the these results in a table for review? Supplemental Material Page 2, Line 34 "The healthy-control (CON) group was free of respiratory diseases and other serious diseases and had no oral and respiratory infections within 1 month. " This wasn't clear, but did these patients/controls also receive RHC? Or was there just for samples? Supplemental Material: Can the authors include IRB protocol numbers and Patient assurances for each of their sites? While the authors include multiple hospitals, they do not include the IRB protocol approvals - please include these assurances. Supplemental Material, Page 2, Line 64 "The extracted fungal genome DNA from positively detected pharyngeal swab sample and pharyngeal swab blank control and buffer blank control were verified by agarose electrophoresis, as shown in Supplementary Figure S2b." Were any control samples were obtained? Supplemental Material, Page 7, Line 137 "Figure S2: Quality control for pharyngeal swab samples a: Bar graphs showing the averaged concentration of PCR amplified DNA products and assigned " For Figure S2, please include all points for Panels A, for Panel C please also include averages of control and PH - these are difficult to interpret. Page 8, Line 148 "The #-diversity was performed using mothur (version v. 1.30.2, https:// mothur.org/wiki/calculators/), with the evaluation index applied at a similarity level of 97% for OTUs (0.97). The #-diversity distance matrix is computed by Qiime (2020.2.0, http://qiime.org/ install/index.html)." I am wondering why the authors decided to use two different pipelines to calculate alpha and beta diversity. I would suggest using one, rather than another. Stastical anlaysis Page 7 to 9 I am wondering if this would be better moved into the supplementary and the discussion about patient recruitment moved to the paper methods. Results: Page 10, Line 177 "As shown in Figure 1a, #-diversity indicated no statistical difference in mycobiome richness (Sobs index and Ace index), while significantly lower diversity (indicated by decreased Shannon index and increased Simpson index) was observed in patients with PH than in CON. For #-diversity, both non-metric multidimensional scaling (NMDS) using the Bray-Curtis distance algorithm (Figure 1b) and Partial Least Squares Discriminant Analysis (PLS-DA) (Figure 1c)" The p-values should be expressed on each comparison, even if there are p=ns. The Beta-diversity comparisons in Panel B and Panel C are possibly significant. Page 10, Line 187 "At the genus level, Candida, Cutaneotrichosporon, Apiotrichum, and Sarocladium were the most abundant genera with the highest proportion in the PH group, while Candida, Fusarium, Cutaneotrichosporon, and Cladosporium in the CON group (Figure 1e). " Can the authors reconcile this with candida found in COVID19 and ILD. Page 12, Line 222 "As seen in Figure 2b, divergent fungal diversity was found by both #- diversity (Shannon index) and #-diversity (NMDS) analyses among three subgroups, with genera Holtermanniella, Trametes, Itersonilia, Psathyrella, and Geotrichum showing dramatic enrichment in IPAH but not in CHD-PAH or CTD-PAH." In Panels 2a, 2b, and 2c - needs p- values to be placed on the figure. Page 13, Line 259 "...PH subgroups based on the mPAP levels. Simultaneously, Candida increased dramatically in the PH-low and PH-medium groups (Figure 2d)." As it's presented, the role of candida is very interesting, have the authors considered the role of candida in other diseases and how it may relate to pulmonary hypertension? Page 14, Line 265 "ANT/CORT (Supplementary Figure S7b), and ANT (Supplementary Figure S7c), and CORT (Supplementary Figure S7d), and ANT+CORT groups (Supplementary Figure S7e), using Random Forest analysis." Can the authors also include the type of antibiotics that the patients were exposed to? Could you include this as a table? Page 14 Line 280 "he abundance of Ascomycota exhibited a gradual increase in non-ANT/ CORT, ANT, CORT, and ANT+CORT subgroups, whereas the abundance of Basidiomycota showed a gradual decline, and only ANT+CORT group and CON group had statistical difference (Figure 3d). " Is this due to relative abundance diagnosis, can the authors pull out read counts to see if this pattern is still true? Page 15, Line 289 ". LEfSe multilevel species difference discriminant analysis also indicated similar fungal genera between the CON and non-ANT/CORT (Figure 4a), or ANT (Figure 4b), or CORT (Figure 4c), or ANT+CORT (Figure 4d) groups. Moreover, the LEfSe multi- level species difference discriminant analysis also suggested similar and distinct genera between the non-ANT/CORT and ANT (Figure 4e), or CORT (Figure 4f), or ANT+CORT (Figure 4g) groups." Can the authors also use different orthogonal approaches such as DESEq2 or EdgeR to calculate other differential enrichment. Page 17, Line 337 "White blood cells and cardiac index were excluded, and the correlation between the remaining 30 clinical factors and different mycobiome taxa (phyla and genera) was analyzed" Could the authors explain why this was done? It is not clear that this is actually helpful or why these were excluded. Discussion: Page 20, Line 380 "Blockage of the metabolite, trimethylamine N-oxide, which is derived from the intestinal microbial flora and has been proven to be enriched in patients with PH..." This seems as though it's a non-sequitur - is there anything that ties the trimethylamine N-oxide to the mycobiome? I suggest this introduction is tied closer to the mycobiome. Page 21, Line 404 "Notably, through multiple comparisons, we identified stable and consistent mycobiome signatures in PH (and subgroups) compared to CON without being influenced by ANT, CORT, or both, characterized by specific enrichment of the fungal genera Purpureocillium, Issatchenkia, and Cyberlindnera and a decrease in the fungal genera Peroneutypa, Simplicillium, and Metarhizium in PH (and subgroups) compared to CON." I am not entirely sure that the authors performed multiple comparisons per se, I understand there are multiple comparisons, but the authors should consider also applying multiple comparisons to their analysis. LEFSE does not put in adjustment for multiple comparisons, but would be great if they could do this in EdgeR. Page 21, Line 411 "Moreover, a specific correlation pattern was observed between the airway mycobiome signature and clinical parameters of PH, strongly indicating a potential association between the altered airway mycobiome and disease progression of PH" I would recommend that while this is the hypothesis that the authors are testing, the presentiation of this is difficult to understand. I suggest that the authors consider significant re-organization of their work - for example - the redundancy of clinical groups and WHO groups does not help discern the message and hypothesis of the patients/particiapnts with PH. Especially, when clinicians tend to think about pulmonary hypertension as a syndrome or symptom of a larger issue - thus - I suggest to either discuss among authors which Ph groups you would like to use, but I think the use of both clinical groups and WHO groups confounds the conclusions. I suggest picking one and moving the other analysis to the supplementary. Page 21, Line 418 "Antibiotics modulate host microbiome rapidly and remarkably. 33,34 Ng et al. reported that antibiotics significantly reshape the gut microbiota composition, and postantibiotic recovery depends on multiple factors, including the host diet, community context, and environmental reservoirs. 35 Ward et al. showed that antibiotics can alter the #-diversity and #-diversity of lung mycobiome. 36 Corticosteroids are immunosuppressive agents that affect host microbiomes. In a meta-analysis of patients with COPD, asthma, and chronic rhinosinusitis, Hartmann et al. demonstrated that corticosteroids significantly affected the airway microbiome composition. 37 Our study showed similar results: the #-diversity, #-diversity, and mycobiome composition were remarkably reduced in the ANT, CORT, or ANT+CORT groups versus the non-ANT/CORT group. " I think that the authors should consider explaining how antibiotics which do not affect the mycobiome but the microbiome, how the use of antibiotics may be associated with mycobiome changes. There is a logical leap between the mycobiome and microbiome, the authors may consider bridging this gap during the discussion. Corticosteroids is much more understandable, but needs to be contextualized into the change associated with possible immune suppression. Page 23, Line 450 "A recent study reported that P. lilacinum might induce fetal fungal pneumonia in a green tree Python by excluding other potential pathogens." Not sure if this is actually helpful. Minor Page 18, Line 369 "animal pathogens,s " there is a typo here.	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 0 Date: 15 Nov 2024 Reviewer's report: I am reviewing a manuscript titled "Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups" submitted for publication by Dr. Zhang and colleagues. Overall, the manuscript is well written and well described. The authors put in detailed work in their publication. There are some issues I would like to see addressed: 1. There is a lot of information that is not clearly connected in the manuscript. The message and hypothesis needs to be tightened up and made more cohesive. As it stands, the manuscript has interesting conclusions and observations, but perhaps tying it to more cause would actually help the manuscript give more cohesion. For example, describing or using two different classifications in the manuscript between clinical groups and WHO classifications is difficult to understand the choice of authors. I suggest that the authors choose one and then put the other groups in the supplementary figure. 2. The details surrounding antibiotic use should be better described e.g, what antibiotics were the participants exposed to. And the authors should consider explaining in detail how the mycobiome may be affected by antibiotics which should not directly affect this form of -oMics. 3. Finally, One important aspect is that pulmonary hypertension is a symptom of larger diagnoses, for example, COPD and cor pulmonale - could the authors do subanalyses associated with diagnoses instead of classes and WHO groups? I will be using the word document page numbers and leftmost line numbers. Abstract: Page 2, Line 61 "Dramatically opposite patterns of the two major fungal phyla, Ascomycota and Basidiomycota..." I suggest tempering down this statement, which borders on being an over- statement. Background: Page 5, Line 96 "Although PH is mainly a cardiopulmonary disease, recent study has proposed that it could be considered a systemic disease affecting multiple organs, such as the lungs, heart, central nervous system, bone marrow, and gut. " I think there's some issues here is pulmonary hypertension is not a disease in it of itself, it is rather a symptom or a syndrome associated with multiple other diseased. I would carefully re-write this sentences to reflect this. Page 7 Line 123 "Extended recruitment procedure and methods are provided in the online Supplementary Material." In regards to the recruitment, can the authors provide a consort diagram of people screened for recruitment. I would like to see the number of patients who were excluded. Moreover, if all patients/participants received a RHC, could the authors also discuss if the RHC was to make the diagnosis or/and if it includes a table of the results from the RHC. Supplemental Material Page 2, Line 28 "The PH group was further divided into the subgroups of non-use of antibiotics and/or corticosteroids (non-ANT/CORT) and use of ANT, CORT, or ANT+CORT within 1 mont" Can the authors explain why this was done? This is a good category to analyze, but I would consider the PH WHO categories more clinical relevant. Supplemental Material Page 2, Line 30 "The patients were diagnosed with chronic obstructive pulmonary disease, bronchiectasis, interstitial lung disease, and other relevant conditions. All of the patients experienced dyspnea, but their echocardiographic probability of PH was low. " I'm surprised that the pH probability was low - can the authors also include the these results in a table for review? Supplemental Material Page 2, Line 34 "The healthy-control (CON) group was free of respiratory diseases and other serious diseases and had no oral and respiratory infections within 1 month. " This wasn't clear, but did these patients/controls also receive RHC? Or was there just for samples? Supplemental Material: Can the authors include IRB protocol numbers and Patient assurances for each of their sites? While the authors include multiple hospitals, they do not include the IRB protocol approvals - please include these assurances. Supplemental Material, Page 2, Line 64 "The extracted fungal genome DNA from positively detected pharyngeal swab sample and pharyngeal swab blank control and buffer blank control were verified by agarose electrophoresis, as shown in Supplementary Figure S2b." Were any control samples were obtained? Supplemental Material, Page 7, Line 137 "Figure S2: Quality control for pharyngeal swab samples a: Bar graphs showing the averaged concentration of PCR amplified DNA products and assigned " For Figure S2, please include all points for Panels A, for Panel C please also include averages of control and PH - these are difficult to interpret. Page 8, Line 148 "The #-diversity was performed using mothur (version v. 1.30.2, https:// mothur.org/wiki/calculators/), with the evaluation index applied at a similarity level of 97% for OTUs (0.97). The #-diversity distance matrix is computed by Qiime (2020.2.0, http://qiime.org/ install/index.html)." I am wondering why the authors decided to use two different pipelines to calculate alpha and beta diversity. I would suggest using one, rather than another. Stastical anlaysis Page 7 to 9 I am wondering if this would be better moved into the supplementary and the discussion about patient recruitment moved to the paper methods. Results: Page 10, Line 177 "As shown in Figure 1a, #-diversity indicated no statistical difference in mycobiome richness (Sobs index and Ace index), while significantly lower diversity (indicated by decreased Shannon index and increased Simpson index) was observed in patients with PH than in CON. For #-diversity, both non-metric multidimensional scaling (NMDS) using the Bray-Curtis distance algorithm (Figure 1b) and Partial Least Squares Discriminant Analysis (PLS-DA) (Figure 1c)" The p-values should be expressed on each comparison, even if there are p=ns. The Beta-diversity comparisons in Panel B and Panel C are possibly significant. Page 10, Line 187 "At the genus level, Candida, Cutaneotrichosporon, Apiotrichum, and Sarocladium were the most abundant genera with the highest proportion in the PH group, while Candida, Fusarium, Cutaneotrichosporon, and Cladosporium in the CON group (Figure 1e). " Can the authors reconcile this with candida found in COVID19 and ILD. Page 12, Line 222 "As seen in Figure 2b, divergent fungal diversity was found by both #- diversity (Shannon index) and #-diversity (NMDS) analyses among three subgroups, with genera Holtermanniella, Trametes, Itersonilia, Psathyrella, and Geotrichum showing dramatic enrichment in IPAH but not in CHD-PAH or CTD-PAH." In Panels 2a, 2b, and 2c - needs p- values to be placed on the figure. Page 13, Line 259 "...PH subgroups based on the mPAP levels. Simultaneously, Candida increased dramatically in the PH-low and PH-medium groups (Figure 2d)." As it's presented, the role of candida is very interesting, have the authors considered the role of candida in other diseases and how it may relate to pulmonary hypertension? Page 14, Line 265 "ANT/CORT (Supplementary Figure S7b), and ANT (Supplementary Figure S7c), and CORT (Supplementary Figure S7d), and ANT+CORT groups (Supplementary Figure S7e), using Random Forest analysis." Can the authors also include the type of antibiotics that the patients were exposed to? Could you include this as a table? Page 14 Line 280 "he abundance of Ascomycota exhibited a gradual increase in non-ANT/ CORT, ANT, CORT, and ANT+CORT subgroups, whereas the abundance of Basidiomycota showed a gradual decline, and only ANT+CORT group and CON group had statistical difference (Figure 3d). " Is this due to relative abundance diagnosis, can the authors pull out read counts to see if this pattern is still true? Page 15, Line 289 ". LEfSe multilevel species difference discriminant analysis also indicated similar fungal genera between the CON and non-ANT/CORT (Figure 4a), or ANT (Figure 4b), or CORT (Figure 4c), or ANT+CORT (Figure 4d) groups. Moreover, the LEfSe multi- level species difference discriminant analysis also suggested similar and distinct genera between the non-ANT/CORT and ANT (Figure 4e), or CORT (Figure 4f), or ANT+CORT (Figure 4g) groups." Can the authors also use different orthogonal approaches such as DESEq2 or EdgeR to calculate other differential enrichment. Page 17, Line 337 "White blood cells and cardiac index were excluded, and the correlation between the remaining 30 clinical factors and different mycobiome taxa (phyla and genera) was analyzed" Could the authors explain why this was done? It is not clear that this is actually helpful or why these were excluded. Discussion: Page 20, Line 380 "Blockage of the metabolite, trimethylamine N-oxide, which is derived from the intestinal microbial flora and has been proven to be enriched in patients with PH..." This seems as though it's a non-sequitur - is there anything that ties the trimethylamine N-oxide to the mycobiome? I suggest this introduction is tied closer to the mycobiome. Page 21, Line 404 "Notably, through multiple comparisons, we identified stable and consistent mycobiome signatures in PH (and subgroups) compared to CON without being influenced by ANT, CORT, or both, characterized by specific enrichment of the fungal genera Purpureocillium, Issatchenkia, and Cyberlindnera and a decrease in the fungal genera Peroneutypa, Simplicillium, and Metarhizium in PH (and subgroups) compared to CON." I am not entirely sure that the authors performed multiple comparisons per se, I understand there are multiple comparisons, but the authors should consider also applying multiple comparisons to their analysis. LEFSE does not put in adjustment for multiple comparisons, but would be great if they could do this in EdgeR. Page 21, Line 411 "Moreover, a specific correlation pattern was observed between the airway mycobiome signature and clinical parameters of PH, strongly indicating a potential association between the altered airway mycobiome and disease progression of PH" I would recommend that while this is the hypothesis that the authors are testing, the presentiation of this is difficult to understand. I suggest that the authors consider significant re-organization of their work - for example - the redundancy of clinical groups and WHO groups does not help discern the message and hypothesis of the patients/particiapnts with PH. Especially, when clinicians tend to think about pulmonary hypertension as a syndrome or symptom of a larger issue - thus - I suggest to either discuss among authors which Ph groups you would like to use, but I think the use of both clinical groups and WHO groups confounds the conclusions. I suggest picking one and moving the other analysis to the supplementary. Page 21, Line 418 "Antibiotics modulate host microbiome rapidly and remarkably. 33,34 Ng et al. reported that antibiotics significantly reshape the gut microbiota composition, and postantibiotic recovery depends on multiple factors, including the host diet, community context, and environmental reservoirs. 35 Ward et al. showed that antibiotics can alter the #-diversity and #-diversity of lung mycobiome. 36 Corticosteroids are immunosuppressive agents that affect host microbiomes. In a meta-analysis of patients with COPD, asthma, and chronic rhinosinusitis, Hartmann et al. demonstrated that corticosteroids significantly affected the airway microbiome composition. 37 Our study showed similar results: the #-diversity, #-diversity, and mycobiome composition were remarkably reduced in the ANT, CORT, or ANT+CORT groups versus the non-ANT/CORT group. " I think that the authors should consider explaining how antibiotics which do not affect the mycobiome but the microbiome, how the use of antibiotics may be associated with mycobiome changes. There is a logical leap between the mycobiome and microbiome, the authors may consider bridging this gap during the discussion. Corticosteroids is much more understandable, but needs to be contextualized into the change associated with possible immune suppression. Page 23, Line 450 "A recent study reported that P. lilacinum might induce fetal fungal pneumonia in a green tree Python by excluding other potential pathogens." Not sure if this is actually helpful. Minor Page 18, Line 369 "animal pathogens,s " there is a typo here.	BMC	12916_2025_3982_ReviewerReport_V0_R3.pdf	{ "criticism": 9, "example": 30, "importance_and_relevance": 2, "materials_and_methods": 47, "praise": 5, "presentation_and_reporting": 19, "results_and_discussion": 11, "suggestion_and_solution": 29, "total": 86 }	{ "criticism": 0.10465116279069768, "example": 0.3488372093023256, "importance_and_relevance": 0.023255813953488372, "materials_and_methods": 0.5465116279069767, "praise": 0.05813953488372093, "presentation_and_reporting": 0.22093023255813954, "results_and_discussion": 0.12790697674418605, "suggestion_and_solution": 0.3372093023255814 }	1.767442	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 0 Date: 15 Nov 2024\nReviewer's report:\nI am reviewing a manuscript titled \"Distinct Airway Mycobiome Signature in Patients\nwith Pulmonary Hypertension and Subgroups\" submitted for publication by Dr. Zhang and\ncolleagues. Overall, the manuscript is well written and well described. The authors put in detailed\nwork in their publication. There are some issues I would like to see addressed:\n1. There is a lot of information that is not clearly connected in the manuscript. The message\nand hypothesis needs to be tightened up and made more cohesive. As it stands, the manuscript\nhas interesting conclusions and observations, but perhaps tying it to more cause would actually\nhelp the manuscript give more cohesion. For example, describing or using two different\nclassifications in the manuscript between clinical groups and WHO classifications is difficult to\nunderstand the choice of authors. I suggest that the authors choose one and then put the other\ngroups in the supplementary figure.\n2. The details surrounding antibiotic use should be better described e.g, what antibiotics were\nthe participants exposed to. And the authors should consider explaining in detail how the\nmycobiome may be affected by antibiotics which should not directly affect this form of -oMics.\n3. Finally, One important aspect is that pulmonary hypertension is a symptom of larger\ndiagnoses, for example, COPD and cor pulmonale - could the authors do subanalyses associated\nwith diagnoses instead of classes and WHO groups?\nI will be using the word document page numbers and leftmost line numbers.\nAbstract:\nPage 2, Line 61 \"Dramatically opposite patterns of the two major fungal phyla, Ascomycota and\nBasidiomycota...\" I suggest tempering down this statement, which borders on being an over-\nstatement.\nBackground:\nPage 5, Line 96 \"Although PH is mainly a cardiopulmonary disease, recent study has proposed\nthat it could be considered a systemic disease affecting multiple organs, such as the lungs, heart,\ncentral nervous system, bone marrow, and gut. \" I think there's some issues here is pulmonary\nhypertension is not a disease in it of itself, it is rather a symptom or a syndrome associated with\nmultiple other diseased. I would carefully re-write this sentences to reflect this.\nPage 7 Line 123 \"Extended recruitment procedure and methods are provided in the online\nSupplementary Material.\" In regards to the recruitment, can the authors provide a consort\ndiagram of people screened for recruitment. I would like to see the number of patients who were\nexcluded. Moreover, if all patients/participants received a RHC, could the authors also discuss\nif the RHC was to make the diagnosis or/and if it includes a table of the results from the RHC.\nSupplemental Material Page 2, Line 28 \"The PH group was further divided into the subgroups\nof non-use of antibiotics and/or corticosteroids (non-ANT/CORT) and use of ANT, CORT, or\nANT+CORT within 1 mont\" Can the authors explain why this was done? This is a good category\nto analyze, but I would consider the PH WHO categories more clinical relevant.\nSupplemental Material Page 2, Line 30 \"The patients were diagnosed with chronic obstructive\npulmonary disease, bronchiectasis, interstitial lung disease, and other relevant conditions. All\nof the patients experienced dyspnea, but their echocardiographic probability of PH was low. \"\nI'm surprised that the pH probability was low - can the authors also include the these results in\na table for review?\nSupplemental Material Page 2, Line 34 \"The healthy-control (CON) group was free of\nrespiratory diseases and other serious diseases and had no oral and respiratory infections within\n1 month. \" This wasn't clear, but did these patients/controls also receive RHC? Or was there\njust for samples?\nSupplemental Material: Can the authors include IRB protocol numbers and Patient assurances\nfor each of their sites? While the authors include multiple hospitals, they do not include the IRB\nprotocol approvals - please include these assurances.\nSupplemental Material, Page 2, Line 64 \"The extracted fungal genome DNA from positively\ndetected pharyngeal swab sample and pharyngeal swab blank control and buffer blank control\nwere verified by agarose electrophoresis, as shown in Supplementary Figure S2b.\" Were any\ncontrol samples were obtained?\nSupplemental Material, Page 7, Line 137 \"Figure S2: Quality control for pharyngeal swab\nsamples\na: Bar graphs showing the averaged concentration of PCR amplified DNA products and assigned\n\" For Figure S2, please include all points for Panels A, for Panel C please also include averages\nof control and PH - these are difficult to interpret.\nPage 8, Line 148 \"The #-diversity was performed using mothur (version v. 1.30.2, https://\nmothur.org/wiki/calculators/), with the evaluation index applied at a similarity level of 97% for\nOTUs (0.97). The #-diversity distance matrix is computed by Qiime (2020.2.0, http://qiime.org/\ninstall/index.html).\" I am wondering why the authors decided to use two different pipelines to\ncalculate alpha and beta diversity. I would suggest using one, rather than another.\nStastical anlaysis Page 7 to 9 I am wondering if this would be better moved into the\nsupplementary and the discussion about patient recruitment moved to the paper methods.\nResults:\nPage 10, Line 177 \"As shown in Figure 1a, #-diversity indicated no statistical difference in\nmycobiome richness (Sobs index and Ace index), while significantly lower diversity (indicated\nby decreased Shannon index and increased Simpson index) was observed in patients with PH\nthan in CON. For #-diversity, both non-metric multidimensional scaling (NMDS) using the\nBray-Curtis distance algorithm (Figure 1b) and Partial Least Squares Discriminant Analysis\n(PLS-DA) (Figure 1c)\" The p-values should be expressed on each comparison, even if there are\np=ns. The Beta-diversity comparisons in Panel B and Panel C are possibly significant.\nPage 10, Line 187 \"At the genus level, Candida, Cutaneotrichosporon, Apiotrichum, and\nSarocladium were the most abundant genera with the highest proportion in the PH group, while\nCandida, Fusarium, Cutaneotrichosporon, and Cladosporium in the CON group (Figure 1e). \"\nCan the authors reconcile this with candida found in COVID19 and ILD.\nPage 12, Line 222 \"As seen in Figure 2b, divergent fungal diversity was found by both #-\ndiversity (Shannon index) and #-diversity (NMDS) analyses among three subgroups, with\ngenera Holtermanniella, Trametes, Itersonilia, Psathyrella, and Geotrichum showing dramatic\nenrichment in IPAH but not in CHD-PAH or CTD-PAH.\" In Panels 2a, 2b, and 2c - needs p-\nvalues to be placed on the figure.\nPage 13, Line 259 \"...PH subgroups based on the mPAP levels. Simultaneously, Candida\nincreased dramatically in the PH-low and PH-medium groups (Figure 2d).\" As it's presented,\nthe role of candida is very interesting, have the authors considered the role of candida in other\ndiseases and how it may relate to pulmonary hypertension?\nPage 14, Line 265 \"ANT/CORT (Supplementary Figure S7b), and ANT (Supplementary Figure\nS7c), and CORT (Supplementary Figure S7d), and ANT+CORT groups (Supplementary Figure\nS7e), using Random Forest analysis.\" Can the authors also include the type of antibiotics that\nthe patients were exposed to? Could you include this as a table?\nPage 14 Line 280 \"he abundance of Ascomycota exhibited a gradual increase in non-ANT/\nCORT, ANT, CORT, and ANT+CORT subgroups, whereas the abundance of Basidiomycota\nshowed a gradual decline, and only ANT+CORT group and CON group had statistical difference\n(Figure 3d). \" Is this due to relative abundance diagnosis, can the authors pull out read counts\nto see if this pattern is still true?\nPage 15, Line 289 \". LEfSe multilevel species difference discriminant analysis also indicated\nsimilar fungal genera between the CON and non-ANT/CORT (Figure 4a), or ANT (Figure\n4b), or CORT (Figure 4c), or ANT+CORT (Figure 4d) groups. Moreover, the LEfSe multi-\nlevel species difference discriminant analysis also suggested similar and distinct genera between\nthe non-ANT/CORT and ANT (Figure 4e), or CORT (Figure 4f), or ANT+CORT (Figure 4g)\ngroups.\" Can the authors also use different orthogonal approaches such as DESEq2 or EdgeR\nto calculate other differential enrichment.\nPage 17, Line 337 \"White blood cells and cardiac index were excluded, and the correlation\nbetween the remaining 30 clinical factors and different mycobiome taxa (phyla and genera) was\nanalyzed\" Could the authors explain why this was done? It is not clear that this is actually helpful\nor why these were excluded.\nDiscussion:\nPage 20, Line 380 \"Blockage of the metabolite, trimethylamine N-oxide, which is derived from\nthe intestinal microbial flora and has been proven to be enriched in patients with PH...\" This\nseems as though it's a non-sequitur - is there anything that ties the trimethylamine N-oxide to\nthe mycobiome? I suggest this introduction is tied closer to the mycobiome.\nPage 21, Line 404 \"Notably, through multiple comparisons, we identified stable and\nconsistent mycobiome signatures in PH (and subgroups) compared to CON without being\ninfluenced by ANT, CORT, or both, characterized by specific enrichment of the fungal\ngenera Purpureocillium, Issatchenkia, and Cyberlindnera and a decrease in the fungal genera\nPeroneutypa, Simplicillium, and Metarhizium in PH (and subgroups) compared to CON.\" I am\nnot entirely sure that the authors performed multiple comparisons per se, I understand there are\nmultiple comparisons, but the authors should consider also applying multiple comparisons to\ntheir analysis. LEFSE does not put in adjustment for multiple comparisons, but would be great\nif they could do this in EdgeR.\nPage 21, Line 411 \"Moreover, a specific correlation pattern was observed between the airway\nmycobiome signature and clinical parameters of PH, strongly indicating a potential association\nbetween the altered airway mycobiome and disease progression of PH\" I would recommend that\nwhile this is the hypothesis that the authors are testing, the presentiation of this is difficult to\nunderstand. I suggest that the authors consider significant re-organization of their work - for\nexample - the redundancy of clinical groups and WHO groups does not help discern the message\nand hypothesis of the patients/particiapnts with PH. Especially, when clinicians tend to think\nabout pulmonary hypertension as a syndrome or symptom of a larger issue - thus - I suggest to\neither discuss among authors which Ph groups you would like to use, but I think the use of both\nclinical groups and WHO groups confounds the conclusions. I suggest picking one and moving\nthe other analysis to the supplementary.\nPage 21, Line 418 \"Antibiotics modulate host microbiome rapidly and remarkably. 33,34\nNg et al. reported that antibiotics significantly reshape the gut microbiota composition, and\npostantibiotic recovery depends on multiple factors, including the host diet, community context,\nand environmental reservoirs. 35 Ward et al. showed that antibiotics can alter the #-diversity and\n#-diversity of lung mycobiome. 36 Corticosteroids are immunosuppressive agents that affect\nhost microbiomes. In a meta-analysis of patients with COPD, asthma, and chronic rhinosinusitis,\nHartmann et al. demonstrated that corticosteroids significantly affected the airway microbiome\ncomposition. 37 Our study showed similar results: the #-diversity, #-diversity, and mycobiome\ncomposition were remarkably reduced in the ANT, CORT, or ANT+CORT groups versus the\nnon-ANT/CORT group. \" I think that the authors should consider explaining how antibiotics\nwhich do not affect the mycobiome but the microbiome, how the use of antibiotics may be\nassociated with mycobiome changes. There is a logical leap between the mycobiome and\nmicrobiome, the authors may consider bridging this gap during the discussion. Corticosteroids\nis much more understandable, but needs to be contextualized into the change associated with\npossible immune suppression.\nPage 23, Line 450 \"A recent study reported that P. lilacinum might induce fetal fungal\npneumonia in a green tree Python by excluding other potential pathogens.\" Not sure if this is\nactually helpful.\nMinor\nPage 18, Line 369 \"animal pathogens,s \" there is a typo here.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 1 Date: 17 Jan 2025 Reviewer's report: On review, the authors have addressed my major concerns and criticism. There are couple of small corrections to the discussion I would recommend: Page 21, Line 403 "don’t directly " please avoid conjunctions change to "do not ..." Page 22, Line 435 "Antibiotics modulate ..." I am not sure if "modulation" is the correct way we would use or describe the actions of antibiotics. I recommend a better word choice here. Page 24, Line 469 "Purpureocillium (specifically, P. lilacinum) causes several human diseases." This is an overstatement and needs to either include the human diseases or include citations. Page 25, Line 507 "Salivarius" should be not capitalized "salivarius." Page 25, Line 508 "strongly indicating a causal link between lung/airway bacteria and disease progression of PH." I think this is a slight overstatement and needs to be softened a bit. There is not necessarily a causal link as it may be inflammation from the xposure driving PH? The authors should consider slightly reducing the causal aspect of this sentence and say the association with microbiota exposure may correlate with PH progression.	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 1 Date: 17 Jan 2025 Reviewer's report: On review, the authors have addressed my major concerns and criticism. There are couple of small corrections to the discussion I would recommend: Page 21, Line 403 "don’t directly " please avoid conjunctions change to "do not ..." Page 22, Line 435 "Antibiotics modulate ..." I am not sure if "modulation" is the correct way we would use or describe the actions of antibiotics. I recommend a better word choice here. Page 24, Line 469 "Purpureocillium (specifically, P. lilacinum) causes several human diseases." This is an overstatement and needs to either include the human diseases or include citations. Page 25, Line 507 "Salivarius" should be not capitalized "salivarius." Page 25, Line 508 "strongly indicating a causal link between lung/airway bacteria and disease progression of PH." I think this is a slight overstatement and needs to be softened a bit. There is not necessarily a causal link as it may be inflammation from the xposure driving PH? The authors should consider slightly reducing the causal aspect of this sentence and say the association with microbiota exposure may correlate with PH progression.	BMC	12916_2025_3982_ReviewerReport_V1_R3.pdf	{ "criticism": 3, "example": 5, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 1, "presentation_and_reporting": 6, "results_and_discussion": 2, "suggestion_and_solution": 6, "total": 10 }	{ "criticism": 0.3, "example": 0.5, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0.1, "presentation_and_reporting": 0.6, "results_and_discussion": 0.2, "suggestion_and_solution": 0.6 }	2.3	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 1 Date: 17 Jan 2025\nReviewer's report:\nOn review, the authors have addressed my major concerns and criticism. There are couple of\nsmall corrections to the discussion I would recommend:\nPage 21, Line 403 \"don’t directly \" please avoid conjunctions change to \"do not ...\"\nPage 22, Line 435 \"Antibiotics modulate ...\" I am not sure if \"modulation\" is the correct way\nwe would use or describe the actions of antibiotics. I recommend a better word choice here.\nPage 24, Line 469 \"Purpureocillium (specifically, P. lilacinum) causes several human diseases.\"\nThis is an overstatement and needs to either include the human diseases or include citations.\nPage 25, Line 507 \"Salivarius\" should be not capitalized \"salivarius.\"\nPage 25, Line 508 \"strongly indicating a causal link between lung/airway bacteria and disease\nprogression of PH.\" I think this is a slight overstatement and needs to be softened a bit. There is\nnot necessarily a causal link as it may be inflammation from the xposure driving PH? The authors\nshould consider slightly reducing the causal aspect of this sentence and say the association with\nmicrobiota exposure may correlate with PH progression.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 1 Date: 29 Jan 2025 Reviewer's report: I am pleased to review the revised manuscript “Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension Subgroups.” As I have mentioned previously, investigating the mycobiome is novel in pulmonary hypertension. The authors have made some improvements to enhance the presentation of the data since the initial submission May I please get further clarification on the following: 1. During my initial review, I requested for analyses to be performed to determine whether the pharyngeal mycobiome can distinguish PH Group types (e.g. WHO Group 1 vs 3, Group 1 vs 4, Group 3 vs 4). Although the analyses were shown in the response letter, I believe that they should also be shown in the manuscript (in the supplement) for transparency to the readers. Both ROC curves and random forest analyses should be included because the potential advantage of evaluating the mycobiome is not just that there is a difference between control vs PH (which could be due to medication effects) but that the mycobiome may be distinct between these PH groups. 2. Were there any differences in diversity indices (Shannon, Bray-Curtis) when distinguishing by PVR instead of mPAP (the low, medium, and high group)? It appears from Figure 6, which looks at the correlation between phylum level (Ascomycota and Basidiomycota) and clinical factors of PH, PVR has strong correlations. Minor comments: 1. In figure 1G, no p-value was shown for Basidiomycota plot. 2. Figure legend for Figure 2 is incorrect. What is described for (B) in the legend is (C). 3. The figure 4 legend is incorrect here: “e-f: LEfSe analysis showing the most discriminant fungal genera between non-ANT/CORT and ANT (a), CORT (b) or ANT+CORT (c), respectively. Only taxa with LDA scores > 3 was presented.” 4. Table S2 should have row for PVR. 5. For Figure S4, S5, and S6, please include p values for the boxplots. Additionally, as the graphs are so similar, please change nomenclature of the graphs so it is clear whether it is with ANT/ CORT just by looking at the figure without referencing the figure legend.	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 1 Date: 29 Jan 2025 Reviewer's report: I am pleased to review the revised manuscript “Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension Subgroups.” As I have mentioned previously, investigating the mycobiome is novel in pulmonary hypertension. The authors have made some improvements to enhance the presentation of the data since the initial submission May I please get further clarification on the following: 1. During my initial review, I requested for analyses to be performed to determine whether the pharyngeal mycobiome can distinguish PH Group types (e.g. WHO Group 1 vs 3, Group 1 vs 4, Group 3 vs 4). Although the analyses were shown in the response letter, I believe that they should also be shown in the manuscript (in the supplement) for transparency to the readers. Both ROC curves and random forest analyses should be included because the potential advantage of evaluating the mycobiome is not just that there is a difference between control vs PH (which could be due to medication effects) but that the mycobiome may be distinct between these PH groups. 2. Were there any differences in diversity indices (Shannon, Bray-Curtis) when distinguishing by PVR instead of mPAP (the low, medium, and high group)? It appears from Figure 6, which looks at the correlation between phylum level (Ascomycota and Basidiomycota) and clinical factors of PH, PVR has strong correlations. Minor comments: 1. In figure 1G, no p-value was shown for Basidiomycota plot. 2. Figure legend for Figure 2 is incorrect. What is described for (B) in the legend is (C). 3. The figure 4 legend is incorrect here: “e-f: LEfSe analysis showing the most discriminant fungal genera between non-ANT/CORT and ANT (a), CORT (b) or ANT+CORT (c), respectively. Only taxa with LDA scores > 3 was presented.” 4. Table S2 should have row for PVR. 5. For Figure S4, S5, and S6, please include p values for the boxplots. Additionally, as the graphs are so similar, please change nomenclature of the graphs so it is clear whether it is with ANT/ CORT just by looking at the figure without referencing the figure legend.	BMC	12916_2025_3982_ReviewerReport_V1_R1.pdf	{ "criticism": 2, "example": 4, "importance_and_relevance": 0, "materials_and_methods": 8, "praise": 2, "presentation_and_reporting": 9, "results_and_discussion": 1, "suggestion_and_solution": 7, "total": 21 }	{ "criticism": 0.09523809523809523, "example": 0.19047619047619047, "importance_and_relevance": 0, "materials_and_methods": 0.38095238095238093, "praise": 0.09523809523809523, "presentation_and_reporting": 0.42857142857142855, "results_and_discussion": 0.047619047619047616, "suggestion_and_solution": 0.3333333333333333 }	1.571429	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 1 Date: 29 Jan 2025\nReviewer's report:\nI am pleased to review the revised manuscript “Distinct Airway Mycobiome Signature\nin Patients with Pulmonary Hypertension Subgroups.” As I have mentioned previously,\ninvestigating the mycobiome is novel in pulmonary hypertension. The authors have made some\nimprovements to enhance the presentation of the data since the initial submission\nMay I please get further clarification on the following:\n1. During my initial review, I requested for analyses to be performed to determine whether the\npharyngeal mycobiome can distinguish PH Group types (e.g. WHO Group 1 vs 3, Group 1 vs\n4, Group 3 vs 4). Although the analyses were shown in the response letter, I believe that they\nshould also be shown in the manuscript (in the supplement) for transparency to the readers. Both\nROC curves and random forest analyses should be included because the potential advantage of\nevaluating the mycobiome is not just that there is a difference between control vs PH (which\ncould be due to medication effects) but that the mycobiome may be distinct between these PH\ngroups.\n2. Were there any differences in diversity indices (Shannon, Bray-Curtis) when distinguishing\nby PVR instead of mPAP (the low, medium, and high group)? It appears from Figure 6, which\nlooks at the correlation between phylum level (Ascomycota and Basidiomycota) and clinical\nfactors of PH, PVR has strong correlations.\nMinor comments:\n1. In figure 1G, no p-value was shown for Basidiomycota plot.\n2. Figure legend for Figure 2 is incorrect. What is described for (B) in the legend is (C).\n3. The figure 4 legend is incorrect here: “e-f: LEfSe analysis showing the most discriminant\nfungal genera between non-ANT/CORT and ANT (a), CORT (b) or ANT+CORT (c),\nrespectively. Only taxa with LDA scores > 3 was presented.”\n4. Table S2 should have row for PVR.\n5. For Figure S4, S5, and S6, please include p values for the boxplots. Additionally, as the graphs\nare so similar, please change nomenclature of the graphs so it is clear whether it is with ANT/\nCORT just by looking at the figure without referencing the figure legend.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 2 Date: 07 Feb 2025 Reviewer's report: On re-review, the authors have addressed my major concerns and criticism. The issues with association/causation has been addressed . I appreciate the authors attention to detail and work.	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 2 Date: 07 Feb 2025 Reviewer's report: On re-review, the authors have addressed my major concerns and criticism. The issues with association/causation has been addressed . I appreciate the authors attention to detail and work.	BMC	12916_2025_3982_ReviewerReport_V2_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 3 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0.6666666666666666, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 2 Date: 07 Feb 2025\nReviewer's report:\nOn re-review, the authors have addressed my major concerns and criticism. The issues with\nassociation/causation has been addressed . I appreciate the authors attention to detail and work.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03982-7	Reviewed - bmc_medicine	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 2 Date: 10 Feb 2025 Reviewer's report: The authors have addressed my comments.	Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and Subgroups Version: 2 Date: 10 Feb 2025 Reviewer's report: The authors have addressed my comments.	BMC	12916_2025_3982_ReviewerReport_V2_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	0	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Distinct Airway Mycobiome Signature in Patients with Pulmonary Hypertension and\nSubgroups\nVersion: 2 Date: 10 Feb 2025\nReviewer's report:\nThe authors have addressed my comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03976-5	Reviewed - bmc_medicine	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 0 Date: 08 Sep 2024 Reviewer's report: In their manuscript, Sun and colleagues estimate the fraction of stroke (overall, ischemic, hemorrhagic, and subarachnoid hemorrhagic attributable to six reproductive factors (age at menarche, age at menopause, high parity, history of stillbirth, history of miscarriage, history of termination, history of lactation). Data on reproductive factors and covariates were collected from postmenopausal women in China via baseline survey and stroke was ascertained from hospital, disease registry, and insurance claims. Additionally, they conducted analyses stratified by socioeconomic status. They report generally modest population attributable fractions for reproductive factors in the overall population (the highest proportion being 8.1% of all strokes attributed to high parity, ~14% attributable to all factors combined). However, PAFs for investigated factors tended to be much higher among low-SES women compared to high-SES women. These results are generally in line with prior studies that have found higher risk of cardiovascular and cerebrovascular disease among women with early age at menarche, early age at menopause, high parity, and history of adverse pregnancy outcomes. The study benefits from a large sample, and the calculation of PAFs is an interesting one. It is typically interpreted as the fraction of cases of the outcome in a population that could be eliminated if a risk factor could be eliminated. For the risk factors in question in this study, it is unclear the extent to which they may be causal versus markers for other causal factors for stroke, such as cardiometabolic disease. Also, some of these factors are not readily modifiable, and, for those that are, such decisions may not be likely to be made with future stroke risk in mind. However, I feel that it can still be used to identify women at elevated risk of stroke based on reproductive history, as the authors discuss. The results could also, e.g., be used to help highlight risks and challenges faced by low-SES women in their childbearing years. Specific comments are listed below: • Lines 65-67: To what extent do the authors believe these factors are markers for other risk factors versus causal factors in stroke? • Lines 117-19: Dichotomizing early age at menarche at #15 versus >15 seems to be a little high to me. In US studies, early menarche may be defined as <10 or <12 years. Might the association be diluted by using this cutoff? Further, late age at menarche may also be associated with chronic disease. Was this explored at all? Factors such as history of stillbirth, miscarriage, termination, or lactation would more appropriately be restricted to parous women to avoid mixing of the potential impact of infertility and its associated causes and the reproductive risk factor in question. Was this done? • Lines 185-189: Were the population prevalence estimates derived from the survey data or other sources? If from the data, was the uncertainty in these estimates included in the calculation of the confidence intervals for the PAFs? Admittedly, this may not add much given the sample size. • Line 193: it is unclear whether the estimates of the combined PAFs assumed that each of the reproductive factors had an independent association with stroke • Overall Results: differences in PAFs among low and high SES women was striking. However, some estimate of the baseline stroke risk amongst women in these two groups would really help to further emphasize this contrast • Overall Discussion: I felt that a bit more discussion of whether or not the factors investigated were causal or markers for other risk factors, and the potential impact on the interpretation of results would strengthen this section. In addition, how might potential changes in employment over time impact the generalizability of the results?	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 0 Date: 08 Sep 2024 Reviewer's report: In their manuscript, Sun and colleagues estimate the fraction of stroke (overall, ischemic, hemorrhagic, and subarachnoid hemorrhagic attributable to six reproductive factors (age at menarche, age at menopause, high parity, history of stillbirth, history of miscarriage, history of termination, history of lactation). Data on reproductive factors and covariates were collected from postmenopausal women in China via baseline survey and stroke was ascertained from hospital, disease registry, and insurance claims. Additionally, they conducted analyses stratified by socioeconomic status. They report generally modest population attributable fractions for reproductive factors in the overall population (the highest proportion being 8.1% of all strokes attributed to high parity, ~14% attributable to all factors combined). However, PAFs for investigated factors tended to be much higher among low-SES women compared to high-SES women. These results are generally in line with prior studies that have found higher risk of cardiovascular and cerebrovascular disease among women with early age at menarche, early age at menopause, high parity, and history of adverse pregnancy outcomes. The study benefits from a large sample, and the calculation of PAFs is an interesting one. It is typically interpreted as the fraction of cases of the outcome in a population that could be eliminated if a risk factor could be eliminated. For the risk factors in question in this study, it is unclear the extent to which they may be causal versus markers for other causal factors for stroke, such as cardiometabolic disease. Also, some of these factors are not readily modifiable, and, for those that are, such decisions may not be likely to be made with future stroke risk in mind. However, I feel that it can still be used to identify women at elevated risk of stroke based on reproductive history, as the authors discuss. The results could also, e.g., be used to help highlight risks and challenges faced by low-SES women in their childbearing years. Specific comments are listed below: • Lines 65-67: To what extent do the authors believe these factors are markers for other risk factors versus causal factors in stroke? • Lines 117-19: Dichotomizing early age at menarche at #15 versus >15 seems to be a little high to me. In US studies, early menarche may be defined as <10 or <12 years. Might the association be diluted by using this cutoff? Further, late age at menarche may also be associated with chronic disease. Was this explored at all? Factors such as history of stillbirth, miscarriage, termination, or lactation would more appropriately be restricted to parous women to avoid mixing of the potential impact of infertility and its associated causes and the reproductive risk factor in question. Was this done? • Lines 185-189: Were the population prevalence estimates derived from the survey data or other sources? If from the data, was the uncertainty in these estimates included in the calculation of the confidence intervals for the PAFs? Admittedly, this may not add much given the sample size. • Line 193: it is unclear whether the estimates of the combined PAFs assumed that each of the reproductive factors had an independent association with stroke • Overall Results: differences in PAFs among low and high SES women was striking. However, some estimate of the baseline stroke risk amongst women in these two groups would really help to further emphasize this contrast • Overall Discussion: I felt that a bit more discussion of whether or not the factors investigated were causal or markers for other risk factors, and the potential impact on the interpretation of results would strengthen this section. In addition, how might potential changes in employment over time impact the generalizability of the results?	BMC	12916_2025_3976_ReviewerReport_V0_R2.pdf	{ "criticism": 3, "example": 4, "importance_and_relevance": 1, "materials_and_methods": 14, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 8, "suggestion_and_solution": 4, "total": 26 }	{ "criticism": 0.11538461538461539, "example": 0.15384615384615385, "importance_and_relevance": 0.038461538461538464, "materials_and_methods": 0.5384615384615384, "praise": 0.038461538461538464, "presentation_and_reporting": 0, "results_and_discussion": 0.3076923076923077, "suggestion_and_solution": 0.15384615384615385 }	1.346154	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles\namong postmenopausal women in China\nVersion: 0 Date: 08 Sep 2024\nReviewer's report:\nIn their manuscript, Sun and colleagues estimate the fraction of stroke (overall, ischemic,\nhemorrhagic, and subarachnoid hemorrhagic attributable to six reproductive factors (age at\nmenarche, age at menopause, high parity, history of stillbirth, history of miscarriage, history\nof termination, history of lactation). Data on reproductive factors and covariates were collected\nfrom postmenopausal women in China via baseline survey and stroke was ascertained from\nhospital, disease registry, and insurance claims. Additionally, they conducted analyses stratified\nby socioeconomic status. They report generally modest population attributable fractions for\nreproductive factors in the overall population (the highest proportion being 8.1% of all strokes\nattributed to high parity, ~14% attributable to all factors combined). However, PAFs for\ninvestigated factors tended to be much higher among low-SES women compared to high-SES\nwomen.\nThese results are generally in line with prior studies that have found higher risk of cardiovascular\nand cerebrovascular disease among women with early age at menarche, early age at menopause,\nhigh parity, and history of adverse pregnancy outcomes. The study benefits from a large sample,\nand the calculation of PAFs is an interesting one. It is typically interpreted as the fraction of\ncases of the outcome in a population that could be eliminated if a risk factor could be eliminated.\nFor the risk factors in question in this study, it is unclear the extent to which they may be causal\nversus markers for other causal factors for stroke, such as cardiometabolic disease. Also, some\nof these factors are not readily modifiable, and, for those that are, such decisions may not be\nlikely to be made with future stroke risk in mind. However, I feel that it can still be used to\nidentify women at elevated risk of stroke based on reproductive history, as the authors discuss.\nThe results could also, e.g., be used to help highlight risks and challenges faced by low-SES\nwomen in their childbearing years.\nSpecific comments are listed below:\n• Lines 65-67: To what extent do the authors believe these factors are markers for other risk\nfactors versus causal factors in stroke?\n• Lines 117-19: Dichotomizing early age at menarche at #15 versus >15 seems to be a little\nhigh to me. In US studies, early menarche may be defined as <10 or <12 years. Might the\nassociation be diluted by using this cutoff? Further, late age at menarche may also be associated\nwith chronic disease. Was this explored at all? Factors such as history of stillbirth, miscarriage,\ntermination, or lactation would more appropriately be restricted to parous women to avoid\nmixing of the potential impact of infertility and its associated causes and the reproductive risk\nfactor in question. Was this done?\n• Lines 185-189: Were the population prevalence estimates derived from the survey data or other\nsources? If from the data, was the uncertainty in these estimates included in the calculation of the\nconfidence intervals for the PAFs? Admittedly, this may not add much given the sample size.\n• Line 193: it is unclear whether the estimates of the combined PAFs assumed that each of the\nreproductive factors had an independent association with stroke\n• Overall Results: differences in PAFs among low and high SES women was striking. However,\nsome estimate of the baseline stroke risk amongst women in these two groups would really help\nto further emphasize this contrast\n• Overall Discussion: I felt that a bit more discussion of whether or not the factors investigated\nwere causal or markers for other risk factors, and the potential impact on the interpretation of\nresults would strengthen this section. In addition, how might potential changes in employment\nover time impact the generalizability of the results?", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03976-5	Reviewed - bmc_medicine	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 0 Date: 16 Sep 2024 Reviewer's report: Thank you for reviewing this manuscript! The authors examined population-attributable fractions of stroke and its subtypes associated with reproductive factors among Chinese postmenopausal women. There are the following comments: 1. Figure 1: Regarding gynecological operations, it’s suggested that a specific definition be given. It is inappropriate to exclude participants who underwent surgical menopause or surgical delivery. 2. Figure 1: Excluding missing data on covariates, it is better to use the multiple imputations and then do the sensitivity analysis. 3. Figure 1: Follow-up: It’s suggested that more details be added, such as the initial time and number of visits. 4. Table 1: Why is BMI described as both a continuous and categorical variable? It is fine to select continuous BMI. The same comments are for the age of menarche and the age of menopause. 5. Age of menarche: <15 is defined as early menarche. Please provide the references. I didn’t agree with it at all. The early menarche generally refers to #10 years, and the late menarche refers to #15 years. 6. High parity: #3# Please provide the references for the definition. 7. Why not include age at childbirth? It’s a critical factor. 8. It should be multilinear for BMI and Waist circumference. Please choose one of the two variables. 9. For economic status, if the raw data is continuous. It’s unnecessary to categorize them intentionally. It would be better to include continuous income. 10. Table 1 is too lengthy. The rows of “0” and “No” should be removed. 11. Table 3: The association is insignificant with 0.1(-1.6-1.9). However, the prevalence (%) is 37.2%. It doesn’t make sense.	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 0 Date: 16 Sep 2024 Reviewer's report: Thank you for reviewing this manuscript! The authors examined population-attributable fractions of stroke and its subtypes associated with reproductive factors among Chinese postmenopausal women. There are the following comments: 1. Figure 1: Regarding gynecological operations, it’s suggested that a specific definition be given. It is inappropriate to exclude participants who underwent surgical menopause or surgical delivery. 2. Figure 1: Excluding missing data on covariates, it is better to use the multiple imputations and then do the sensitivity analysis. 3. Figure 1: Follow-up: It’s suggested that more details be added, such as the initial time and number of visits. 4. Table 1: Why is BMI described as both a continuous and categorical variable? It is fine to select continuous BMI. The same comments are for the age of menarche and the age of menopause. 5. Age of menarche: <15 is defined as early menarche. Please provide the references. I didn’t agree with it at all. The early menarche generally refers to #10 years, and the late menarche refers to #15 years. 6. High parity: #3# Please provide the references for the definition. 7. Why not include age at childbirth? It’s a critical factor. 8. It should be multilinear for BMI and Waist circumference. Please choose one of the two variables. 9. For economic status, if the raw data is continuous. It’s unnecessary to categorize them intentionally. It would be better to include continuous income. 10. Table 1 is too lengthy. The rows of “0” and “No” should be removed. 11. Table 3: The association is insignificant with 0.1(-1.6-1.9). However, the prevalence (%) is 37.2%. It doesn’t make sense.	BMC	12916_2025_3976_ReviewerReport_V0_R1.pdf	{ "criticism": 5, "example": 4, "importance_and_relevance": 0, "materials_and_methods": 7, "praise": 0, "presentation_and_reporting": 10, "results_and_discussion": 0, "suggestion_and_solution": 12, "total": 37 }	{ "criticism": 0.13513513513513514, "example": 0.10810810810810811, "importance_and_relevance": 0, "materials_and_methods": 0.1891891891891892, "praise": 0, "presentation_and_reporting": 0.2702702702702703, "results_and_discussion": 0, "suggestion_and_solution": 0.32432432432432434 }	1.027027	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles\namong postmenopausal women in China\nVersion: 0 Date: 16 Sep 2024\nReviewer's report:\nThank you for reviewing this manuscript! The authors examined population-attributable\nfractions of stroke and its subtypes associated with reproductive factors among Chinese\npostmenopausal women.\nThere are the following comments:\n1. Figure 1: Regarding gynecological operations, it’s suggested that a specific definition be\ngiven. It is inappropriate to exclude participants who underwent surgical menopause or surgical\ndelivery.\n2. Figure 1: Excluding missing data on covariates, it is better to use the multiple imputations\nand then do the sensitivity analysis.\n3. Figure 1: Follow-up: It’s suggested that more details be added, such as the initial time and\nnumber of visits.\n4. Table 1: Why is BMI described as both a continuous and categorical variable? It is fine\nto select continuous BMI. The same comments are for the age of menarche and the age of\nmenopause.\n5. Age of menarche: <15 is defined as early menarche. Please provide the references. I didn’t\nagree with it at all. The early menarche generally refers to #10 years, and the late menarche\nrefers to #15 years.\n6. High parity: #3# Please provide the references for the definition.\n7. Why not include age at childbirth? It’s a critical factor.\n8. It should be multilinear for BMI and Waist circumference. Please choose one of the two\nvariables.\n9. For economic status, if the raw data is continuous. It’s unnecessary to categorize them\nintentionally. It would be better to include continuous income.\n10. Table 1 is too lengthy. The rows of “0” and “No” should be removed.\n11. Table 3: The association is insignificant with 0.1(-1.6-1.9). However, the prevalence (%) is\n37.2%. It doesn’t make sense.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03976-5	Reviewed - bmc_medicine	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 1 Date: 18 Dec 2024 Reviewer's report: I appreciate the efforts of Sun et al. to address my comments on their manuscript calculating the of risk of stroke (overall and by subtype) attributable to reproductive factors among Chinese women of differing socioeconomic status. Those efforts have added much to what was already a very interesting manuscript. I have only a couple of additional comments 1. The numbers of the individual stroke subtypes in Figure 1 and the text are slightly higher than the total number of strokes. Did some cases fall under more than one subtype? If so, it would be helpful to note this in the footnote and in the text. Or is there some other explanation? Minor comments 2. Line 112: I suggest replacing “abnormal age” with “implausible age”. “Abnormal age” may be interpreted as “unusually early or late age at menopause”. 2. Line 372: I recommend replacing “while” with “however”. I believe this better conveys the authors’ intent.	Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China Version: 1 Date: 18 Dec 2024 Reviewer's report: I appreciate the efforts of Sun et al. to address my comments on their manuscript calculating the of risk of stroke (overall and by subtype) attributable to reproductive factors among Chinese women of differing socioeconomic status. Those efforts have added much to what was already a very interesting manuscript. I have only a couple of additional comments 1. The numbers of the individual stroke subtypes in Figure 1 and the text are slightly higher than the total number of strokes. Did some cases fall under more than one subtype? If so, it would be helpful to note this in the footnote and in the text. Or is there some other explanation? Minor comments 2. Line 112: I suggest replacing “abnormal age” with “implausible age”. “Abnormal age” may be interpreted as “unusually early or late age at menopause”. 2. Line 372: I recommend replacing “while” with “however”. I believe this better conveys the authors’ intent.	BMC	12916_2025_3976_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 3, "importance_and_relevance": 1, "materials_and_methods": 2, "praise": 2, "presentation_and_reporting": 3, "results_and_discussion": 1, "suggestion_and_solution": 4, "total": 14 }	{ "criticism": 0, "example": 0.21428571428571427, "importance_and_relevance": 0.07142857142857142, "materials_and_methods": 0.14285714285714285, "praise": 0.14285714285714285, "presentation_and_reporting": 0.21428571428571427, "results_and_discussion": 0.07142857142857142, "suggestion_and_solution": 0.2857142857142857 }	1.142857	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Socioeconomic variations in the proportions of stroke attributable to reproductive profiles\namong postmenopausal women in China\nVersion: 1 Date: 18 Dec 2024\nReviewer's report:\nI appreciate the efforts of Sun et al. to address my comments on their manuscript calculating\nthe of risk of stroke (overall and by subtype) attributable to reproductive factors among Chinese\nwomen of differing socioeconomic status. Those efforts have added much to what was already\na very interesting manuscript. I have only a couple of additional comments\n1. The numbers of the individual stroke subtypes in Figure 1 and the text are slightly higher than\nthe total number of strokes. Did some cases fall under more than one subtype? If so, it would be\nhelpful to note this in the footnote and in the text. Or is there some other explanation?\nMinor comments\n2. Line 112: I suggest replacing “abnormal age” with “implausible age”. “Abnormal age” may\nbe interpreted as “unusually early or late age at menopause”.\n2. Line 372: I recommend replacing “while” with “however”. I believe this better conveys the\nauthors’ intent.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03973-8	Reviewed - bmc_medicine	Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence pathogens: a scoping review Version: 0 Date: 09 Jan 2025 Reviewer: Amesh A. Adalja Reviewer's report: I think this paper is interesting and straight forward providing good information on how this process occurs. One thing that I might suggest considering (optionally) is to add a line or two about how the pathogens are selected. In my experience, many extraneous considerations factor into decisions for which pathogens are considered “high consequence” and many are not truly pandemic prone	Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence pathogens: a scoping review Version: 0 Date: 09 Jan 2025 Reviewer: Amesh A. Adalja Reviewer's report: I think this paper is interesting and straight forward providing good information on how this process occurs. One thing that I might suggest considering (optionally) is to add a line or two about how the pathogens are selected. In my experience, many extraneous considerations factor into decisions for which pathogens are considered “high consequence” and many are not truly pandemic prone	BMC	12916_2025_3973_ReviewerReport_V0_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 3 }	{ "criticism": 0.3333333333333333, "example": 0, "importance_and_relevance": 0.3333333333333333, "materials_and_methods": 0.3333333333333333, "praise": 0.3333333333333333, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0, "suggestion_and_solution": 0.3333333333333333 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence\npathogens: a scoping review\nVersion: 0 Date: 09 Jan 2025\nReviewer: Amesh A. Adalja\nReviewer's report:\nI think this paper is interesting and straight forward providing good information on how this\nprocess occurs. One thing that I might suggest considering (optionally) is to add a line or two\nabout how the pathogens are selected. In my experience, many extraneous considerations factor\ninto decisions for which pathogens are considered “high consequence” and many are not truly\npandemic prone", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03973-8	Reviewed - bmc_medicine	Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence pathogens: a scoping review Version: 0 Date: 20 Jan 2025 Reviewer's report: Studies such as this are important and add pieces to the puzzle to ultimately help us prepare for the next inevitable public health threat. The paper is generally well-written, flows well, and is easy to read while being engaging. The article does a great job of sharing the most important results and aligned conclusions. The paper would be a valuable addition to BMC Medicine. I recommend accepting this manuscript.	Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence pathogens: a scoping review Version: 0 Date: 20 Jan 2025 Reviewer's report: Studies such as this are important and add pieces to the puzzle to ultimately help us prepare for the next inevitable public health threat. The paper is generally well-written, flows well, and is easy to read while being engaging. The article does a great job of sharing the most important results and aligned conclusions. The paper would be a valuable addition to BMC Medicine. I recommend accepting this manuscript.	BMC	12916_2025_3973_ReviewerReport_V0_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 3, "materials_and_methods": 0, "praise": 5, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 2, "total": 5 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.6, "materials_and_methods": 0, "praise": 1, "presentation_and_reporting": 0.2, "results_and_discussion": 0.2, "suggestion_and_solution": 0.4 }	2.4	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Research prioritisation in preparedness for and response to outbreaks of high-consequence\npathogens: a scoping review\nVersion: 0 Date: 20 Jan 2025\nReviewer's report:\nStudies such as this are important and add pieces to the puzzle to ultimately help us prepare for\nthe next inevitable public health threat. The paper is generally well-written, flows well, and is\neasy to read while being engaging. The article does a great job of sharing the most important\nresults and aligned conclusions. The paper would be a valuable addition to BMC Medicine. I\nrecommend accepting this manuscript.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 19 Nov 2024 Reviewer's report: Duan et al examined the association between smoking-related gut microbiota alteration (represented by smoking-related microbiota index) and obesity, obesity-related disorders, and obesity-related outcomes. The manuscript is well-written, and data analysis seems ok. The major concern is the concept of “smoking-related microbiota index”. 1. What’s the necessity of using UKB, NHANES, CHNS, and CHARLS? It only shows the associations between smoking status (current vs never) and BMI, which has been admitted in your introduction. Could you explain the adding value of Figure 1 for this study? 2. In WELL-China cohort, 50 microbial genera displayed an association with current smoking while in the Lanxi cohort, only 19 microbial genera, and only 9 overlapped. The two populations were of similar age and geographical area. What caused the difference between these two cohorts? If the association between smoking and gut microbiota varied across populations, how to justify the validity and reliability of this smoking-related microbiota index? 3. The authors should use one cohort as a replicate cohort for the index. 4. Is it possible to quantify smoking exposure? According to authors, the index was similar between former smokers and current smokers. Does it suggest cumulative effects of smoking?	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 19 Nov 2024 Reviewer's report: Duan et al examined the association between smoking-related gut microbiota alteration (represented by smoking-related microbiota index) and obesity, obesity-related disorders, and obesity-related outcomes. The manuscript is well-written, and data analysis seems ok. The major concern is the concept of “smoking-related microbiota index”. 1. What’s the necessity of using UKB, NHANES, CHNS, and CHARLS? It only shows the associations between smoking status (current vs never) and BMI, which has been admitted in your introduction. Could you explain the adding value of Figure 1 for this study? 2. In WELL-China cohort, 50 microbial genera displayed an association with current smoking while in the Lanxi cohort, only 19 microbial genera, and only 9 overlapped. The two populations were of similar age and geographical area. What caused the difference between these two cohorts? If the association between smoking and gut microbiota varied across populations, how to justify the validity and reliability of this smoking-related microbiota index? 3. The authors should use one cohort as a replicate cohort for the index. 4. Is it possible to quantify smoking exposure? According to authors, the index was similar between former smokers and current smokers. Does it suggest cumulative effects of smoking?	BMC	12916_2025_3969_ReviewerReport_V0_R6.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 9, "praise": 1, "presentation_and_reporting": 2, "results_and_discussion": 0, "suggestion_and_solution": 2, "total": 18 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.05555555555555555, "materials_and_methods": 0.5, "praise": 0.05555555555555555, "presentation_and_reporting": 0.1111111111111111, "results_and_discussion": 0, "suggestion_and_solution": 0.1111111111111111 }	0.833333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 0 Date: 19 Nov 2024\nReviewer's report:\nDuan et al examined the association between smoking-related gut microbiota alteration\n(represented by smoking-related microbiota index) and obesity, obesity-related disorders, and\nobesity-related outcomes. The manuscript is well-written, and data analysis seems ok. The major\nconcern is the concept of “smoking-related microbiota index”.\n1. What’s the necessity of using UKB, NHANES, CHNS, and CHARLS? It only shows the\nassociations between smoking status (current vs never) and BMI, which has been admitted in\nyour introduction. Could you explain the adding value of Figure 1 for this study?\n2. In WELL-China cohort, 50 microbial genera displayed an association with current smoking\nwhile in the Lanxi cohort, only 19 microbial genera, and only 9 overlapped. The two populations\nwere of similar age and geographical area. What caused the difference between these two\ncohorts? If the association between smoking and gut microbiota varied across populations, how\nto justify the validity and reliability of this smoking-related microbiota index?\n3. The authors should use one cohort as a replicate cohort for the index.\n4. Is it possible to quantify smoking exposure? According to authors, the index was similar\nbetween former smokers and current smokers. Does it suggest cumulative effects of smoking?", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 24 Nov 2024 Reviewer's report: The study design is unclear. The authors initially describe the work as a systematic review. However, they perform association analyses by mixing cohort data with national survey data. Additionally, they include a meta-analysis section. If this is intended as a systematic review (SR) with a meta-analysis (MA), the protocol must be registered. The authors do not provide any details on the protocol registration. Systematic reviews and meta-analyses should be reported in accordance with the most recent update of the PRISMA statement (2020). The authors fail to include key sections from the PRISMA checklist, including, most notably, risk of bias and publication bias. The authors do not provide forest plots typically associated with meta-analyses. The authors do not present funnel plots that are standard for meta-analyses. Finally, the summary measure of association specific to the meta-analysis is not presented.	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 24 Nov 2024 Reviewer's report: The study design is unclear. The authors initially describe the work as a systematic review. However, they perform association analyses by mixing cohort data with national survey data. Additionally, they include a meta-analysis section. If this is intended as a systematic review (SR) with a meta-analysis (MA), the protocol must be registered. The authors do not provide any details on the protocol registration. Systematic reviews and meta-analyses should be reported in accordance with the most recent update of the PRISMA statement (2020). The authors fail to include key sections from the PRISMA checklist, including, most notably, risk of bias and publication bias. The authors do not provide forest plots typically associated with meta-analyses. The authors do not present funnel plots that are standard for meta-analyses. Finally, the summary measure of association specific to the meta-analysis is not presented.	BMC	12916_2025_3969_ReviewerReport_V0_R4.pdf	{ "criticism": 6, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 8, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 2, "total": 11 }	{ "criticism": 0.5454545454545454, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.7272727272727273, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0.18181818181818182 }	1.454545	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 0 Date: 24 Nov 2024\nReviewer's report:\nThe study design is unclear. The authors initially describe the work as a systematic review.\nHowever, they perform association analyses by mixing cohort data with national survey data.\nAdditionally, they include a meta-analysis section.\nIf this is intended as a systematic review (SR) with a meta-analysis (MA), the protocol must be\nregistered. The authors do not provide any details on the protocol registration.\nSystematic reviews and meta-analyses should be reported in accordance with the most recent\nupdate of the PRISMA statement (2020).\nThe authors fail to include key sections from the PRISMA checklist, including, most notably,\nrisk of bias and publication bias.\nThe authors do not provide forest plots typically associated with meta-analyses.\nThe authors do not present funnel plots that are standard for meta-analyses.\nFinally, the summary measure of association specific to the meta-analysis is not presented.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 29 Nov 2024 Reviewer's report: Shankuan Zhu's team utilised population databases to deeply investigate the relationship between smoking and body weight, revealing a downward trend in BMI among smokers. In subsequent research, through microbiome data analyses of the WELL-China cohort and the Lanxi cohort, it was found that the Smoking-Associated Microbiome Index (SMI) was significantly positively correlated with BMI and other obesity indicators. Further analyses indicated that SMI was also closely associated with obesity-related diseases. Moreover, the study effectively addressed potential familial confounding factors through sibling cohort analyses. Based on these findings, the authors attempted to provide a plausible explanation for the smoking-obesity paradox. This study's topic is novel and its content highly compelling, offering a fresh perspective on the complex relationship between smoking and obesity while carrying significant public health implications and practical value. However, I still have some questions that require clarification from the authors. (1)Given that the authors have chosen both population-based studies and microbiome research to address this issue, it would be beneficial to reflect this dual research perspective clearly from the title. However, based on the current study content, the focus seems primarily on microbiome- related analyses. To more comprehensively explore the relationship between smoking and obesity, the inclusion of additional indicators beyond BMI could be considered. For instance, datasets like the UK Biobank or NHANES could provide a broader perspective and enrich the study with supplementary data. Most importantly, it is crucial to incorporate a more objective measure of smoking exposure, such as nicotine levels. Compared to self-reported questionnaires, nicotine exposure provides a more accurate reflection of smoking status, significantly enhancing the scientific robustness and credibility of the study's conclusions. I recommend structuring the study into two main sections: one focusing on population databases to systematically explore the association between smoking and obesity, and another delving into microbiome research to uncover potential biological mechanisms. If it is not feasible to address both aspects comprehensively, I suggest omitting the population database analysis and concentrating on the microbiome study to ensure a clearer and more focused research narrative. (2)The conclusions drawn by the author from the population database are not necessarily specific to the male population. Currently, the # values from the CHNS and CHARLS databases, which are also based on Chinese populations, are relatively large, whereas the # values from the WELL- China cohort and the Lanxi cohort are relatively smaller. How should the author explain this discrepancy? Are there feasible methods to address or adjust this issue? (3)Former smokers should not be overlooked. Existing research evidence indicates that individuals who quit smoking may experience phenomena such as weight gain; however, quitting smoking can also significantly reduce the risk of adverse health outcomes caused by smoking. This is a highly valuable and very interesting topic for research. (4)It is recommended to provide references for certain definitions described in the methodology section, such as the definition of obesity-related cancers and the reasons for choosing a fixed- effects model. Additionally, the author is advised to examine and explain relevant factors one by one to enhance the rigor and scientific validity of the study. (5)The greatest limitation of this study lies in the excessive complexity of the research content, while the description of each part is not detailed or rigorous enough, with some content missing. For example, in the cohort analysis of disease occurrence, the baseline characteristics of the study population (such as comorbidities) were not sufficiently elaborated. These issues are, in my opinion, the key areas that require revision. It is recommended that the author thoroughly refine the structure of the article to ensure clear logic and provide more detailed and scientifically robust descriptions of each section. (6)It is recommended to comprehensively polish the language of the article to ensure clear and fluent expression, as well as to standardize the use of capitalization. Additionally, the supplementary materials should be carefully reviewed and their order adjusted as necessary. (7)Considering the highly complex factors influencing gut microbiota and obesity, it is recommended to provide broader explanations from multiple perspectives regarding the contradictions between population studies and microbiome research. Furthermore, it is suggested to enhance the literature review in the introduction and discussion sections.	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 29 Nov 2024 Reviewer's report: Shankuan Zhu's team utilised population databases to deeply investigate the relationship between smoking and body weight, revealing a downward trend in BMI among smokers. In subsequent research, through microbiome data analyses of the WELL-China cohort and the Lanxi cohort, it was found that the Smoking-Associated Microbiome Index (SMI) was significantly positively correlated with BMI and other obesity indicators. Further analyses indicated that SMI was also closely associated with obesity-related diseases. Moreover, the study effectively addressed potential familial confounding factors through sibling cohort analyses. Based on these findings, the authors attempted to provide a plausible explanation for the smoking-obesity paradox. This study's topic is novel and its content highly compelling, offering a fresh perspective on the complex relationship between smoking and obesity while carrying significant public health implications and practical value. However, I still have some questions that require clarification from the authors. (1)Given that the authors have chosen both population-based studies and microbiome research to address this issue, it would be beneficial to reflect this dual research perspective clearly from the title. However, based on the current study content, the focus seems primarily on microbiome- related analyses. To more comprehensively explore the relationship between smoking and obesity, the inclusion of additional indicators beyond BMI could be considered. For instance, datasets like the UK Biobank or NHANES could provide a broader perspective and enrich the study with supplementary data. Most importantly, it is crucial to incorporate a more objective measure of smoking exposure, such as nicotine levels. Compared to self-reported questionnaires, nicotine exposure provides a more accurate reflection of smoking status, significantly enhancing the scientific robustness and credibility of the study's conclusions. I recommend structuring the study into two main sections: one focusing on population databases to systematically explore the association between smoking and obesity, and another delving into microbiome research to uncover potential biological mechanisms. If it is not feasible to address both aspects comprehensively, I suggest omitting the population database analysis and concentrating on the microbiome study to ensure a clearer and more focused research narrative. (2)The conclusions drawn by the author from the population database are not necessarily specific to the male population. Currently, the # values from the CHNS and CHARLS databases, which are also based on Chinese populations, are relatively large, whereas the # values from the WELL- China cohort and the Lanxi cohort are relatively smaller. How should the author explain this discrepancy? Are there feasible methods to address or adjust this issue? (3)Former smokers should not be overlooked. Existing research evidence indicates that individuals who quit smoking may experience phenomena such as weight gain; however, quitting smoking can also significantly reduce the risk of adverse health outcomes caused by smoking. This is a highly valuable and very interesting topic for research. (4)It is recommended to provide references for certain definitions described in the methodology section, such as the definition of obesity-related cancers and the reasons for choosing a fixed- effects model. Additionally, the author is advised to examine and explain relevant factors one by one to enhance the rigor and scientific validity of the study. (5)The greatest limitation of this study lies in the excessive complexity of the research content, while the description of each part is not detailed or rigorous enough, with some content missing. For example, in the cohort analysis of disease occurrence, the baseline characteristics of the study population (such as comorbidities) were not sufficiently elaborated. These issues are, in my opinion, the key areas that require revision. It is recommended that the author thoroughly refine the structure of the article to ensure clear logic and provide more detailed and scientifically robust descriptions of each section. (6)It is recommended to comprehensively polish the language of the article to ensure clear and fluent expression, as well as to standardize the use of capitalization. Additionally, the supplementary materials should be carefully reviewed and their order adjusted as necessary. (7)Considering the highly complex factors influencing gut microbiota and obesity, it is recommended to provide broader explanations from multiple perspectives regarding the contradictions between population studies and microbiome research. Furthermore, it is suggested to enhance the literature review in the introduction and discussion sections.	BMC	12916_2025_3969_ReviewerReport_V0_R2.pdf	{ "criticism": 4, "example": 0, "importance_and_relevance": 11, "materials_and_methods": 19, "praise": 3, "presentation_and_reporting": 10, "results_and_discussion": 5, "suggestion_and_solution": 16, "total": 32 }	{ "criticism": 0.125, "example": 0, "importance_and_relevance": 0.34375, "materials_and_methods": 0.59375, "praise": 0.09375, "presentation_and_reporting": 0.3125, "results_and_discussion": 0.15625, "suggestion_and_solution": 0.5 }	2.125	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 0 Date: 29 Nov 2024\nReviewer's report:\nShankuan Zhu's team utilised population databases to deeply investigate the relationship\nbetween smoking and body weight, revealing a downward trend in BMI among smokers.\nIn subsequent research, through microbiome data analyses of the WELL-China cohort and\nthe Lanxi cohort, it was found that the Smoking-Associated Microbiome Index (SMI) was\nsignificantly positively correlated with BMI and other obesity indicators. Further analyses\nindicated that SMI was also closely associated with obesity-related diseases. Moreover, the study\neffectively addressed potential familial confounding factors through sibling cohort analyses.\nBased on these findings, the authors attempted to provide a plausible explanation for the\nsmoking-obesity paradox. This study's topic is novel and its content highly compelling, offering\na fresh perspective on the complex relationship between smoking and obesity while carrying\nsignificant public health implications and practical value. However, I still have some questions\nthat require clarification from the authors.\n(1)Given that the authors have chosen both population-based studies and microbiome research\nto address this issue, it would be beneficial to reflect this dual research perspective clearly from\nthe title. However, based on the current study content, the focus seems primarily on microbiome-\nrelated analyses. To more comprehensively explore the relationship between smoking and\nobesity, the inclusion of additional indicators beyond BMI could be considered. For instance,\ndatasets like the UK Biobank or NHANES could provide a broader perspective and enrich the\nstudy with supplementary data. Most importantly, it is crucial to incorporate a more objective\nmeasure of smoking exposure, such as nicotine levels. Compared to self-reported questionnaires,\nnicotine exposure provides a more accurate reflection of smoking status, significantly enhancing\nthe scientific robustness and credibility of the study's conclusions. I recommend structuring\nthe study into two main sections: one focusing on population databases to systematically\nexplore the association between smoking and obesity, and another delving into microbiome\nresearch to uncover potential biological mechanisms. If it is not feasible to address both aspects\ncomprehensively, I suggest omitting the population database analysis and concentrating on the\nmicrobiome study to ensure a clearer and more focused research narrative.\n(2)The conclusions drawn by the author from the population database are not necessarily specific\nto the male population. Currently, the # values from the CHNS and CHARLS databases, which\nare also based on Chinese populations, are relatively large, whereas the # values from the WELL-\nChina cohort and the Lanxi cohort are relatively smaller. How should the author explain this\ndiscrepancy? Are there feasible methods to address or adjust this issue?\n(3)Former smokers should not be overlooked. Existing research evidence indicates that\nindividuals who quit smoking may experience phenomena such as weight gain; however,\nquitting smoking can also significantly reduce the risk of adverse health outcomes caused by\nsmoking. This is a highly valuable and very interesting topic for research.\n(4)It is recommended to provide references for certain definitions described in the methodology\nsection, such as the definition of obesity-related cancers and the reasons for choosing a fixed-\neffects model. Additionally, the author is advised to examine and explain relevant factors one\nby one to enhance the rigor and scientific validity of the study.\n(5)The greatest limitation of this study lies in the excessive complexity of the research content,\nwhile the description of each part is not detailed or rigorous enough, with some content missing.\nFor example, in the cohort analysis of disease occurrence, the baseline characteristics of the\nstudy population (such as comorbidities) were not sufficiently elaborated. These issues are, in\nmy opinion, the key areas that require revision. It is recommended that the author thoroughly\nrefine the structure of the article to ensure clear logic and provide more detailed and scientifically\nrobust descriptions of each section.\n(6)It is recommended to comprehensively polish the language of the article to ensure clear\nand fluent expression, as well as to standardize the use of capitalization. Additionally, the\nsupplementary materials should be carefully reviewed and their order adjusted as necessary.\n(7)Considering the highly complex factors influencing gut microbiota and obesity, it is\nrecommended to provide broader explanations from multiple perspectives regarding the\ncontradictions between population studies and microbiome research. Furthermore, it is\nsuggested to enhance the literature review in the introduction and discussion sections.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 04 Dec 2024 Reviewer's report: I enjoy reading this manuscript. I have the following comments for consideration. 1. Could the authors justify the exclusion of participants with BMI <18.5? 2. Why did the authors use a lenient threshold of 0.25 for the Q value (FDR-adjusted p-value)? 3. Why did the authors analyze SMI in tertiles rather than as a continuous variable? 4. Could the authors include overall cancer as an outcome to increase the power? 5. Figure 1 - What are the differences in BMI between never smokers and former smokers and between current smokers and former smokers? 6. Figure 3 - I recommend the use of log-scale x-axis for odds ratio. 7. Line 376 - What are the potential mechanisms of smoking decreasing obesity?	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 0 Date: 04 Dec 2024 Reviewer's report: I enjoy reading this manuscript. I have the following comments for consideration. 1. Could the authors justify the exclusion of participants with BMI <18.5? 2. Why did the authors use a lenient threshold of 0.25 for the Q value (FDR-adjusted p-value)? 3. Why did the authors analyze SMI in tertiles rather than as a continuous variable? 4. Could the authors include overall cancer as an outcome to increase the power? 5. Figure 1 - What are the differences in BMI between never smokers and former smokers and between current smokers and former smokers? 6. Figure 3 - I recommend the use of log-scale x-axis for odds ratio. 7. Line 376 - What are the potential mechanisms of smoking decreasing obesity?	BMC	12916_2025_3969_ReviewerReport_V0_R5.pdf	{ "criticism": 0, "example": 3, "importance_and_relevance": 0, "materials_and_methods": 6, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 2, "suggestion_and_solution": 1, "total": 16 }	{ "criticism": 0, "example": 0.1875, "importance_and_relevance": 0, "materials_and_methods": 0.375, "praise": 0.0625, "presentation_and_reporting": 0.0625, "results_and_discussion": 0.125, "suggestion_and_solution": 0.0625 }	0.875	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 0 Date: 04 Dec 2024\nReviewer's report:\nI enjoy reading this manuscript. I have the following comments for consideration.\n1. Could the authors justify the exclusion of participants with BMI <18.5?\n2. Why did the authors use a lenient threshold of 0.25 for the Q value (FDR-adjusted p-value)?\n3. Why did the authors analyze SMI in tertiles rather than as a continuous variable?\n4. Could the authors include overall cancer as an outcome to increase the power?\n5. Figure 1 - What are the differences in BMI between never smokers and former smokers and\nbetween current smokers and former smokers?\n6. Figure 3 - I recommend the use of log-scale x-axis for odds ratio.\n7. Line 376 - What are the potential mechanisms of smoking decreasing obesity?", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 07 Jan 2025 Reviewer's report: The author has addressed all my concerns. However, there are still minor details that require revision. 1.The author needs to recheck the citations of figures and tables in the manuscript, as I noticed that Figure 1 seems to have not been uploaded. 2.Both BMI and smoking are associated with the recently proposed Life’s Essential 8 by the American Heart Association, and both are closely linked to vascular inflammation. Moreover, existing studies have supported the role of the gut microbiota as a key mediator of vascular wall inflammation. Additional discussion on this topic is warranted to expand on the public health significance of this study.(DOI: 10.3390/microorganisms12112341;DOI: 10.1016/ j.micinf.2024.105406)	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 07 Jan 2025 Reviewer's report: The author has addressed all my concerns. However, there are still minor details that require revision. 1.The author needs to recheck the citations of figures and tables in the manuscript, as I noticed that Figure 1 seems to have not been uploaded. 2.Both BMI and smoking are associated with the recently proposed Life’s Essential 8 by the American Heart Association, and both are closely linked to vascular inflammation. Moreover, existing studies have supported the role of the gut microbiota as a key mediator of vascular wall inflammation. Additional discussion on this topic is warranted to expand on the public health significance of this study.(DOI: 10.3390/microorganisms12112341;DOI: 10.1016/ j.micinf.2024.105406)	BMC	12916_2025_3969_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 2, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 3, "total": 7 }	{ "criticism": 0.14285714285714285, "example": 0, "importance_and_relevance": 0.2857142857142857, "materials_and_methods": 0.14285714285714285, "praise": 0.2857142857142857, "presentation_and_reporting": 0.14285714285714285, "results_and_discussion": 0.14285714285714285, "suggestion_and_solution": 0.42857142857142855 }	1.571429	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 1 Date: 07 Jan 2025\nReviewer's report:\nThe author has addressed all my concerns. However, there are still minor details that require\nrevision.\n1.The author needs to recheck the citations of figures and tables in the manuscript, as I noticed\nthat Figure 1 seems to have not been uploaded.\n2.Both BMI and smoking are associated with the recently proposed Life’s Essential 8 by\nthe American Heart Association, and both are closely linked to vascular inflammation.\nMoreover, existing studies have supported the role of the gut microbiota as a key mediator of\nvascular wall inflammation. Additional discussion on this topic is warranted to expand on the\npublic health significance of this study.(DOI: 10.3390/microorganisms12112341;DOI: 10.1016/\nj.micinf.2024.105406)", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 11 Jan 2025 Reviewer's report: The authors' responses to my questions are reasonable.	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 11 Jan 2025 Reviewer's report: The authors' responses to my questions are reasonable.	BMC	12916_2025_3969_ReviewerReport_V1_R6.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	0	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 1 Date: 11 Jan 2025\nReviewer's report:\nThe authors' responses to my questions are reasonable.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03969-4	Reviewed - bmc_medicine	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 22 Jan 2025 Reviewer's report: The authors have addressed all my concerns. I do not have further comments.	Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related diseases: results from two cohorts with sibling comparison analyses Version: 1 Date: 22 Jan 2025 Reviewer's report: The authors have addressed all my concerns. I do not have further comments.	BMC	12916_2025_3969_ReviewerReport_V1_R5.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0.5, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Smoking-related gut microbiota alteration is associated with obesity and obesity-related\ndiseases: results from two cohorts with sibling comparison analyses\nVersion: 1 Date: 22 Jan 2025\nReviewer's report:\nThe authors have addressed all my concerns. I do not have further comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03978-3	Reviewed - bmc_medicine	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 0 Date: 15 Nov 2024 Reviewer's report: The current work is to raise awareness of multiple outcome event prediction, and present clinical examples where such prediction is essential to help inform individual decision-making. I have several comments: 1. This is not a original type article, it may be suitable as a technical note or statistical methods introduction. 2. in the example of CVD, this can be a composite outcome that include multiple events such as myocardial infarction, coronary disease and so on. 3. more explanations for the ISARIC 4C model in the main text is needed to facilitate the reading. 4. It is important to decide whether these outcome events are mutually exclusive; for example, bleeding and clotting can occur simutaneously in one patient. this can cause the situation different. The probability of events can sum to > 100%. 5. Machine learning/deep learning models can have multiple classification in the output; This is an important technical tool with the development of AI, they have special Taxonomy in machine learning context for the classification purpose. For example, in ensemble modeling ( https:// doi.org/10.1016/j.lers.2021.12.003), many models can handle regression and classification problem.	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 0 Date: 15 Nov 2024 Reviewer's report: The current work is to raise awareness of multiple outcome event prediction, and present clinical examples where such prediction is essential to help inform individual decision-making. I have several comments: 1. This is not a original type article, it may be suitable as a technical note or statistical methods introduction. 2. in the example of CVD, this can be a composite outcome that include multiple events such as myocardial infarction, coronary disease and so on. 3. more explanations for the ISARIC 4C model in the main text is needed to facilitate the reading. 4. It is important to decide whether these outcome events are mutually exclusive; for example, bleeding and clotting can occur simutaneously in one patient. this can cause the situation different. The probability of events can sum to > 100%. 5. Machine learning/deep learning models can have multiple classification in the output; This is an important technical tool with the development of AI, they have special Taxonomy in machine learning context for the classification purpose. For example, in ensemble modeling ( https:// doi.org/10.1016/j.lers.2021.12.003), many models can handle regression and classification problem.	BMC	12916_2025_3978_ReviewerReport_V0_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 2, "materials_and_methods": 5, "praise": 1, "presentation_and_reporting": 2, "results_and_discussion": 4, "suggestion_and_solution": 3, "total": 12 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.16666666666666666, "materials_and_methods": 0.4166666666666667, "praise": 0.08333333333333333, "presentation_and_reporting": 0.16666666666666666, "results_and_discussion": 0.3333333333333333, "suggestion_and_solution": 0.25 }	1.416667	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production\nof Clinical Prediction Models: defining a taxonomy of risk estimands\nVersion: 0 Date: 15 Nov 2024\nReviewer's report:\nThe current work is to raise awareness of multiple outcome event prediction, and present clinical\nexamples where such prediction is essential to help inform individual decision-making. I have\nseveral comments:\n1. This is not a original type article, it may be suitable as a technical note or statistical methods\nintroduction.\n2. in the example of CVD, this can be a composite outcome that include multiple events such\nas myocardial infarction, coronary disease and so on.\n3. more explanations for the ISARIC 4C model in the main text is needed to facilitate the\nreading.\n4. It is important to decide whether these outcome events are mutually exclusive; for example,\nbleeding and clotting can occur simutaneously in one patient. this can cause the situation\ndifferent. The probability of events can sum to > 100%.\n5. Machine learning/deep learning models can have multiple classification in the output; This is\nan important technical tool with the development of AI, they have special Taxonomy in machine\nlearning context for the classification purpose. For example, in ensemble modeling ( https://\ndoi.org/10.1016/j.lers.2021.12.003), many models can handle regression and classification\nproblem.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03978-3	Reviewed - bmc_medicine	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 0 Date: 09 Dec 2024 Reviewer: Ulrich Mansmann Reviewer's report: I do congratulate the authors for this comprehensive and needed paper. There are many medical contexts where healthcare decision-making needs to consider risks of multiple outcome events. Thus, CPMs need to estimate the probability of multiple outcome events co-occurring. Understanding when, and how, to incorporate multiple outcomes into CPM is challenging Relevant are intended estimand (the type of predicted risks that we wish the CPM to estimate). The submitted paper plans to give direction on how to manoeuvre through this difficult landscape. It raises awareness of multiple outcome event prediction, and presents clinical examples where such prediction is essential to help inform individual decision-making. It presents an important contribution to reflect on the ongoing algorithmizing of clinical decision making. The authors introduce four taxonomic levels: Level 1: Estimand is the Predicted Risk of a Single Outcome Level 2: Estimand is the Predicted Risk of Multiple Competing Outcome Events Level 3: Estimand is the Predicted Risk of a Composite of Multiple Outcomes Level 4: Estimand is the Predicted Risk of Different Combinations of Multiple Outcomes Here my comments: 1. General comment (1): The paper only looks on estimands for the risk estimation. It ignores that more complicated estimands are needed for the estimation of the patients’ advantage. The need to combine risk estimates with utilities or other values of patient preferences is ignores. 2. General comment (2): The paper ignores situations when the decision has to be performed regarding the choice on an optimal treatment out of a large set of options. For example a diabetic patient has to switch to a new therapy. 3. The introduction identifies two problems: 1.) Unappropriated use of the term multivariate analysis and 2.) Unprecise definitions of relevant estimands. It would be helpful to give a short example of an unprecise estimand (after line 20). 4. In 4.1. the prediction horizon is not clear. 5. Regarding box 1, it may helpful to describe risk estimands and risk estimates. The need to define timeframes and events (Outcome and prediction horizon) as well as the predictors used. The measurement(s) used for prediction that characterize the individual, that is, that individualize the predictions. The measurement(s) must be available at the moment(s) of intended use and measurement procedures must correspond to those in the setting of intended use. Especially the history of the patient or a clinical status at time of the prediction. 6. Chapter 2 uses the concept of utilities which is not mentioned in the introduction. There should be a short sentence preparing the use of utilities in chapter 2. 7. The paper does not touch the problem how to quantify the utilities. They may differ from patient to patient and may underly a multi-criteria problem (his own health, family aspects, professional aspects…). 8. Especially, each taxonomic level of the risk estimand needs a different concept to quantify utilities. We also use estimands for the utilities to get correct estimates of the utilities. 9. How helpful is the section between lines 99 and 109? The authors discuss very complex models which a non-trivial and in general unfamiliar background. Would it be possible to exemplify this in more detail? Maybe in an electronic methodological supplement? 10. Decision-making is more than risk estimation. Why is the estimand of interest in this paper not the final risk/utility combination. The title should take care about this by stating that the authors study risk estimands. 11. The examples given in lines 160 – 162 may also be seen as ordinal: Benign / borderline / metastatic. 12. It would be good to extend Box 1 from the estimand to the estimator and the estimate. 13. At the end of the paper, I was a bit confused. What is the purpose of the paper? Who is the addressed reader? Is it the clinician who wants to apply CPMs? Is it the clinician who evaluates the CPM? Is it the biostatistician starting the journey of CPM development? It would be good to give to a clinician an example how to apply the taxonomy and how to gain advantage out of it.	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 0 Date: 09 Dec 2024 Reviewer: Ulrich Mansmann Reviewer's report: I do congratulate the authors for this comprehensive and needed paper. There are many medical contexts where healthcare decision-making needs to consider risks of multiple outcome events. Thus, CPMs need to estimate the probability of multiple outcome events co-occurring. Understanding when, and how, to incorporate multiple outcomes into CPM is challenging Relevant are intended estimand (the type of predicted risks that we wish the CPM to estimate). The submitted paper plans to give direction on how to manoeuvre through this difficult landscape. It raises awareness of multiple outcome event prediction, and presents clinical examples where such prediction is essential to help inform individual decision-making. It presents an important contribution to reflect on the ongoing algorithmizing of clinical decision making. The authors introduce four taxonomic levels: Level 1: Estimand is the Predicted Risk of a Single Outcome Level 2: Estimand is the Predicted Risk of Multiple Competing Outcome Events Level 3: Estimand is the Predicted Risk of a Composite of Multiple Outcomes Level 4: Estimand is the Predicted Risk of Different Combinations of Multiple Outcomes Here my comments: 1. General comment (1): The paper only looks on estimands for the risk estimation. It ignores that more complicated estimands are needed for the estimation of the patients’ advantage. The need to combine risk estimates with utilities or other values of patient preferences is ignores. 2. General comment (2): The paper ignores situations when the decision has to be performed regarding the choice on an optimal treatment out of a large set of options. For example a diabetic patient has to switch to a new therapy. 3. The introduction identifies two problems: 1.) Unappropriated use of the term multivariate analysis and 2.) Unprecise definitions of relevant estimands. It would be helpful to give a short example of an unprecise estimand (after line 20). 4. In 4.1. the prediction horizon is not clear. 5. Regarding box 1, it may helpful to describe risk estimands and risk estimates. The need to define timeframes and events (Outcome and prediction horizon) as well as the predictors used. The measurement(s) used for prediction that characterize the individual, that is, that individualize the predictions. The measurement(s) must be available at the moment(s) of intended use and measurement procedures must correspond to those in the setting of intended use. Especially the history of the patient or a clinical status at time of the prediction. 6. Chapter 2 uses the concept of utilities which is not mentioned in the introduction. There should be a short sentence preparing the use of utilities in chapter 2. 7. The paper does not touch the problem how to quantify the utilities. They may differ from patient to patient and may underly a multi-criteria problem (his own health, family aspects, professional aspects…). 8. Especially, each taxonomic level of the risk estimand needs a different concept to quantify utilities. We also use estimands for the utilities to get correct estimates of the utilities. 9. How helpful is the section between lines 99 and 109? The authors discuss very complex models which a non-trivial and in general unfamiliar background. Would it be possible to exemplify this in more detail? Maybe in an electronic methodological supplement? 10. Decision-making is more than risk estimation. Why is the estimand of interest in this paper not the final risk/utility combination. The title should take care about this by stating that the authors study risk estimands. 11. The examples given in lines 160 – 162 may also be seen as ordinal: Benign / borderline / metastatic. 12. It would be good to extend Box 1 from the estimand to the estimator and the estimate. 13. At the end of the paper, I was a bit confused. What is the purpose of the paper? Who is the addressed reader? Is it the clinician who wants to apply CPMs? Is it the clinician who evaluates the CPM? Is it the biostatistician starting the journey of CPM development? It would be good to give to a clinician an example how to apply the taxonomy and how to gain advantage out of it.	BMC	12916_2025_3978_ReviewerReport_V0_R3.pdf	{ "criticism": 5, "example": 5, "importance_and_relevance": 2, "materials_and_methods": 26, "praise": 3, "presentation_and_reporting": 9, "results_and_discussion": 10, "suggestion_and_solution": 11, "total": 57 }	{ "criticism": 0.08771929824561403, "example": 0.08771929824561403, "importance_and_relevance": 0.03508771929824561, "materials_and_methods": 0.45614035087719296, "praise": 0.05263157894736842, "presentation_and_reporting": 0.15789473684210525, "results_and_discussion": 0.17543859649122806, "suggestion_and_solution": 0.19298245614035087 }	1.245614	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production\nof Clinical Prediction Models: defining a taxonomy of risk estimands\nVersion: 0 Date: 09 Dec 2024\nReviewer: Ulrich Mansmann\nReviewer's report:\nI do congratulate the authors for this comprehensive and needed paper.\nThere are many medical contexts where healthcare decision-making needs to consider risks of\nmultiple outcome events. Thus, CPMs need to estimate the probability of multiple outcome\nevents co-occurring. Understanding when, and how, to incorporate multiple outcomes into CPM\nis challenging Relevant are intended estimand (the type of predicted risks that we wish the\nCPM to estimate). The submitted paper plans to give direction on how to manoeuvre through\nthis difficult landscape. It raises awareness of multiple outcome event prediction, and presents\nclinical examples where such prediction is essential to help inform individual decision-making.\nIt presents an important contribution to reflect on the ongoing algorithmizing of clinical decision\nmaking.\nThe authors introduce four taxonomic levels:\nLevel 1: Estimand is the Predicted Risk of a Single Outcome\nLevel 2: Estimand is the Predicted Risk of Multiple Competing Outcome Events\nLevel 3: Estimand is the Predicted Risk of a Composite of Multiple Outcomes\nLevel 4: Estimand is the Predicted Risk of Different Combinations of Multiple Outcomes\nHere my comments:\n1. General comment (1): The paper only looks on estimands for the risk estimation. It ignores\nthat more complicated estimands are needed for the estimation of the patients’ advantage. The\nneed to combine risk estimates with utilities or other values of patient preferences is ignores.\n2. General comment (2): The paper ignores situations when the decision has to be performed\nregarding the choice on an optimal treatment out of a large set of options. For example a diabetic\npatient has to switch to a new therapy.\n3. The introduction identifies two problems: 1.) Unappropriated use of the term multivariate\nanalysis and 2.) Unprecise definitions of relevant estimands. It would be helpful to give a short\nexample of an unprecise estimand (after line 20).\n4. In 4.1. the prediction horizon is not clear.\n5. Regarding box 1, it may helpful to describe risk estimands and risk estimates. The need\nto define timeframes and events (Outcome and prediction horizon) as well as the predictors\nused. The measurement(s) used for prediction that characterize the individual, that is, that\nindividualize the predictions. The measurement(s) must be available at the moment(s) of\nintended use and measurement procedures must correspond to those in the setting of intended\nuse. Especially the history of the patient or a clinical status at time of the prediction.\n6. Chapter 2 uses the concept of utilities which is not mentioned in the introduction. There should\nbe a short sentence preparing the use of utilities in chapter 2.\n7. The paper does not touch the problem how to quantify the utilities. They may differ from\npatient to patient and may underly a multi-criteria problem (his own health, family aspects,\nprofessional aspects…).\n8. Especially, each taxonomic level of the risk estimand needs a different concept to quantify\nutilities. We also use estimands for the utilities to get correct estimates of the utilities.\n9. How helpful is the section between lines 99 and 109? The authors discuss very complex\nmodels which a non-trivial and in general unfamiliar background. Would it be possible to\nexemplify this in more detail? Maybe in an electronic methodological supplement?\n10. Decision-making is more than risk estimation. Why is the estimand of interest in this paper\nnot the final risk/utility combination. The title should take care about this by stating that the\nauthors study risk estimands.\n11. The examples given in lines 160 – 162 may also be seen as ordinal: Benign / borderline /\nmetastatic.\n12. It would be good to extend Box 1 from the estimand to the estimator and the estimate.\n13. At the end of the paper, I was a bit confused. What is the purpose of the paper? Who is the\naddressed reader? Is it the clinician who wants to apply CPMs? Is it the clinician who evaluates\nthe CPM? Is it the biostatistician starting the journey of CPM development? It would be good to\ngive to a clinician an example how to apply the taxonomy and how to gain advantage out of it.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03978-3	Reviewed - bmc_medicine	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 1 Date: 27 Jan 2025 Reviewer's report: my comments are well addressed.	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 1 Date: 27 Jan 2025 Reviewer's report: my comments are well addressed.	BMC	12916_2025_3978_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production\nof Clinical Prediction Models: defining a taxonomy of risk estimands\nVersion: 1 Date: 27 Jan 2025\nReviewer's report:\nmy comments are well addressed.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03978-3	Reviewed - bmc_medicine	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 1 Date: 02 Feb 2025 Reviewer: Ulrich Mansmann Reviewer's report: Many thanks for this important and timely paper. The use of prediction models to improve clinical decision making is growing and getting more complex. The provided manuscript provides guidance to structrure this growing field of research activities. I miss a few aspects in the paper and it would be great if you could incorporate them: 1.) Please mention, that one problem of multi-outcome prediction is also the availability of appropriate data on the multiple outcomes under study of high quality. Clinical trial data may be helpfull. It is not clear how data based of electronisc patients recourds may help 2.) A central concept in your manuscript are utilities. From where do you get the utilities? In your paper they are simply given. No reference for realistic utilities can be found. Or is each patient defining her/his own utilities? What are tools to elucidate utilities? 3.) At the end you mention dynamic simulation models to derive for a patient a decision between different options. Multi-state models may be useful but there are may other simulation techniques for patient histories which could help to settle complex scenarios. There is a causal issue if you compare different scenarios for a specific patient. An interesting tool to derive such dynamic models from observational data are model around the g-formula. 4.) You should also mention the large body of literature on multi-criteria decision making.	Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production of Clinical Prediction Models: defining a taxonomy of risk estimands Version: 1 Date: 02 Feb 2025 Reviewer: Ulrich Mansmann Reviewer's report: Many thanks for this important and timely paper. The use of prediction models to improve clinical decision making is growing and getting more complex. The provided manuscript provides guidance to structrure this growing field of research activities. I miss a few aspects in the paper and it would be great if you could incorporate them: 1.) Please mention, that one problem of multi-outcome prediction is also the availability of appropriate data on the multiple outcomes under study of high quality. Clinical trial data may be helpfull. It is not clear how data based of electronisc patients recourds may help 2.) A central concept in your manuscript are utilities. From where do you get the utilities? In your paper they are simply given. No reference for realistic utilities can be found. Or is each patient defining her/his own utilities? What are tools to elucidate utilities? 3.) At the end you mention dynamic simulation models to derive for a patient a decision between different options. Multi-state models may be useful but there are may other simulation techniques for patient histories which could help to settle complex scenarios. There is a causal issue if you compare different scenarios for a specific patient. An interesting tool to derive such dynamic models from observational data are model around the g-formula. 4.) You should also mention the large body of literature on multi-criteria decision making.	BMC	12916_2025_3978_ReviewerReport_V1_R3.pdf	{ "criticism": 3, "example": 0, "importance_and_relevance": 4, "materials_and_methods": 13, "praise": 4, "presentation_and_reporting": 6, "results_and_discussion": 3, "suggestion_and_solution": 6, "total": 20 }	{ "criticism": 0.15, "example": 0, "importance_and_relevance": 0.2, "materials_and_methods": 0.65, "praise": 0.2, "presentation_and_reporting": 0.3, "results_and_discussion": 0.15, "suggestion_and_solution": 0.3 }	1.95	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: A Decision-Analytical Perspective on Incorporating Multiple Outcomes in the Production\nof Clinical Prediction Models: defining a taxonomy of risk estimands\nVersion: 1 Date: 02 Feb 2025\nReviewer: Ulrich Mansmann\nReviewer's report:\nMany thanks for this important and timely paper. The use of prediction models to improve\nclinical decision making is growing and getting more complex. The provided manuscript\nprovides guidance to structrure this growing field of research activities.\nI miss a few aspects in the paper and it would be great if you could incorporate them:\n1.) Please mention, that one problem of multi-outcome prediction is also the availability of\nappropriate data on the multiple outcomes under study of high quality. Clinical trial data may\nbe helpfull. It is not clear how data based of electronisc patients recourds may help\n2.) A central concept in your manuscript are utilities. From where do you get the utilities? In\nyour paper they are simply given. No reference for realistic utilities can be found. Or is each\npatient defining her/his own utilities? What are tools to elucidate utilities?\n3.) At the end you mention dynamic simulation models to derive for a patient a decision between\ndifferent options. Multi-state models may be useful but there are may other\nsimulation techniques for patient histories which could help to settle complex scenarios. There\nis a causal issue if you compare different scenarios for a specific patient. An interesting tool to\nderive such dynamic models from observational data are model around the g-formula.\n4.) You should also mention the large body of literature on multi-criteria decision making.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 08 Oct 2024 Reviewer's report: This is a large scale multinational study of psychiatric sequelae of COVID-19. The paper is clearly written, the methods are reasonable and thoroughly described. A main strength of the authors’ analytical approach is to examine time-dependence of the effect of COVID-19 on mental health, something that has not often been done. The authors acknowledge some important limitations, in my opinion lack of info on acute illness severity is a major one. My main comments regard the interpretation of the findings. Comment #1 Lines 309-312: “Biologically, the SARS-CoV-2 virus can invade the central nervous system, leading to neuroinflammation and potential neural damage, facilitated by the virus’s interaction with angiotensin-converting enzyme 2 (ACE2) receptors on neurons and glial cells, disrupting normal brain function and possibly resulting in psychiatric symptoms.35-37” In my opinion, the references provided by the authors do not give any empirical support for CNS invasion in humans. They are from 2020-2021 and only include conjectures and the theoretical possibility of this happening. In fact, recent reviews (eg. https:// doi.org/10.1016/j.mib.2024.102474) state that the mechanisms behind neurological and psychiatric manifestations connected to SARS-CoV-2 are not understood. Invasion of the CNS by SARS-CoV-2 has poor empirical support in humans. It is not resolved if invasion occurs, let alone the mechanism of entry (through PNS or hematogenically). Well conducted clinical studies that I am aware of (eg. https://pubmed.ncbi.nlm.nih.gov/35604688/, there may be several others) do not find credible evidence of viral CNS invasion as a direct cause of neurological manifestation in acute COVID-19. It then seems far-fetched that they should play a role in long- term sequelae. Systemic inflammation not directly related to viral invasion of CNS seems to me an important mechanism of neurological manifestations in acute COVID-19, potentially resulting in long-term sequelae. The level of systemic inflammation is obviously related to acute illness severity and can be seen as especially relevant in primary infections in unvaccinated individuals, which the current study mainly examines. If the authors wish to stand by the statement above, that invasion of the CNS may be a driver of neuroinflammation, the authors have to provide references that clearly support this mechanism. Otherwise I suggest that they revise this. Comment #2 The authors discuss (page 16, first paragraph) several explanations to the short-lived elevation of risk for mental disorders. The authors rightly acknowledge the possibility of detection bias (p. 18, line 377 and onwards). I think the authors may consider to even bring up detection bias as a reasonable explanation to their findings alongside the others, rather than a limitation. The authors have made reasonable efforts to correct for detection bias by excluding prevalent cases. Still, mental disorders are severely underdiagnosed or are associated with considerable diagnostic delay. Arguments for this interpretation: 1. It is difficult to understand how COVID-19 could double the incidence of chronic health conditions such as neurodevelopmental disorders (how can ADHD or autism be of new onset in adults, for example) and dementia (an in most cases slowly progressive disorder with relatively well defined pathophysiology). 2. Considerable heterogeneity between countries in relative risks are difficult to explain by any SARS-CoV-2 / COVID-19 related mechanism. 3. There is no established knowledge about such a mechanism (see previous comment). 4. The short-lived effect is at least compatible with detection bias, the longer effect on dementia in the UK can simply reflect longer waiting times for dementia work-up. Bringing up the possibility that authors simply find ongoing but undiagnosed disorders has important implications for further research. If findings are to some extent driven by detection bias, we should not put large effort into finding putative biological mechanisms linking COVID-19 with neurodevelopmental disorders or dementia in adults. Comment #3 Conclusions: “This phenomenon may be attributed to the redirection of healthcare resources, diverse pandemic management strategies, and differing rates of socioeconomic recovery rather than the direct impact of COVID-19 itself.” Comment #4 Is it not a limitation that the authors study sequelae after COVID-19 in 2020-2021, i.e. mostly primary infections in unvaccinated people? Such infections are now a small proportion of all cases of COVID-19. It is known that re-infection or breakthrough infection is associated with lower risk of adverse outcomes in general. Thus findings cannot be generalized to current situation as authors are not able to take illness severity, vaccination or previous infection into account.	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 08 Oct 2024 Reviewer's report: This is a large scale multinational study of psychiatric sequelae of COVID-19. The paper is clearly written, the methods are reasonable and thoroughly described. A main strength of the authors’ analytical approach is to examine time-dependence of the effect of COVID-19 on mental health, something that has not often been done. The authors acknowledge some important limitations, in my opinion lack of info on acute illness severity is a major one. My main comments regard the interpretation of the findings. Comment #1 Lines 309-312: “Biologically, the SARS-CoV-2 virus can invade the central nervous system, leading to neuroinflammation and potential neural damage, facilitated by the virus’s interaction with angiotensin-converting enzyme 2 (ACE2) receptors on neurons and glial cells, disrupting normal brain function and possibly resulting in psychiatric symptoms.35-37” In my opinion, the references provided by the authors do not give any empirical support for CNS invasion in humans. They are from 2020-2021 and only include conjectures and the theoretical possibility of this happening. In fact, recent reviews (eg. https:// doi.org/10.1016/j.mib.2024.102474) state that the mechanisms behind neurological and psychiatric manifestations connected to SARS-CoV-2 are not understood. Invasion of the CNS by SARS-CoV-2 has poor empirical support in humans. It is not resolved if invasion occurs, let alone the mechanism of entry (through PNS or hematogenically). Well conducted clinical studies that I am aware of (eg. https://pubmed.ncbi.nlm.nih.gov/35604688/, there may be several others) do not find credible evidence of viral CNS invasion as a direct cause of neurological manifestation in acute COVID-19. It then seems far-fetched that they should play a role in long- term sequelae. Systemic inflammation not directly related to viral invasion of CNS seems to me an important mechanism of neurological manifestations in acute COVID-19, potentially resulting in long-term sequelae. The level of systemic inflammation is obviously related to acute illness severity and can be seen as especially relevant in primary infections in unvaccinated individuals, which the current study mainly examines. If the authors wish to stand by the statement above, that invasion of the CNS may be a driver of neuroinflammation, the authors have to provide references that clearly support this mechanism. Otherwise I suggest that they revise this. Comment #2 The authors discuss (page 16, first paragraph) several explanations to the short-lived elevation of risk for mental disorders. The authors rightly acknowledge the possibility of detection bias (p. 18, line 377 and onwards). I think the authors may consider to even bring up detection bias as a reasonable explanation to their findings alongside the others, rather than a limitation. The authors have made reasonable efforts to correct for detection bias by excluding prevalent cases. Still, mental disorders are severely underdiagnosed or are associated with considerable diagnostic delay. Arguments for this interpretation: 1. It is difficult to understand how COVID-19 could double the incidence of chronic health conditions such as neurodevelopmental disorders (how can ADHD or autism be of new onset in adults, for example) and dementia (an in most cases slowly progressive disorder with relatively well defined pathophysiology). 2. Considerable heterogeneity between countries in relative risks are difficult to explain by any SARS-CoV-2 / COVID-19 related mechanism. 3. There is no established knowledge about such a mechanism (see previous comment). 4. The short-lived effect is at least compatible with detection bias, the longer effect on dementia in the UK can simply reflect longer waiting times for dementia work-up. Bringing up the possibility that authors simply find ongoing but undiagnosed disorders has important implications for further research. If findings are to some extent driven by detection bias, we should not put large effort into finding putative biological mechanisms linking COVID-19 with neurodevelopmental disorders or dementia in adults. Comment #3 Conclusions: “This phenomenon may be attributed to the redirection of healthcare resources, diverse pandemic management strategies, and differing rates of socioeconomic recovery rather than the direct impact of COVID-19 itself.” Comment #4 Is it not a limitation that the authors study sequelae after COVID-19 in 2020-2021, i.e. mostly primary infections in unvaccinated people? Such infections are now a small proportion of all cases of COVID-19. It is known that re-infection or breakthrough infection is associated with lower risk of adverse outcomes in general. Thus findings cannot be generalized to current situation as authors are not able to take illness severity, vaccination or previous infection into account.	BMC	12916_2025_3952_ReviewerReport_V0_R1.pdf	{ "criticism": 7, "example": 4, "importance_and_relevance": 4, "materials_and_methods": 9, "praise": 5, "presentation_and_reporting": 2, "results_and_discussion": 8, "suggestion_and_solution": 5, "total": 38 }	{ "criticism": 0.18421052631578946, "example": 0.10526315789473684, "importance_and_relevance": 0.10526315789473684, "materials_and_methods": 0.23684210526315788, "praise": 0.13157894736842105, "presentation_and_reporting": 0.05263157894736842, "results_and_discussion": 0.21052631578947367, "suggestion_and_solution": 0.13157894736842105 }	1.157895	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 0 Date: 08 Oct 2024\nReviewer's report:\nThis is a large scale multinational study of psychiatric sequelae of COVID-19. The paper is\nclearly written, the methods are reasonable and thoroughly described. A main strength of the\nauthors’ analytical approach is to examine time-dependence of the effect of COVID-19 on\nmental health, something that has not often been done. The authors acknowledge some important\nlimitations, in my opinion lack of info on acute illness severity is a major one. My main\ncomments regard the interpretation of the findings.\nComment #1\nLines 309-312: “Biologically, the SARS-CoV-2 virus can invade the central nervous system,\nleading to neuroinflammation and potential neural damage, facilitated by the virus’s interaction\nwith angiotensin-converting enzyme 2 (ACE2) receptors on neurons and glial cells, disrupting\nnormal brain function and possibly resulting in psychiatric symptoms.35-37”\nIn my opinion, the references provided by the authors do not give any empirical support\nfor CNS invasion in humans. They are from 2020-2021 and only include conjectures\nand the theoretical possibility of this happening. In fact, recent reviews (eg. https://\ndoi.org/10.1016/j.mib.2024.102474) state that the mechanisms behind neurological and\npsychiatric manifestations connected to SARS-CoV-2 are not understood. Invasion of the CNS\nby SARS-CoV-2 has poor empirical support in humans. It is not resolved if invasion occurs, let\nalone the mechanism of entry (through PNS or hematogenically). Well conducted clinical studies\nthat I am aware of (eg. https://pubmed.ncbi.nlm.nih.gov/35604688/, there may be several\nothers) do not find credible evidence of viral CNS invasion as a direct cause of neurological\nmanifestation in acute COVID-19. It then seems far-fetched that they should play a role in long-\nterm sequelae. Systemic inflammation not directly related to viral invasion of CNS seems to\nme an important mechanism of neurological manifestations in acute COVID-19, potentially\nresulting in long-term sequelae. The level of systemic inflammation is obviously related to acute\nillness severity and can be seen as especially relevant in primary infections in unvaccinated\nindividuals, which the current study mainly examines.\nIf the authors wish to stand by the statement above, that invasion of the CNS may be a driver of\nneuroinflammation, the authors have to provide references that clearly support this mechanism.\nOtherwise I suggest that they revise this.\nComment #2\nThe authors discuss (page 16, first paragraph) several explanations to the short-lived elevation\nof risk for mental disorders. The authors rightly acknowledge the possibility of detection bias (p.\n18, line 377 and onwards). I think the authors may consider to even bring up detection bias as a\nreasonable explanation to their findings alongside the others, rather than a limitation. The authors\nhave made reasonable efforts to correct for detection bias by excluding prevalent cases. Still,\nmental disorders are severely underdiagnosed or are associated with considerable diagnostic\ndelay. Arguments for this interpretation: 1. It is difficult to understand how COVID-19 could\ndouble the incidence of chronic health conditions such as neurodevelopmental disorders (how\ncan ADHD or autism be of new onset in adults, for example) and dementia (an in most cases\nslowly progressive disorder with relatively well defined pathophysiology). 2. Considerable\nheterogeneity between countries in relative risks are difficult to explain by any SARS-CoV-2 /\nCOVID-19 related mechanism. 3. There is no established knowledge about such a mechanism\n(see previous comment). 4. The short-lived effect is at least compatible with detection bias,\nthe longer effect on dementia in the UK can simply reflect longer waiting times for dementia\nwork-up. Bringing up the possibility that authors simply find ongoing but undiagnosed disorders\nhas important implications for further research. If findings are to some extent driven by\ndetection bias, we should not put large effort into finding putative biological mechanisms linking\nCOVID-19 with neurodevelopmental disorders or dementia in adults.\nComment #3\nConclusions: “This phenomenon may be attributed to the redirection of healthcare resources,\ndiverse pandemic management strategies, and differing rates of socioeconomic recovery rather\nthan the direct impact of COVID-19 itself.”\nComment #4\nIs it not a limitation that the authors study sequelae after COVID-19 in 2020-2021, i.e. mostly\nprimary infections in unvaccinated people? Such infections are now a small proportion of all\ncases of COVID-19. It is known that re-infection or breakthrough infection is associated with\nlower risk of adverse outcomes in general. Thus findings cannot be generalized to current\nsituation as authors are not able to take illness severity, vaccination or previous infection into\naccount.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 21 Oct 2024 Reviewer's report: This study used data from five countries and investigated the short-, medium, and long-term risks of psychiatric and neuropsychiatric disorders following COVID-19 infection. The study is well-written, clear in introduction, results and discussions. I have some questions regarding the methods. 1. Line 189, “Only the first diagnosis of each outcome following the index date was used.” We know that psychiatric disorders are highly corelated with each other. Is it enough to only exclude those with targeted outcome? 2. Line 195, “. For the analysis of each outcome, individuals were excluded if they had the outcome of interest within 365 days prior to the start of the short- (the index date), medium-, and long-term observation to ensure the identification of incident cases.” Authors exclude individuals if they had the outcome of interest within one year prior to the start of the observations. But some psychiatric disorders can be exit for a longer period and are frequently relapsed. E.g., After having depression once, people may experience a relapse, either before recovery is complete or as a later, separate episode. How to address this issue? 3. Another question regarding comparators: How about if they had a diagnosis of COVID-19 during follow-up? When excluding individuals having the outcome of interest before observation, did the balances after propensity score matching remain?	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 21 Oct 2024 Reviewer's report: This study used data from five countries and investigated the short-, medium, and long-term risks of psychiatric and neuropsychiatric disorders following COVID-19 infection. The study is well-written, clear in introduction, results and discussions. I have some questions regarding the methods. 1. Line 189, “Only the first diagnosis of each outcome following the index date was used.” We know that psychiatric disorders are highly corelated with each other. Is it enough to only exclude those with targeted outcome? 2. Line 195, “. For the analysis of each outcome, individuals were excluded if they had the outcome of interest within 365 days prior to the start of the short- (the index date), medium-, and long-term observation to ensure the identification of incident cases.” Authors exclude individuals if they had the outcome of interest within one year prior to the start of the observations. But some psychiatric disorders can be exit for a longer period and are frequently relapsed. E.g., After having depression once, people may experience a relapse, either before recovery is complete or as a later, separate episode. How to address this issue? 3. Another question regarding comparators: How about if they had a diagnosis of COVID-19 during follow-up? When excluding individuals having the outcome of interest before observation, did the balances after propensity score matching remain?	BMC	12916_2025_3952_ReviewerReport_V0_R2.pdf	{ "criticism": 0, "example": 2, "importance_and_relevance": 0, "materials_and_methods": 6, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 5, "suggestion_and_solution": 0, "total": 15 }	{ "criticism": 0, "example": 0.13333333333333333, "importance_and_relevance": 0, "materials_and_methods": 0.4, "praise": 0.06666666666666667, "presentation_and_reporting": 0.06666666666666667, "results_and_discussion": 0.3333333333333333, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 0 Date: 21 Oct 2024\nReviewer's report:\nThis study used data from five countries and investigated the short-, medium, and long-term\nrisks of psychiatric and neuropsychiatric disorders following COVID-19 infection. The study\nis well-written, clear in introduction, results and discussions. I have some questions regarding\nthe methods.\n1. Line 189, “Only the first diagnosis of each outcome following the index date was used.” We\nknow that psychiatric disorders are highly corelated with each other. Is it enough to only exclude\nthose with targeted outcome?\n2. Line 195, “. For the analysis of each outcome, individuals were excluded if they had\nthe outcome of interest within 365 days prior to the start of the short- (the index date),\nmedium-, and long-term observation to ensure the identification of incident cases.” Authors\nexclude individuals if they had the outcome of interest within one year prior to the start of the\nobservations. But some psychiatric disorders can be exit for a longer period and are frequently\nrelapsed. E.g., After having depression once, people may experience a relapse, either before\nrecovery is complete or as a later, separate episode. How to address this issue?\n3. Another question regarding comparators: How about if they had a diagnosis of COVID-19\nduring follow-up? When excluding individuals having the outcome of interest before\nobservation, did the balances after propensity score matching remain?", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 31 Oct 2024 Reviewer's report: Authors should provide an abbreviated description of the databases they accessed across countries and are they comparable (e.g., do they represent diverse patients of socioeconomic backgrounds). - The authors noted that elevated risk for a psychiatric diagnosis the first 6 months following the infection. How do they know if the diagnosis is new versus continued? And those who had a diagnosis before and suddenly had exacerbation of symptoms? - The authors should consider completing separate analyses for those who had the infection during the peak of the pandemic (i.e., during social distancing and quarantine practices) as compared to towards the end or post-pandemic. I question if the initial elevated risk for psychiatric disorders are compounded by pandemic-related stressors such as reduced social supports, anxiety about pandemic-related disruptions to school/work/social life, etc. - What was the rational for the age cohorts (e.g. 18-24 years, 25-44 years, 45-64 years)? - Are sleep disorders defined as behavioral sleep disruptions (e.g. insomnia, hypersomnia, etc.) or sleep breathing disorders? - Neurodevelopmental disorders is a very broad group and is not very meaningful when authors collapse this all into one (Intellectual disability/IDD, autism and ADHD are all considered a developmental disorder but have different implications on functioning). Authors should strongly consider separating this into more common developmental disorders e.g., ADHD, IDD, Specific Learning Disability as it is much more likely some disorders are more evident with worsened symptoms (e.g., ADHD) whereas others neuropsychologist would not expect significant change following COVID (e.g. IDD). -Authors should include information on the cohort’s preexisting diagnoses (i.e., diagnoses pre- COVID infection) if they have the data, and if not, provide more in depth discussion about this.	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 0 Date: 31 Oct 2024 Reviewer's report: Authors should provide an abbreviated description of the databases they accessed across countries and are they comparable (e.g., do they represent diverse patients of socioeconomic backgrounds). - The authors noted that elevated risk for a psychiatric diagnosis the first 6 months following the infection. How do they know if the diagnosis is new versus continued? And those who had a diagnosis before and suddenly had exacerbation of symptoms? - The authors should consider completing separate analyses for those who had the infection during the peak of the pandemic (i.e., during social distancing and quarantine practices) as compared to towards the end or post-pandemic. I question if the initial elevated risk for psychiatric disorders are compounded by pandemic-related stressors such as reduced social supports, anxiety about pandemic-related disruptions to school/work/social life, etc. - What was the rational for the age cohorts (e.g. 18-24 years, 25-44 years, 45-64 years)? - Are sleep disorders defined as behavioral sleep disruptions (e.g. insomnia, hypersomnia, etc.) or sleep breathing disorders? - Neurodevelopmental disorders is a very broad group and is not very meaningful when authors collapse this all into one (Intellectual disability/IDD, autism and ADHD are all considered a developmental disorder but have different implications on functioning). Authors should strongly consider separating this into more common developmental disorders e.g., ADHD, IDD, Specific Learning Disability as it is much more likely some disorders are more evident with worsened symptoms (e.g., ADHD) whereas others neuropsychologist would not expect significant change following COVID (e.g. IDD). -Authors should include information on the cohort’s preexisting diagnoses (i.e., diagnoses pre- COVID infection) if they have the data, and if not, provide more in depth discussion about this.	BMC	12916_2025_3952_ReviewerReport_V0_R3.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 5, "praise": 0, "presentation_and_reporting": 2, "results_and_discussion": 1, "suggestion_and_solution": 4, "total": 15 }	{ "criticism": 0.06666666666666667, "example": 0, "importance_and_relevance": 0.06666666666666667, "materials_and_methods": 0.3333333333333333, "praise": 0, "presentation_and_reporting": 0.13333333333333333, "results_and_discussion": 0.06666666666666667, "suggestion_and_solution": 0.26666666666666666 }	0.933333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 0 Date: 31 Oct 2024\nReviewer's report:\nAuthors should provide an abbreviated description of the databases they accessed across\ncountries and are they comparable (e.g., do they represent diverse patients of socioeconomic\nbackgrounds).\n- The authors noted that elevated risk for a psychiatric diagnosis the first 6 months following\nthe infection. How do they know if the diagnosis is new versus continued? And those who had\na diagnosis before and suddenly had exacerbation of symptoms?\n- The authors should consider completing separate analyses for those who had the infection\nduring the peak of the pandemic (i.e., during social distancing and quarantine practices) as\ncompared to towards the end or post-pandemic. I question if the initial elevated risk for\npsychiatric disorders are compounded by pandemic-related stressors such as reduced social\nsupports, anxiety about pandemic-related disruptions to school/work/social life, etc.\n- What was the rational for the age cohorts (e.g. 18-24 years, 25-44 years, 45-64 years)?\n- Are sleep disorders defined as behavioral sleep disruptions (e.g. insomnia, hypersomnia, etc.)\nor sleep breathing disorders?\n- Neurodevelopmental disorders is a very broad group and is not very meaningful when authors\ncollapse this all into one (Intellectual disability/IDD, autism and ADHD are all considered a\ndevelopmental disorder but have different implications on functioning). Authors should strongly\nconsider separating this into more common developmental disorders e.g., ADHD, IDD, Specific\nLearning Disability as it is much more likely some disorders are more evident with worsened\nsymptoms (e.g., ADHD) whereas others neuropsychologist would not expect significant change\nfollowing COVID (e.g. IDD).\n-Authors should include information on the cohort’s preexisting diagnoses (i.e., diagnoses pre-\nCOVID infection) if they have the data, and if not, provide more in depth discussion about this.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 11 Dec 2024 Reviewer's report: I thank the authors for thoroughly addressing my comments. I am satisfied with their answers and revisions.	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 11 Dec 2024 Reviewer's report: I thank the authors for thoroughly addressing my comments. I am satisfied with their answers and revisions.	BMC	12916_2025_3952_ReviewerReport_V1_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 1 Date: 11 Dec 2024\nReviewer's report:\nI thank the authors for thoroughly addressing my comments. I am satisfied with their answers\nand revisions.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 13 Dec 2024 Reviewer's report: I have no further comments.	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 13 Dec 2024 Reviewer's report: I have no further comments.	BMC	12916_2025_3952_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 1 Date: 13 Dec 2024\nReviewer's report:\nI have no further comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03952-z	Reviewed - bmc_medicine	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 08 Jan 2025 Reviewer's report: The manuscript “Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study” outlines a study that includes data from electronic medical records across countries to examine risk of psychiatric diagnoses including depression, anxiety disorder, and alcohol abuse/dependence, in addition to others such as sleep disorders, dementia and neurodevelopmental disorders within the first 6 months 6-12 months or 12-24 months post infection. Overall, I believe the authors addressed my concerns to their best ability by expanding their discussion/limitations sections or clarifying with appropriate references/supplemental information. I do not have further comments at this time.	Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study Version: 1 Date: 08 Jan 2025 Reviewer's report: The manuscript “Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A multinational cohort study” outlines a study that includes data from electronic medical records across countries to examine risk of psychiatric diagnoses including depression, anxiety disorder, and alcohol abuse/dependence, in addition to others such as sleep disorders, dementia and neurodevelopmental disorders within the first 6 months 6-12 months or 12-24 months post infection. Overall, I believe the authors addressed my concerns to their best ability by expanding their discussion/limitations sections or clarifying with appropriate references/supplemental information. I do not have further comments at this time.	BMC	12916_2025_3952_ReviewerReport_V1_R3.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 1, "total": 3 }	{ "criticism": 0.3333333333333333, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.3333333333333333, "praise": 0.3333333333333333, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0.3333333333333333, "suggestion_and_solution": 0.3333333333333333 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study\nVersion: 1 Date: 08 Jan 2025\nReviewer's report:\nThe manuscript “Psychiatric and neuropsychiatric sequelae of COVID-19 within two years: A\nmultinational cohort study” outlines a study that includes data from electronic medical records\nacross countries to examine risk of psychiatric diagnoses including depression, anxiety disorder,\nand alcohol abuse/dependence, in addition to others such as sleep disorders, dementia and\nneurodevelopmental disorders within the first 6 months 6-12 months or 12-24 months post\ninfection. Overall, I believe the authors addressed my concerns to their best ability by expanding\ntheir discussion/limitations sections or clarifying with appropriate references/supplemental\ninformation. I do not have further comments at this time.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03958-7	Reviewed - bmc_medicine	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 08 Oct 2024 Reviewer: Jan Št#pán Reviewer's report: Previously, the authors reported that a single injection of denosumab may be used to improve male fertility potential in a sub-population of infertile men. This study provides evidence that a single injection of denosumab in infertile men has no major persistent impact on bone or mineral homeostasis. The hypothesis to be tested is well defined. The methods, data and analysis are described in sufficient detail to be reproduced, ant they adequately test the hypothesis and support the conclusions. Appropriate figures have been provided. The information provided by the paper is clinically relevant. Minor comment Please, consider mentioning absence of other biomarkers in the limitations of the study. A more reliable marker of osteoblast activity, such as PINP was not provided. Total serum alkaline phosphatase was measured, but is it known whether there any effects of denosumab on the liver isoform? Were the extended effects of denosumab on PTH accompanied by changes in FGF23 and 1,25(OH)2D3? Serum betaCTX could provide evidence on suppression of osteoclastic bone resorption.	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 08 Oct 2024 Reviewer: Jan Št#pán Reviewer's report: Previously, the authors reported that a single injection of denosumab may be used to improve male fertility potential in a sub-population of infertile men. This study provides evidence that a single injection of denosumab in infertile men has no major persistent impact on bone or mineral homeostasis. The hypothesis to be tested is well defined. The methods, data and analysis are described in sufficient detail to be reproduced, ant they adequately test the hypothesis and support the conclusions. Appropriate figures have been provided. The information provided by the paper is clinically relevant. Minor comment Please, consider mentioning absence of other biomarkers in the limitations of the study. A more reliable marker of osteoblast activity, such as PINP was not provided. Total serum alkaline phosphatase was measured, but is it known whether there any effects of denosumab on the liver isoform? Were the extended effects of denosumab on PTH accompanied by changes in FGF23 and 1,25(OH)2D3? Serum betaCTX could provide evidence on suppression of osteoclastic bone resorption.	BMC	12916_2025_3958_ReviewerReport_V0_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 6, "praise": 4, "presentation_and_reporting": 4, "results_and_discussion": 1, "suggestion_and_solution": 2, "total": 11 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5454545454545454, "praise": 0.36363636363636365, "presentation_and_reporting": 0.36363636363636365, "results_and_discussion": 0.09090909090909091, "suggestion_and_solution": 0.18181818181818182 }	1.545455	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights\nfrom a Pilot Intervention Study and a Randomized Controlled Trial\nVersion: 0 Date: 08 Oct 2024\nReviewer: Jan Št#pán\nReviewer's report:\nPreviously, the authors reported that a single injection of denosumab may be used to improve\nmale fertility potential in a sub-population of infertile men. This study provides evidence that\na single injection of denosumab in infertile men has no major persistent impact on bone or\nmineral homeostasis. The hypothesis to be tested is well defined. The methods, data and analysis\nare described in sufficient detail to be reproduced, ant they adequately test the hypothesis and\nsupport the conclusions. Appropriate figures have been provided. The information provided by\nthe paper is clinically relevant.\nMinor comment\nPlease, consider mentioning absence of other biomarkers in the limitations of the study. A more\nreliable marker of osteoblast activity, such as PINP was not provided. Total serum alkaline\nphosphatase was measured, but is it known whether there any effects of denosumab on the liver\nisoform? Were the extended effects of denosumab on PTH accompanied by changes in FGF23\nand 1,25(OH)2D3? Serum betaCTX could provide evidence on suppression of osteoclastic bone\nresorption.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03958-7	Reviewed - bmc_medicine	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 24 Oct 2024 Reviewer's report: The authors present the results of a pilot and a RCT study of a single dosage of denosumab on infertile men to demonstrate changes in serum and bone markers representing bone metabolism. The manuscript is well-structured, and the data is presented clearly. Addressing some points will improve the overall quality of the manuscript: Abstract: The background would benefit from clearly stating the rationale for studying denosumab treatment in infertile men in the first place. Introduction: It could be elaborated a bit more how denosumab improves male fertility to underline the potential of denosumab application in infertile men. Results: Page 7 the authors state the mean age with 32.4 while in table 1A it is 33.4. Please double check the mean age and adjust accordingly. Please structure the figures in the order of the result presentation from A-F according to which result is first described. This applies to all figures. Also, assure that the text refers to the figures it is referring to. Please add significances in the figures. On page 10 the authors state that data on albumin levels are not included, however, table 3A and B show albumin levels. Is this different data than the one the authors refer to within the text? One could consider visualizing total BMD, hip and spine BMD in figure 4 and name z-scores only in the text to visualize the significant differences. Vitamin D levels are reported in tables 3 A and B – figure 4A seems redundant if this is the same levels reported here, consider removing it. Please refer to placebo group throughout the manuscript including the figures to keep consistency. Discussion: More detailed information on the suggested relationship between impaired fertility and disturbances in mineral homeostasis would be appreciated.	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 24 Oct 2024 Reviewer's report: The authors present the results of a pilot and a RCT study of a single dosage of denosumab on infertile men to demonstrate changes in serum and bone markers representing bone metabolism. The manuscript is well-structured, and the data is presented clearly. Addressing some points will improve the overall quality of the manuscript: Abstract: The background would benefit from clearly stating the rationale for studying denosumab treatment in infertile men in the first place. Introduction: It could be elaborated a bit more how denosumab improves male fertility to underline the potential of denosumab application in infertile men. Results: Page 7 the authors state the mean age with 32.4 while in table 1A it is 33.4. Please double check the mean age and adjust accordingly. Please structure the figures in the order of the result presentation from A-F according to which result is first described. This applies to all figures. Also, assure that the text refers to the figures it is referring to. Please add significances in the figures. On page 10 the authors state that data on albumin levels are not included, however, table 3A and B show albumin levels. Is this different data than the one the authors refer to within the text? One could consider visualizing total BMD, hip and spine BMD in figure 4 and name z-scores only in the text to visualize the significant differences. Vitamin D levels are reported in tables 3 A and B – figure 4A seems redundant if this is the same levels reported here, consider removing it. Please refer to placebo group throughout the manuscript including the figures to keep consistency. Discussion: More detailed information on the suggested relationship between impaired fertility and disturbances in mineral homeostasis would be appreciated.	BMC	12916_2025_3958_ReviewerReport_V0_R2.pdf	{ "criticism": 2, "example": 4, "importance_and_relevance": 0, "materials_and_methods": 7, "praise": 1, "presentation_and_reporting": 14, "results_and_discussion": 3, "suggestion_and_solution": 10, "total": 16 }	{ "criticism": 0.125, "example": 0.25, "importance_and_relevance": 0, "materials_and_methods": 0.4375, "praise": 0.0625, "presentation_and_reporting": 0.875, "results_and_discussion": 0.1875, "suggestion_and_solution": 0.625 }	2.5625	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights\nfrom a Pilot Intervention Study and a Randomized Controlled Trial\nVersion: 0 Date: 24 Oct 2024\nReviewer's report:\nThe authors present the results of a pilot and a RCT study of a single dosage of denosumab on\ninfertile men to demonstrate changes in serum and bone markers representing bone metabolism.\nThe manuscript is well-structured, and the data is presented clearly. Addressing some points\nwill improve the overall quality of the manuscript:\nAbstract:\nThe background would benefit from clearly stating the rationale for studying denosumab\ntreatment in infertile men in the first place.\nIntroduction:\nIt could be elaborated a bit more how denosumab improves male fertility to underline the\npotential of denosumab application in infertile men.\nResults:\nPage 7 the authors state the mean age with 32.4 while in table 1A it is 33.4. Please double check\nthe mean age and adjust accordingly.\nPlease structure the figures in the order of the result presentation from A-F according to which\nresult is first described. This applies to all figures. Also, assure that the text refers to the figures\nit is referring to.\nPlease add significances in the figures.\nOn page 10 the authors state that data on albumin levels are not included, however, table 3A and\nB show albumin levels. Is this different data than the one the authors refer to within the text?\nOne could consider visualizing total BMD, hip and spine BMD in figure 4 and name z-scores\nonly in the text to visualize the significant differences.\nVitamin D levels are reported in tables 3 A and B – figure 4A seems redundant if this is the\nsame levels reported here, consider removing it.\nPlease refer to placebo group throughout the manuscript including the figures to keep\nconsistency.\nDiscussion:\nMore detailed information on the suggested relationship between impaired fertility and\ndisturbances in mineral homeostasis would be appreciated.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03958-7	Reviewed - bmc_medicine	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 28 Oct 2024 Reviewer: Alexander Shinkov Reviewer's report: Denosumab is currently a first/second line antiresorptive drug. It exerts a powerful inhibition of osteoclast maturation and function by switching off the RANKL/RANK signalling. The imediate effect is a drop in the calcium and phospate influx into the circulation and a secondary increase in PTH secretion. These effects are intrinsic to the drug and population-independent with sume variations in the size of the effect depending on bone turnover. The authors of the manuscript investigate these effects in a young male population in a two- part interventional trial. The results however are not new and do not contribute significantly to the current knowledge. I have some particular comments: 1. 1,25(OH)2D was measured at baseline but not followed. What was the rationale? 2. CTX and P1NP were evidently measured in the "randomized control trial" and they were not described in the Methods section. These markers are important and should be a major finding (though no novelty). Moreover, the authors stated that the reduction in the bone remodelling in their study was much less than reported in PM women. That is not really true. Alkaline phosphatase never drops as much as P1NP does since the bone is by far not the only source. A reduction of 25% is what is typically seen in DMAb treated osteoporotic subjects. However, the discussion would look different if P1NP is analyzed as it decreases by 70-80%, according to the results section. That means that the reduction in bone remodelling in the studied young male cohort is similar to that among older osteoporotic subjects, 3. The change in BMD is very small and apparently below the LSC, that is clinically insignificant. 4. The second timepoint in the follow up in the "randomized control trial" is 160 days which is before the bioavailability of DMAb drops and an increase in bone turnover is to be expectd. Therefore, no conclusions concerning the lack of suck increas e are relevant. 5. The Mixed model for repeat measurements is a robust test but still 12 participants is a small count and any statistic should be interpreteded with caution. 6. No chahge in 25(OH)D is to be expected to be caused by DMAb, especially when supplemented.. 7. "Therefore, understanding the effects of denosumab on mineral homeostasis in infertile men may provide valuable insights into the endocrine crosstalk between reproductive function and bone metabolism." No data in the manuscript crroborates this statement. Some minor ones: Background - RANKL is both membrane-bound and soluble Page 8, second paragraph - manner to blinded... Please. correct. Page 9, 49+50=99, not 98. Please, correct.	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 28 Oct 2024 Reviewer: Alexander Shinkov Reviewer's report: Denosumab is currently a first/second line antiresorptive drug. It exerts a powerful inhibition of osteoclast maturation and function by switching off the RANKL/RANK signalling. The imediate effect is a drop in the calcium and phospate influx into the circulation and a secondary increase in PTH secretion. These effects are intrinsic to the drug and population-independent with sume variations in the size of the effect depending on bone turnover. The authors of the manuscript investigate these effects in a young male population in a two- part interventional trial. The results however are not new and do not contribute significantly to the current knowledge. I have some particular comments: 1. 1,25(OH)2D was measured at baseline but not followed. What was the rationale? 2. CTX and P1NP were evidently measured in the "randomized control trial" and they were not described in the Methods section. These markers are important and should be a major finding (though no novelty). Moreover, the authors stated that the reduction in the bone remodelling in their study was much less than reported in PM women. That is not really true. Alkaline phosphatase never drops as much as P1NP does since the bone is by far not the only source. A reduction of 25% is what is typically seen in DMAb treated osteoporotic subjects. However, the discussion would look different if P1NP is analyzed as it decreases by 70-80%, according to the results section. That means that the reduction in bone remodelling in the studied young male cohort is similar to that among older osteoporotic subjects, 3. The change in BMD is very small and apparently below the LSC, that is clinically insignificant. 4. The second timepoint in the follow up in the "randomized control trial" is 160 days which is before the bioavailability of DMAb drops and an increase in bone turnover is to be expectd. Therefore, no conclusions concerning the lack of suck increas e are relevant. 5. The Mixed model for repeat measurements is a robust test but still 12 participants is a small count and any statistic should be interpreteded with caution. 6. No chahge in 25(OH)D is to be expected to be caused by DMAb, especially when supplemented.. 7. "Therefore, understanding the effects of denosumab on mineral homeostasis in infertile men may provide valuable insights into the endocrine crosstalk between reproductive function and bone metabolism." No data in the manuscript crroborates this statement. Some minor ones: Background - RANKL is both membrane-bound and soluble Page 8, second paragraph - manner to blinded... Please. correct. Page 9, 49+50=99, not 98. Please, correct.	BMC	12916_2025_3958_ReviewerReport_V0_R4.pdf	{ "criticism": 5, "example": 2, "importance_and_relevance": 3, "materials_and_methods": 14, "praise": 2, "presentation_and_reporting": 5, "results_and_discussion": 6, "suggestion_and_solution": 5, "total": 33 }	{ "criticism": 0.15151515151515152, "example": 0.06060606060606061, "importance_and_relevance": 0.09090909090909091, "materials_and_methods": 0.42424242424242425, "praise": 0.06060606060606061, "presentation_and_reporting": 0.15151515151515152, "results_and_discussion": 0.18181818181818182, "suggestion_and_solution": 0.15151515151515152 }	1.272727	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights\nfrom a Pilot Intervention Study and a Randomized Controlled Trial\nVersion: 0 Date: 28 Oct 2024\nReviewer: Alexander Shinkov\nReviewer's report:\nDenosumab is currently a first/second line antiresorptive drug. It exerts a powerful inhibition of\nosteoclast maturation and function by switching off the RANKL/RANK signalling. The imediate\neffect is a drop in the calcium and phospate influx into the circulation and a secondary increase\nin PTH secretion. These effects are intrinsic to the drug and population-independent with sume\nvariations in the size of the effect depending on bone turnover.\nThe authors of the manuscript investigate these effects in a young male population in a two-\npart interventional trial.\nThe results however are not new and do not contribute significantly to the current knowledge.\nI have some particular comments:\n1. 1,25(OH)2D was measured at baseline but not followed. What was the rationale?\n2. CTX and P1NP were evidently measured in the \"randomized control trial\" and they were not\ndescribed in the Methods section. These markers are important and should be a major finding\n(though no novelty). Moreover, the authors stated that the reduction in the bone remodelling\nin their study was much less than reported in PM women. That is not really true. Alkaline\nphosphatase never drops as much as P1NP does since the bone is by far not the only source.\nA reduction of 25% is what is typically seen in DMAb treated osteoporotic subjects. However,\nthe discussion would look different if P1NP is analyzed as it decreases by 70-80%, according\nto the results section. That means that the reduction in bone remodelling in the studied young\nmale cohort is similar to that among older osteoporotic subjects,\n3. The change in BMD is very small and apparently below the LSC, that is clinically\ninsignificant.\n4. The second timepoint in the follow up in the \"randomized control trial\" is 160 days which\nis before the bioavailability of DMAb drops and an increase in bone turnover is to be expectd.\nTherefore, no conclusions concerning the lack of suck increas e are relevant.\n5. The Mixed model for repeat measurements is a robust test but still 12 participants is a small\ncount and any statistic should be interpreteded with caution.\n6. No chahge in 25(OH)D is to be expected to be caused by DMAb, especially when\nsupplemented..\n7. \"Therefore, understanding the effects of denosumab on mineral homeostasis in infertile men\nmay provide valuable insights into the endocrine crosstalk between reproductive function and\nbone metabolism.\" No data in the manuscript crroborates this statement.\nSome minor ones:\nBackground - RANKL is both membrane-bound and soluble\nPage 8, second paragraph - manner to blinded... Please. correct.\nPage 9, 49+50=99, not 98. Please, correct.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03958-7	Reviewed - bmc_medicine	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 15 Nov 2024 Reviewer's report:	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 0 Date: 15 Nov 2024 Reviewer's report:	BMC	12916_2025_3958_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights\nfrom a Pilot Intervention Study and a Randomized Controlled Trial\nVersion: 0 Date: 15 Nov 2024\nReviewer's report:", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03958-7	Reviewed - bmc_medicine	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 1 Date: 09 Jan 2025 Reviewer's report: The authors have thoroughly addressed all points raised. No further comments remain. Thank you.	Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights from a Pilot Intervention Study and a Randomized Controlled Trial Version: 1 Date: 09 Jan 2025 Reviewer's report: The authors have thoroughly addressed all points raised. No further comments remain. Thank you.	BMC	12916_2025_3958_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 3 }	{ "criticism": 0.3333333333333333, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.3333333333333333, "praise": 0.3333333333333333, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Effect of a Single-dose Denosumab on Mineral Homeostasis in Infertile Men: Insights\nfrom a Pilot Intervention Study and a Randomized Controlled Trial\nVersion: 1 Date: 09 Jan 2025\nReviewer's report:\nThe authors have thoroughly addressed all points raised. No further comments remain. Thank\nyou.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 02 Oct 2024 Reviewer: David N. Dhanraj Reviewer's report: This was a well written study with very reasonable study design. I think it might be a good discuss a little more on next steps for implementation and/or future study opportunities.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 02 Oct 2024 Reviewer: David N. Dhanraj Reviewer's report: This was a well written study with very reasonable study design. I think it might be a good discuss a little more on next steps for implementation and/or future study opportunities.	BMC	12916_2025_3966_ReviewerReport_V0_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.5, "materials_and_methods": 0.5, "praise": 1, "presentation_and_reporting": 0.5, "results_and_discussion": 0, "suggestion_and_solution": 0.5 }	3	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 0 Date: 02 Oct 2024\nReviewer: David N. Dhanraj\nReviewer's report:\nThis was a well written study with very reasonable study design. I think it might be a good\ndiscuss a little more on next steps for implementation and/or future study opportunities.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 01 Nov 2024 Reviewer's report: The study of Meng et al compares three strategies of the screening of familiar hypercholesterolemia in the population and propose the implementation of universal FH genetic screening in order to improve cost-effectiveness in the current management of the disease diagnosis and screening. The manuscript is well written and explains the aim, as well as study design and modeling. I have no major objections. Minor changes should be done in order to improve clear delivery of the results to readers. I would propose to include a summary paragraph at the beginning of the discussion, that would contain all major as well as minor findings.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 01 Nov 2024 Reviewer's report: The study of Meng et al compares three strategies of the screening of familiar hypercholesterolemia in the population and propose the implementation of universal FH genetic screening in order to improve cost-effectiveness in the current management of the disease diagnosis and screening. The manuscript is well written and explains the aim, as well as study design and modeling. I have no major objections. Minor changes should be done in order to improve clear delivery of the results to readers. I would propose to include a summary paragraph at the beginning of the discussion, that would contain all major as well as minor findings.	BMC	12916_2025_3966_ReviewerReport_V0_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 2, "praise": 1, "presentation_and_reporting": 2, "results_and_discussion": 2, "suggestion_and_solution": 2, "total": 5 }	{ "criticism": 0.2, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.4, "praise": 0.2, "presentation_and_reporting": 0.4, "results_and_discussion": 0.4, "suggestion_and_solution": 0.4 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 0 Date: 01 Nov 2024\nReviewer's report:\nThe study of Meng et al compares three strategies of the screening of familiar\nhypercholesterolemia in the population and propose the implementation of universal FH genetic\nscreening in order to improve cost-effectiveness in the current management of the disease\ndiagnosis and screening. The manuscript is well written and explains the aim, as well as study\ndesign and modeling.\nI have no major objections.\nMinor changes should be done in order to improve clear delivery of the results to readers. I\nwould propose to include a summary paragraph at the beginning of the discussion, that would\ncontain all major as well as minor findings.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 01 Dec 2024 Reviewer's report: This is an important article on the cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China compared universal cholesterol screening or current passive screening strategies. Happy with the methodology, results and discussion. A few suggestions are: 1. What are the implications of the findings and how does that translate from research to policy and practice? 2. The result section needs to be more simplified to make the comparison between the screening tests.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 01 Dec 2024 Reviewer's report: This is an important article on the cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China compared universal cholesterol screening or current passive screening strategies. Happy with the methodology, results and discussion. A few suggestions are: 1. What are the implications of the findings and how does that translate from research to policy and practice? 2. The result section needs to be more simplified to make the comparison between the screening tests.	BMC	12916_2025_3966_ReviewerReport_V0_R5.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 2, "materials_and_methods": 3, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 3, "suggestion_and_solution": 1, "total": 6 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.3333333333333333, "materials_and_methods": 0.5, "praise": 0.3333333333333333, "presentation_and_reporting": 0.16666666666666666, "results_and_discussion": 0.5, "suggestion_and_solution": 0.16666666666666666 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 0 Date: 01 Dec 2024\nReviewer's report:\nThis is an important article on the cost-effectiveness of universal genetic screening for familial\nhypercholesterolemia in young adults aged 18-40 years in China compared universal cholesterol\nscreening or current passive screening strategies. Happy with the methodology, results and\ndiscussion. A few suggestions are:\n1. What are the implications of the findings and how does that translate from research to policy\nand practice?\n2. The result section needs to be more simplified to make the comparison between the screening\ntests.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 09 Dec 2024 Reviewer: Sandeep S. Nayak Reviewer's report: This study uses a decision-analytic Markov model to compare universal genetic screening, universal cholesterol screening, and current passive screening strategies for FH in young adults. The authors demonstrate that universal genetic screening is cost-effective, especially when initiated at younger ages. Sensitivity analyses validate the robustness of the results, and threshold analyses highlight critical factors influencing cost-effectiveness, such as genetic testing costs and FH prevalence. Strengths: Relevance: The study addresses a critical gap in FH management and provides evidence for health policy in a populous country like China. Comprehensive Modeling: The authors incorporate long-term outcomes, cost parameters, and utility adjustments, which strengthen the analysis. Sensitivity Analyses: Extensive one-way and probabilistic sensitivity analyses add robustness to the findings. Weaknesses: Transparency in Model Assumptions: Some assumptions, such as the FH prevalence and treatment adherence rates, lack justification or supporting data. Validation of Parameters: The manuscript does not sufficiently validate key model inputs, such as transition probabilities and sensitivity estimates for genetic testing. Generality of Results: Practical challenges, such as limited healthcare access in rural areas, are mentioned but not incorporated into the model. Title: The title is clear, concise, and accurately reflects the study's scope. Abstract: Strengths: The abstract is well-structured, providing an informative overview of the study's background, methodology, results, and implications. Suggestions: Explicitly state the Markov model’s time horizon. Include sensitivity analysis highlights (e.g., the most impactful parameters). Introduction: Strengths: The introduction effectively frames the problem of FH underdiagnosis and its economic burden in China. It also justifies the need for universal genetic screening. Suggestions: Clearly define the research question at the end of the introduction to emphasize the study’s primary focus. Briefly discuss previous studies on FH screening in low- and middle-income countries to provide a broader context. Methods: Model Structure: Strengths: The combination of decision tree and Markov models is appropriate for lifetime cost- effectiveness analyses. Suggestions: Include a diagram of the decision tree for clarity (not just the Markov model). Explain the rationale for the one-year cycle length and justify whether smaller intervals could yield more precise results. Model Inputs: Transition Probabilities: Provide more details on the derivation of transition probabilities for CHD states. Were these validated against real-world data? Costs: Clarify how the costs for post-CHD management were adjusted for inflation or regional variability. Utility Weights: Specify how age-specific utilities were adjusted for individuals transitioning to the "alive with CHD" state. Screening Strategies: The paper mentions a 1% coverage rate for current passive screening. Provide evidence or references supporting this assumption. Sensitivity Analyses: Strengths: One-way and probabilistic sensitivity analyses are comprehensive. Suggestions: Clarify the rationale for parameter ranges in one-way sensitivity analyses. For example, why is genetic testing sensitivity varied between 45%-100%? Results: Presentation: The results are well-structured and supported by tables and figures. For Table 2, include a summary of key parameters, such as the number needed to screen to prevent one CHD event. Granularity: Include subgroup analyses, such as cost-effectiveness differences between urban and rural populations, to enhance generalizability. Provide individual ICER values for each age group in a supplemental table for clarity. Figures: Figures are clear, but sensitivity analysis results could be more informative if the tornado diagram included a ranking of the most impactful parameters. Discussion: Interpretation of Results: While the discussion highlights the advantages of universal genetic screening, avoid overstating its feasibility without considering infrastructural and economic constraints in rural China. Comparison with Literature: Compare findings more extensively with global cost-effectiveness studies to position the study in a broader context. Limitations: The limitations section is well-written but should address the exclusion of rural healthcare constraints in the model. For example, low testing uptake rates in rural areas could affect the cost-effectiveness. Policy Implications: Include a brief discussion on implementation strategies, such as subsidizing genetic testing or integrating it with existing public health programs. Conclusion: Restate the study's key findings, particularly emphasizing age-specific differences in cost- effectiveness. Avoid definitive claims about feasibility until practical challenges are addressed or modeled. Figures and Tables: Strengths: Figures and tables are well-designed and adequately complement the text. Suggestions: Add confidence intervals to ICER estimates in the tables. Ensure all axes are labeled clearly in sensitivity analysis figures. Additional Suggestions: Model Validation: Discuss any efforts to validate the Markov model (e.g., comparison with real- world data or prior models). Data Availability: Include raw input parameters and results in supplementary materials for transparency and reproducibility.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 09 Dec 2024 Reviewer: Sandeep S. Nayak Reviewer's report: This study uses a decision-analytic Markov model to compare universal genetic screening, universal cholesterol screening, and current passive screening strategies for FH in young adults. The authors demonstrate that universal genetic screening is cost-effective, especially when initiated at younger ages. Sensitivity analyses validate the robustness of the results, and threshold analyses highlight critical factors influencing cost-effectiveness, such as genetic testing costs and FH prevalence. Strengths: Relevance: The study addresses a critical gap in FH management and provides evidence for health policy in a populous country like China. Comprehensive Modeling: The authors incorporate long-term outcomes, cost parameters, and utility adjustments, which strengthen the analysis. Sensitivity Analyses: Extensive one-way and probabilistic sensitivity analyses add robustness to the findings. Weaknesses: Transparency in Model Assumptions: Some assumptions, such as the FH prevalence and treatment adherence rates, lack justification or supporting data. Validation of Parameters: The manuscript does not sufficiently validate key model inputs, such as transition probabilities and sensitivity estimates for genetic testing. Generality of Results: Practical challenges, such as limited healthcare access in rural areas, are mentioned but not incorporated into the model. Title: The title is clear, concise, and accurately reflects the study's scope. Abstract: Strengths: The abstract is well-structured, providing an informative overview of the study's background, methodology, results, and implications. Suggestions: Explicitly state the Markov model’s time horizon. Include sensitivity analysis highlights (e.g., the most impactful parameters). Introduction: Strengths: The introduction effectively frames the problem of FH underdiagnosis and its economic burden in China. It also justifies the need for universal genetic screening. Suggestions: Clearly define the research question at the end of the introduction to emphasize the study’s primary focus. Briefly discuss previous studies on FH screening in low- and middle-income countries to provide a broader context. Methods: Model Structure: Strengths: The combination of decision tree and Markov models is appropriate for lifetime cost- effectiveness analyses. Suggestions: Include a diagram of the decision tree for clarity (not just the Markov model). Explain the rationale for the one-year cycle length and justify whether smaller intervals could yield more precise results. Model Inputs: Transition Probabilities: Provide more details on the derivation of transition probabilities for CHD states. Were these validated against real-world data? Costs: Clarify how the costs for post-CHD management were adjusted for inflation or regional variability. Utility Weights: Specify how age-specific utilities were adjusted for individuals transitioning to the "alive with CHD" state. Screening Strategies: The paper mentions a 1% coverage rate for current passive screening. Provide evidence or references supporting this assumption. Sensitivity Analyses: Strengths: One-way and probabilistic sensitivity analyses are comprehensive. Suggestions: Clarify the rationale for parameter ranges in one-way sensitivity analyses. For example, why is genetic testing sensitivity varied between 45%-100%? Results: Presentation: The results are well-structured and supported by tables and figures. For Table 2, include a summary of key parameters, such as the number needed to screen to prevent one CHD event. Granularity: Include subgroup analyses, such as cost-effectiveness differences between urban and rural populations, to enhance generalizability. Provide individual ICER values for each age group in a supplemental table for clarity. Figures: Figures are clear, but sensitivity analysis results could be more informative if the tornado diagram included a ranking of the most impactful parameters. Discussion: Interpretation of Results: While the discussion highlights the advantages of universal genetic screening, avoid overstating its feasibility without considering infrastructural and economic constraints in rural China. Comparison with Literature: Compare findings more extensively with global cost-effectiveness studies to position the study in a broader context. Limitations: The limitations section is well-written but should address the exclusion of rural healthcare constraints in the model. For example, low testing uptake rates in rural areas could affect the cost-effectiveness. Policy Implications: Include a brief discussion on implementation strategies, such as subsidizing genetic testing or integrating it with existing public health programs. Conclusion: Restate the study's key findings, particularly emphasizing age-specific differences in cost- effectiveness. Avoid definitive claims about feasibility until practical challenges are addressed or modeled. Figures and Tables: Strengths: Figures and tables are well-designed and adequately complement the text. Suggestions: Add confidence intervals to ICER estimates in the tables. Ensure all axes are labeled clearly in sensitivity analysis figures. Additional Suggestions: Model Validation: Discuss any efforts to validate the Markov model (e.g., comparison with real- world data or prior models). Data Availability: Include raw input parameters and results in supplementary materials for transparency and reproducibility.	BMC	12916_2025_3966_ReviewerReport_V0_R8.pdf	{ "criticism": 2, "example": 1, "importance_and_relevance": 8, "materials_and_methods": 36, "praise": 12, "presentation_and_reporting": 13, "results_and_discussion": 18, "suggestion_and_solution": 23, "total": 46 }	{ "criticism": 0.043478260869565216, "example": 0.021739130434782608, "importance_and_relevance": 0.17391304347826086, "materials_and_methods": 0.782608695652174, "praise": 0.2608695652173913, "presentation_and_reporting": 0.2826086956521739, "results_and_discussion": 0.391304347826087, "suggestion_and_solution": 0.5 }	2.456522	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 0 Date: 09 Dec 2024\nReviewer: Sandeep S. Nayak\nReviewer's report:\nThis study uses a decision-analytic Markov model to compare universal genetic screening,\nuniversal cholesterol screening, and current passive screening strategies for FH in young adults.\nThe authors demonstrate that universal genetic screening is cost-effective, especially when\ninitiated at younger ages. Sensitivity analyses validate the robustness of the results, and threshold\nanalyses highlight critical factors influencing cost-effectiveness, such as genetic testing costs\nand FH prevalence.\nStrengths:\nRelevance: The study addresses a critical gap in FH management and provides evidence for\nhealth policy in a populous country like China.\nComprehensive Modeling: The authors incorporate long-term outcomes, cost parameters, and\nutility adjustments, which strengthen the analysis.\nSensitivity Analyses: Extensive one-way and probabilistic sensitivity analyses add robustness\nto the findings.\nWeaknesses:\nTransparency in Model Assumptions: Some assumptions, such as the FH prevalence and\ntreatment adherence rates, lack justification or supporting data.\nValidation of Parameters: The manuscript does not sufficiently validate key model inputs, such\nas transition probabilities and sensitivity estimates for genetic testing.\nGenerality of Results: Practical challenges, such as limited healthcare access in rural areas, are\nmentioned but not incorporated into the model.\nTitle:\nThe title is clear, concise, and accurately reflects the study's scope.\nAbstract:\nStrengths: The abstract is well-structured, providing an informative overview of the study's\nbackground, methodology, results, and implications.\nSuggestions:\nExplicitly state the Markov model’s time horizon.\nInclude sensitivity analysis highlights (e.g., the most impactful parameters).\nIntroduction:\nStrengths: The introduction effectively frames the problem of FH underdiagnosis and its\neconomic burden in China. It also justifies the need for universal genetic screening.\nSuggestions:\nClearly define the research question at the end of the introduction to emphasize the study’s\nprimary focus.\nBriefly discuss previous studies on FH screening in low- and middle-income countries to provide\na broader context.\nMethods:\nModel Structure:\nStrengths: The combination of decision tree and Markov models is appropriate for lifetime cost-\neffectiveness analyses.\nSuggestions:\nInclude a diagram of the decision tree for clarity (not just the Markov model).\nExplain the rationale for the one-year cycle length and justify whether smaller intervals could\nyield more precise results.\nModel Inputs:\nTransition Probabilities: Provide more details on the derivation of transition probabilities for\nCHD states. Were these validated against real-world data?\nCosts: Clarify how the costs for post-CHD management were adjusted for inflation or regional\nvariability.\nUtility Weights: Specify how age-specific utilities were adjusted for individuals transitioning\nto the \"alive with CHD\" state.\nScreening Strategies:\nThe paper mentions a 1% coverage rate for current passive screening. Provide evidence or\nreferences supporting this assumption.\nSensitivity Analyses:\nStrengths: One-way and probabilistic sensitivity analyses are comprehensive.\nSuggestions: Clarify the rationale for parameter ranges in one-way sensitivity analyses. For\nexample, why is genetic testing sensitivity varied between 45%-100%?\nResults:\nPresentation:\nThe results are well-structured and supported by tables and figures.\nFor Table 2, include a summary of key parameters, such as the number needed to screen to\nprevent one CHD event.\nGranularity:\nInclude subgroup analyses, such as cost-effectiveness differences between urban and rural\npopulations, to enhance generalizability.\nProvide individual ICER values for each age group in a supplemental table for clarity.\nFigures:\nFigures are clear, but sensitivity analysis results could be more informative if the tornado\ndiagram included a ranking of the most impactful parameters.\nDiscussion:\nInterpretation of Results:\nWhile the discussion highlights the advantages of universal genetic screening, avoid overstating\nits feasibility without considering infrastructural and economic constraints in rural China.\nComparison with Literature:\nCompare findings more extensively with global cost-effectiveness studies to position the study\nin a broader context.\nLimitations:\nThe limitations section is well-written but should address the exclusion of rural healthcare\nconstraints in the model. For example, low testing uptake rates in rural areas could affect the\ncost-effectiveness.\nPolicy Implications:\nInclude a brief discussion on implementation strategies, such as subsidizing genetic testing or\nintegrating it with existing public health programs.\nConclusion:\nRestate the study's key findings, particularly emphasizing age-specific differences in cost-\neffectiveness.\nAvoid definitive claims about feasibility until practical challenges are addressed or modeled.\nFigures and Tables:\nStrengths: Figures and tables are well-designed and adequately complement the text.\nSuggestions:\nAdd confidence intervals to ICER estimates in the tables.\nEnsure all axes are labeled clearly in sensitivity analysis figures.\nAdditional Suggestions:\nModel Validation: Discuss any efforts to validate the Markov model (e.g., comparison with real-\nworld data or prior models).\nData Availability: Include raw input parameters and results in supplementary materials for\ntransparency and reproducibility.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 11 Dec 2024 Reviewer: Joo Hee Jeong Reviewer's report: Dr. Meng and the co-authors assessed the cost-effectiveness of universal genetic screening of familial hypercholesterolemia (FH), and suggested that universal genetic screening is more cost-effective in preventing adverse cardiovascular event compared to conventional screening strategy. I admire their excellent work that fills the gap in current recommendation in FH. However, there are several concerns that might limit the application of the results in clinical practice. 1. Although FH could be diagnosed with the identification of pathogenic variant (LDLR, APOB, PCSK9), there may be several cases that might not be fully confirmed by genetic testing, such as false-negative result, polygenic origin, or autosomal recessive type of pathogenic variant. I wonder if these specific circumstances were considered in the analysis. 2. How were the non-pathogenic variants (i.e, VUSs or benign) were analyzed? 3. Increased yield of detecting undiagnosed FH do not directly translate into reduction of cardiovascular outcome, which is also addressed in the Discussion section. Several factors influence the treatment and outcome, such as drug adherence, poor insight of the disease, ethnic variations (lower LDL-cholesterol in Asians than Caucasians), and paucity of professionals (dealing with genetic interpretation and counseling) to cover universal genetic screening. If the universal genetic screening is performed in the real-world, significant efforts and financial expense to fulfill these factors may be needed additionally, which may diminish the benefits of universal genetic screening. Were these factors concerned in the analysis? 4. The manuscript overall seems too lengthy, especially the Introduction section. Please consider reducing the Introduction section, and may be removing some of the sentences to Discussion section. 5. How was the CHD or fatal CHD defined? Was the angiographic confirmation of obstructive coronary artery disease needed for this? 6. The sensitivity of lipid screening (48%) seems to be much lower than expected (Line 195-196). How was this calculated? Could this affect the results? 7. The following sentence in Introduction seems too wordy and repetitive. : By comparing with the current passive screening approaches (opportunistic cholesterol screening and genetic cascade screening), this study aims to evaluate the cost-effectiveness of universal genetic screening in China for young adults aged 18-40 years with decision-tree Markov model, compared with the universal cholesterol screening and current passive screening.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 0 Date: 11 Dec 2024 Reviewer: Joo Hee Jeong Reviewer's report: Dr. Meng and the co-authors assessed the cost-effectiveness of universal genetic screening of familial hypercholesterolemia (FH), and suggested that universal genetic screening is more cost-effective in preventing adverse cardiovascular event compared to conventional screening strategy. I admire their excellent work that fills the gap in current recommendation in FH. However, there are several concerns that might limit the application of the results in clinical practice. 1. Although FH could be diagnosed with the identification of pathogenic variant (LDLR, APOB, PCSK9), there may be several cases that might not be fully confirmed by genetic testing, such as false-negative result, polygenic origin, or autosomal recessive type of pathogenic variant. I wonder if these specific circumstances were considered in the analysis. 2. How were the non-pathogenic variants (i.e, VUSs or benign) were analyzed? 3. Increased yield of detecting undiagnosed FH do not directly translate into reduction of cardiovascular outcome, which is also addressed in the Discussion section. Several factors influence the treatment and outcome, such as drug adherence, poor insight of the disease, ethnic variations (lower LDL-cholesterol in Asians than Caucasians), and paucity of professionals (dealing with genetic interpretation and counseling) to cover universal genetic screening. If the universal genetic screening is performed in the real-world, significant efforts and financial expense to fulfill these factors may be needed additionally, which may diminish the benefits of universal genetic screening. Were these factors concerned in the analysis? 4. The manuscript overall seems too lengthy, especially the Introduction section. Please consider reducing the Introduction section, and may be removing some of the sentences to Discussion section. 5. How was the CHD or fatal CHD defined? Was the angiographic confirmation of obstructive coronary artery disease needed for this? 6. The sensitivity of lipid screening (48%) seems to be much lower than expected (Line 195-196). How was this calculated? Could this affect the results? 7. The following sentence in Introduction seems too wordy and repetitive. : By comparing with the current passive screening approaches (opportunistic cholesterol screening and genetic cascade screening), this study aims to evaluate the cost-effectiveness of universal genetic screening in China for young adults aged 18-40 years with decision-tree Markov model, compared with the universal cholesterol screening and current passive screening.	BMC	12916_2025_3966_ReviewerReport_V0_R7.pdf	{ "criticism": 2, "example": 1, "importance_and_relevance": 3, "materials_and_methods": 12, "praise": 1, "presentation_and_reporting": 3, "results_and_discussion": 8, "suggestion_and_solution": 2, "total": 26 }	{ "criticism": 0.07692307692307693, "example": 0.038461538461538464, "importance_and_relevance": 0.11538461538461539, "materials_and_methods": 0.46153846153846156, "praise": 0.038461538461538464, "presentation_and_reporting": 0.11538461538461539, "results_and_discussion": 0.3076923076923077, "suggestion_and_solution": 0.07692307692307693 }	1.230769	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 0 Date: 11 Dec 2024\nReviewer: Joo Hee Jeong\nReviewer's report:\nDr. Meng and the co-authors assessed the cost-effectiveness of universal genetic screening\nof familial hypercholesterolemia (FH), and suggested that universal genetic screening is more\ncost-effective in preventing adverse cardiovascular event compared to conventional screening\nstrategy. I admire their excellent work that fills the gap in current recommendation in FH.\nHowever, there are several concerns that might limit the application of the results in clinical\npractice.\n1. Although FH could be diagnosed with the identification of pathogenic variant (LDLR, APOB,\nPCSK9), there may be several cases that might not be fully confirmed by genetic testing, such\nas false-negative result, polygenic origin, or autosomal recessive type of pathogenic variant. I\nwonder if these specific circumstances were considered in the analysis.\n2. How were the non-pathogenic variants (i.e, VUSs or benign) were analyzed?\n3. Increased yield of detecting undiagnosed FH do not directly translate into reduction of\ncardiovascular outcome, which is also addressed in the Discussion section. Several factors\ninfluence the treatment and outcome, such as drug adherence, poor insight of the disease, ethnic\nvariations (lower LDL-cholesterol in Asians than Caucasians), and paucity of professionals\n(dealing with genetic interpretation and counseling) to cover universal genetic screening. If\nthe universal genetic screening is performed in the real-world, significant efforts and financial\nexpense to fulfill these factors may be needed additionally, which may diminish the benefits of\nuniversal genetic screening. Were these factors concerned in the analysis?\n4. The manuscript overall seems too lengthy, especially the Introduction section. Please consider\nreducing the Introduction section, and may be removing some of the sentences to Discussion\nsection.\n5. How was the CHD or fatal CHD defined? Was the angiographic confirmation of obstructive\ncoronary artery disease needed for this?\n6. The sensitivity of lipid screening (48%) seems to be much lower than expected (Line 195-196).\nHow was this calculated? Could this affect the results?\n7. The following sentence in Introduction seems too wordy and repetitive.\n: By comparing with the current passive screening approaches (opportunistic cholesterol\nscreening and genetic cascade screening), this study aims to evaluate the cost-effectiveness\nof universal genetic screening in China for young adults aged 18-40 years with decision-tree\nMarkov model, compared with the universal cholesterol screening and current passive screening.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 16 Jan 2025 Reviewer: Joo Hee Jeong Reviewer's report: Quality of the manuscript has significantly improved and the questions I have raised was fully addressed. Thank you.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 16 Jan 2025 Reviewer: Joo Hee Jeong Reviewer's report: Quality of the manuscript has significantly improved and the questions I have raised was fully addressed. Thank you.	BMC	12916_2025_3966_ReviewerReport_V1_R7.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0.5, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 1 Date: 16 Jan 2025\nReviewer: Joo Hee Jeong\nReviewer's report:\nQuality of the manuscript has significantly improved and the questions I have raised was fully\naddressed. Thank you.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 09 Feb 2025 Reviewer: David N. Dhanraj Reviewer's report: Very thorough addressing of my comments and those of the other reviewers. I am comfortable with this being ready for publication.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 09 Feb 2025 Reviewer: David N. Dhanraj Reviewer's report: Very thorough addressing of my comments and those of the other reviewers. I am comfortable with this being ready for publication.	BMC	12916_2025_3966_ReviewerReport_V1_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 1 Date: 09 Feb 2025\nReviewer: David N. Dhanraj\nReviewer's report:\nVery thorough addressing of my comments and those of the other reviewers. I am comfortable\nwith this being ready for publication.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03966-7	Reviewed - bmc_medicine	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 09 Feb 2025 Reviewer's report: The authors have satisfactorily addressed my concerns in the revised manuscript; I appreciate the quality of work completed.	Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in young adults aged 18-40 years in China Version: 1 Date: 09 Feb 2025 Reviewer's report: The authors have satisfactorily addressed my concerns in the revised manuscript; I appreciate the quality of work completed.	BMC	12916_2025_3966_ReviewerReport_V1_R5.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Cost-effectiveness of universal genetic screening for familial hypercholesterolemia in\nyoung adults aged 18-40 years in China\nVersion: 1 Date: 09 Feb 2025\nReviewer's report:\nThe authors have satisfactorily addressed my concerns in the revised manuscript; I appreciate\nthe quality of work completed.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03950-1	Reviewed - bmc_medicine	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 0 Date: 14 Nov 2024 Reviewer's report: The present study is a pooled analysis of four cohort studies that examines whether lifestyle behaviours might modify the association of retrospectively reported childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. The findings suggest that such moderation effects were not present. Although the present findings are interesting and important addition to the current literature, there are number of conceptual and theoretical issues that require further clarification. 1) The present study has rather high overlap with the study previously published by the same research team in the same journal (Souama C et al. Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants. BMC Med. 2023). In the introduction and elsewhere, it should more clearly stated that the present study is a follow-up to the previously published paper. Moreover, it should be clearly stated what findings are novel and what were already previously reported. 2) The rationale for choosing the study cohorts for the present study is not clear. The previous paper included a vast number of more study cohorts than the present study – what was the reason for leaving them out? In addition, part of the title (“a meta-analysis of over 180,000 individuals”) is technically correct, but in a sense misleading as over 90% of the study participants are from the UK Biobank and the rest are mainly from ALSPAC. 4) Having such an imbalanced cohorts for using meta-analytical methods is not ideal – this is clearly shown by how the weights between analyses across cohort differ substantially. 5) I am less familiar with ALSPAC and NESDA, but I am wondering whether authors think that UK Biobank is an optimal study for the present research questions? At the study baseline participants are on average 66 years of old. Depression onset after the age of 66 is not common and mostly likely related to dementia (e.g., Singh-Manoux et al. 2017. JAMA psychiatry). Participants in the UK Biobank are also highly selected that is likely to bias the associations (e.g., van Alten et al. 2024. International Journal of Epidemiology) 6) Retrospective assessment of chilhood maltreatment is a clear limitation that should be discussed in more detail (e.g., Baldwin et al. 2019 and 2024. JAMA psychiatry)	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 0 Date: 14 Nov 2024 Reviewer's report: The present study is a pooled analysis of four cohort studies that examines whether lifestyle behaviours might modify the association of retrospectively reported childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. The findings suggest that such moderation effects were not present. Although the present findings are interesting and important addition to the current literature, there are number of conceptual and theoretical issues that require further clarification. 1) The present study has rather high overlap with the study previously published by the same research team in the same journal (Souama C et al. Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants. BMC Med. 2023). In the introduction and elsewhere, it should more clearly stated that the present study is a follow-up to the previously published paper. Moreover, it should be clearly stated what findings are novel and what were already previously reported. 2) The rationale for choosing the study cohorts for the present study is not clear. The previous paper included a vast number of more study cohorts than the present study – what was the reason for leaving them out? In addition, part of the title (“a meta-analysis of over 180,000 individuals”) is technically correct, but in a sense misleading as over 90% of the study participants are from the UK Biobank and the rest are mainly from ALSPAC. 4) Having such an imbalanced cohorts for using meta-analytical methods is not ideal – this is clearly shown by how the weights between analyses across cohort differ substantially. 5) I am less familiar with ALSPAC and NESDA, but I am wondering whether authors think that UK Biobank is an optimal study for the present research questions? At the study baseline participants are on average 66 years of old. Depression onset after the age of 66 is not common and mostly likely related to dementia (e.g., Singh-Manoux et al. 2017. JAMA psychiatry). Participants in the UK Biobank are also highly selected that is likely to bias the associations (e.g., van Alten et al. 2024. International Journal of Epidemiology) 6) Retrospective assessment of chilhood maltreatment is a clear limitation that should be discussed in more detail (e.g., Baldwin et al. 2019 and 2024. JAMA psychiatry)	BMC	12916_2025_3950_ReviewerReport_V0_R1.pdf	{ "criticism": 4, "example": 0, "importance_and_relevance": 2, "materials_and_methods": 10, "praise": 1, "presentation_and_reporting": 2, "results_and_discussion": 3, "suggestion_and_solution": 4, "total": 22 }	{ "criticism": 0.18181818181818182, "example": 0, "importance_and_relevance": 0.09090909090909091, "materials_and_methods": 0.45454545454545453, "praise": 0.045454545454545456, "presentation_and_reporting": 0.09090909090909091, "results_and_discussion": 0.13636363636363635, "suggestion_and_solution": 0.18181818181818182 }	1.181818	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Lifestyle behaviours do not moderate the association between childhood maltreatment\nand comorbid depression and cardiometabolic disease in older adults: a meta-analysis\nVersion: 0 Date: 14 Nov 2024\nReviewer's report:\nThe present study is a pooled analysis of four cohort studies that examines whether lifestyle\nbehaviours might modify the association of retrospectively reported childhood maltreatment\nwith depression, cardiometabolic disease, and their comorbidity. The findings suggest that such\nmoderation effects were not present.\nAlthough the present findings are interesting and important addition to the current literature,\nthere are number of conceptual and theoretical issues that require further clarification.\n1) The present study has rather high overlap with the study previously published by the same\nresearch team in the same journal (Souama C et al. Depression, cardiometabolic disease, and\ntheir co-occurrence after childhood maltreatment: an individual participant data meta-analysis\nincluding over 200,000 participants. BMC Med. 2023). In the introduction and elsewhere, it\nshould more clearly stated that the present study is a follow-up to the previously published paper.\nMoreover, it should be clearly stated what findings are novel and what were already previously\nreported.\n2) The rationale for choosing the study cohorts for the present study is not clear. The previous\npaper included a vast number of more study cohorts than the present study – what was the reason\nfor leaving them out? In addition, part of the title (“a meta-analysis of over 180,000 individuals”)\nis technically correct, but in a sense misleading as over 90% of the study participants are from\nthe UK Biobank and the rest are mainly from ALSPAC.\n4) Having such an imbalanced cohorts for using meta-analytical methods is not ideal – this is\nclearly shown by how the weights between analyses across cohort differ substantially.\n5) I am less familiar with ALSPAC and NESDA, but I am wondering whether authors think\nthat UK Biobank is an optimal study for the present research questions? At the study baseline\nparticipants are on average 66 years of old. Depression onset after the age of 66 is not common\nand mostly likely related to dementia (e.g., Singh-Manoux et al. 2017. JAMA psychiatry).\nParticipants in the UK Biobank are also highly selected that is likely to bias the associations\n(e.g., van Alten et al. 2024. International Journal of Epidemiology)\n6) Retrospective assessment of chilhood maltreatment is a clear limitation that should be\ndiscussed in more detail (e.g., Baldwin et al. 2019 and 2024. JAMA psychiatry)", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03950-1	Reviewed - bmc_medicine	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 0 Date: 29 Nov 2024 Reviewer's report: Thank you for the chance to review this very interesting manuscript. In general, I think it is well thought out and written, however, I have some concerns which should be assessed before publication. 1. I suggest that the self-report outcomes used in the included studies should be named in the method section. 2. Ideally, the economical status of the study participants should be included as covariate. If this is not possible, this should at least be discussed as a limitation. 3. The extent of missing data should be mentioned for transparency reasons. 4. While no moderation effect has been found, it might be interesting discuss the possibility of mediation effects of lifestyle behaviors. 5. In the statistical analysis section it should be mentioned how heterogeneity was assessed.	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 0 Date: 29 Nov 2024 Reviewer's report: Thank you for the chance to review this very interesting manuscript. In general, I think it is well thought out and written, however, I have some concerns which should be assessed before publication. 1. I suggest that the self-report outcomes used in the included studies should be named in the method section. 2. Ideally, the economical status of the study participants should be included as covariate. If this is not possible, this should at least be discussed as a limitation. 3. The extent of missing data should be mentioned for transparency reasons. 4. While no moderation effect has been found, it might be interesting discuss the possibility of mediation effects of lifestyle behaviors. 5. In the statistical analysis section it should be mentioned how heterogeneity was assessed.	BMC	12916_2025_3950_ReviewerReport_V0_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 2, "materials_and_methods": 5, "praise": 3, "presentation_and_reporting": 5, "results_and_discussion": 3, "suggestion_and_solution": 7, "total": 13 }	{ "criticism": 0.07692307692307693, "example": 0, "importance_and_relevance": 0.15384615384615385, "materials_and_methods": 0.38461538461538464, "praise": 0.23076923076923078, "presentation_and_reporting": 0.38461538461538464, "results_and_discussion": 0.23076923076923078, "suggestion_and_solution": 0.5384615384615384 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Lifestyle behaviours do not moderate the association between childhood maltreatment\nand comorbid depression and cardiometabolic disease in older adults: a meta-analysis\nVersion: 0 Date: 29 Nov 2024\nReviewer's report:\nThank you for the chance to review this very interesting manuscript. In general, I think it is\nwell thought out and written, however, I have some concerns which should be assessed before\npublication.\n1. I suggest that the self-report outcomes used in the included studies should be named in the\nmethod section.\n2. Ideally, the economical status of the study participants should be included as covariate. If this\nis not possible, this should at least be discussed as a limitation.\n3. The extent of missing data should be mentioned for transparency reasons.\n4. While no moderation effect has been found, it might be interesting discuss the possibility of\nmediation effects of lifestyle behaviors.\n5. In the statistical analysis section it should be mentioned how heterogeneity was assessed.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03950-1	Reviewed - bmc_medicine	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 1 Date: 20 Jan 2025 Reviewer's report: The authors revised their manuscript sufficiently well.	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 1 Date: 20 Jan 2025 Reviewer's report: The authors revised their manuscript sufficiently well.	BMC	12916_2025_3950_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Lifestyle behaviours do not moderate the association between childhood maltreatment\nand comorbid depression and cardiometabolic disease in older adults: a meta-analysis\nVersion: 1 Date: 20 Jan 2025\nReviewer's report:\nThe authors revised their manuscript sufficiently well.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03950-1	Reviewed - bmc_medicine	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 1 Date: 20 Jan 2025 Reviewer's report: Thank you for addressing all the issues I have raised, I have no further comments.	Title: Lifestyle behaviours do not moderate the association between childhood maltreatment and comorbid depression and cardiometabolic disease in older adults: a meta-analysis Version: 1 Date: 20 Jan 2025 Reviewer's report: Thank you for addressing all the issues I have raised, I have no further comments.	BMC	12916_2025_3950_ReviewerReport_V1_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Lifestyle behaviours do not moderate the association between childhood maltreatment\nand comorbid depression and cardiometabolic disease in older adults: a meta-analysis\nVersion: 1 Date: 20 Jan 2025\nReviewer's report:\nThank you for addressing all the issues I have raised, I have no further comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03968-5	Reviewed - bmc_medicine	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 11 Oct 2024 Reviewer's report: In this manuscript by Zhu et al, the authors investigate the correlation between the baseline CD10- fraction of neutrophils with response rates, remission time, and overall survival. This is based on the fact that CD10- neutrophils can display myeloid derived suppressor activity against T-cells and thus can do the same for CAR-T cells, and show reduction in CAR persistence with higher CD10- fraction. Although the sample size is relatively small, the study is offers a baseline biomarker with independent predictive value of other clinical variables. Critiques In addition to the CD10- fraction, analysis should be performed also on the total CD10+ neutrophil number and the CD10+ neutrophils/nucleated cells. Please indicate if any of the patients were given G-CSF within the months leading up to CAR infusions and if so, how this impacted the CD10- fraction. Is there any longitudinal measurements of the neutrophil fractions as a function of time and the effect of persistent CD10- neutrophil fraction on CAR persistence? If not, please discuss this as a potential limitation of this study. On the flow diagram in the first figure, the CD10- fraction does not appear as a distinct population and is rather continuous with the CD10+ population. Was there any other functional markers that were analyzed between CD10- and CD10+ to indicated differences in functionality between these two fractions? Previous data by Marini et al (Blood (2017) 129 (10): 1343–1356) has indicated that it the CD10- fraction was actually promotes T-cell survival, proliferation and IFN-gamma release, in contrast to what is noted in this manuscript. Please discuss this discrepancy in the discussion. Please have the manuscript reviewed for grammar as there were multiple grammatical errors throughout the manuscript.	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 11 Oct 2024 Reviewer's report: In this manuscript by Zhu et al, the authors investigate the correlation between the baseline CD10- fraction of neutrophils with response rates, remission time, and overall survival. This is based on the fact that CD10- neutrophils can display myeloid derived suppressor activity against T-cells and thus can do the same for CAR-T cells, and show reduction in CAR persistence with higher CD10- fraction. Although the sample size is relatively small, the study is offers a baseline biomarker with independent predictive value of other clinical variables. Critiques In addition to the CD10- fraction, analysis should be performed also on the total CD10+ neutrophil number and the CD10+ neutrophils/nucleated cells. Please indicate if any of the patients were given G-CSF within the months leading up to CAR infusions and if so, how this impacted the CD10- fraction. Is there any longitudinal measurements of the neutrophil fractions as a function of time and the effect of persistent CD10- neutrophil fraction on CAR persistence? If not, please discuss this as a potential limitation of this study. On the flow diagram in the first figure, the CD10- fraction does not appear as a distinct population and is rather continuous with the CD10+ population. Was there any other functional markers that were analyzed between CD10- and CD10+ to indicated differences in functionality between these two fractions? Previous data by Marini et al (Blood (2017) 129 (10): 1343–1356) has indicated that it the CD10- fraction was actually promotes T-cell survival, proliferation and IFN-gamma release, in contrast to what is noted in this manuscript. Please discuss this discrepancy in the discussion. Please have the manuscript reviewed for grammar as there were multiple grammatical errors throughout the manuscript.	BMC	12916_2025_3968_ReviewerReport_V0_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 8, "praise": 0, "presentation_and_reporting": 4, "results_and_discussion": 2, "suggestion_and_solution": 5, "total": 12 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.6666666666666666, "praise": 0, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0.16666666666666666, "suggestion_and_solution": 0.4166666666666667 }	1.583333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19\nCAR T-cell therapy for B-cell acute lymphoblastic leukemia\nVersion: 0 Date: 11 Oct 2024\nReviewer's report:\nIn this manuscript by Zhu et al, the authors investigate the correlation between the baseline\nCD10- fraction of neutrophils with response rates, remission time, and overall survival. This is\nbased on the fact that CD10- neutrophils can display myeloid derived suppressor activity against\nT-cells and thus can do the same for CAR-T cells, and show reduction in CAR persistence with\nhigher CD10- fraction. Although the sample size is relatively small, the study is offers a baseline\nbiomarker with independent predictive value of other clinical variables.\nCritiques\nIn addition to the CD10- fraction, analysis should be performed also on the total CD10+\nneutrophil number and the CD10+ neutrophils/nucleated cells.\nPlease indicate if any of the patients were given G-CSF within the months leading up to CAR\ninfusions and if so, how this impacted the CD10- fraction.\nIs there any longitudinal measurements of the neutrophil fractions as a function of time and the\neffect of persistent CD10- neutrophil fraction on CAR persistence? If not, please discuss this as\na potential limitation of this study.\nOn the flow diagram in the first figure, the CD10- fraction does not appear as a distinct\npopulation and is rather continuous with the CD10+ population. Was there any other functional\nmarkers that were analyzed between CD10- and CD10+ to indicated differences in functionality\nbetween these two fractions?\nPrevious data by Marini et al (Blood (2017) 129 (10): 1343–1356) has indicated that it the CD10-\nfraction was actually promotes T-cell survival, proliferation and IFN-gamma release, in contrast\nto what is noted in this manuscript. Please discuss this discrepancy in the discussion.\nPlease have the manuscript reviewed for grammar as there were multiple grammatical errors\nthroughout the manuscript.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03968-5	Reviewed - bmc_medicine	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 11 Oct 2024 Reviewer's report: The paper titled "Elevated CD10+ Neutrophils Correlate with Non-Response and Poor Prognosis of CD19 CAR T-Cell Therapy for B-cell Acute Lymphoblastic Leukemia" by J Zhu et al. investigates the association between CD10+ neutrophils and outcomes in 44 B-ALL cases treated with CAR T-cells. The study compares two groups: responders (clinical remission, complete or incomplete) and non-responders, demonstrating that elevated CD10+ neutrophils are detrimental to response, overall survival, and relapse-free survival. The authors reveal that prior to CAR-T cell infusion, peripheral blood CD10+ neutrophils are elevated in B-ALL patients compared to healthy donors. Additionally, the ratio of CD10+ neutrophils to nucleated cells is higher in non-responding patients. Multivariate analysis indicates that a CD10+ neutrophils/neutrophils ratio below 21.5% and active extra-medullary disease are statistically significant predictors. From my perspective, additional confounding factors should be considered in both univariate and multivariate analyses, such as non-hematological adverse events (CRS, ICANS...) and molecular abnormalities associated with poor risk, like IKZF1 deletions or TP53 abnormalities. Furthermore, the cytogenetic abnormalities retained for the study should be detailed. This comprehensive clinical and biological information would significantly enhance the value of Table 2 (responders vs. non-responders). Moreover, the classical G-MDSCs phenotypic profile is CD11b+CD14-CD15+HLA- DRlowCD66b+. Since the study did not evaluate CD11b or CD15, the relevance of the studied population may be limited. Additionally, information regarding monocytic-MDSCs (M- MDSCs), which often maintain a balance with neutrophil-MDSCs, would be valuable. Minor corrections: Line 76: Correct "aslo" to "also" Line 83: Add a missing space.	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 11 Oct 2024 Reviewer's report: The paper titled "Elevated CD10+ Neutrophils Correlate with Non-Response and Poor Prognosis of CD19 CAR T-Cell Therapy for B-cell Acute Lymphoblastic Leukemia" by J Zhu et al. investigates the association between CD10+ neutrophils and outcomes in 44 B-ALL cases treated with CAR T-cells. The study compares two groups: responders (clinical remission, complete or incomplete) and non-responders, demonstrating that elevated CD10+ neutrophils are detrimental to response, overall survival, and relapse-free survival. The authors reveal that prior to CAR-T cell infusion, peripheral blood CD10+ neutrophils are elevated in B-ALL patients compared to healthy donors. Additionally, the ratio of CD10+ neutrophils to nucleated cells is higher in non-responding patients. Multivariate analysis indicates that a CD10+ neutrophils/neutrophils ratio below 21.5% and active extra-medullary disease are statistically significant predictors. From my perspective, additional confounding factors should be considered in both univariate and multivariate analyses, such as non-hematological adverse events (CRS, ICANS...) and molecular abnormalities associated with poor risk, like IKZF1 deletions or TP53 abnormalities. Furthermore, the cytogenetic abnormalities retained for the study should be detailed. This comprehensive clinical and biological information would significantly enhance the value of Table 2 (responders vs. non-responders). Moreover, the classical G-MDSCs phenotypic profile is CD11b+CD14-CD15+HLA- DRlowCD66b+. Since the study did not evaluate CD11b or CD15, the relevance of the studied population may be limited. Additionally, information regarding monocytic-MDSCs (M- MDSCs), which often maintain a balance with neutrophil-MDSCs, would be valuable. Minor corrections: Line 76: Correct "aslo" to "also" Line 83: Add a missing space.	BMC	12916_2025_3968_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 1, "importance_and_relevance": 0, "materials_and_methods": 9, "praise": 0, "presentation_and_reporting": 2, "results_and_discussion": 1, "suggestion_and_solution": 5, "total": 13 }	{ "criticism": 0, "example": 0.07692307692307693, "importance_and_relevance": 0, "materials_and_methods": 0.6923076923076923, "praise": 0, "presentation_and_reporting": 0.15384615384615385, "results_and_discussion": 0.07692307692307693, "suggestion_and_solution": 0.38461538461538464 }	1.384615	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19\nCAR T-cell therapy for B-cell acute lymphoblastic leukemia\nVersion: 0 Date: 11 Oct 2024\nReviewer's report:\nThe paper titled \"Elevated CD10+ Neutrophils Correlate with Non-Response and Poor Prognosis\nof CD19 CAR T-Cell Therapy for B-cell Acute Lymphoblastic Leukemia\" by J Zhu et al.\ninvestigates the association between CD10+ neutrophils and outcomes in 44 B-ALL cases\ntreated with CAR T-cells.\nThe study compares two groups: responders (clinical remission, complete or incomplete) and\nnon-responders, demonstrating that elevated CD10+ neutrophils are detrimental to response,\noverall survival, and relapse-free survival.\nThe authors reveal that prior to CAR-T cell infusion, peripheral blood CD10+ neutrophils are\nelevated in B-ALL patients compared to healthy donors. Additionally, the ratio of CD10+\nneutrophils to nucleated cells is higher in non-responding patients. Multivariate analysis\nindicates that a CD10+ neutrophils/neutrophils ratio below 21.5% and active extra-medullary\ndisease are statistically significant predictors.\nFrom my perspective, additional confounding factors should be considered in both univariate\nand multivariate analyses, such as non-hematological adverse events (CRS, ICANS...) and\nmolecular abnormalities associated with poor risk, like IKZF1 deletions or TP53 abnormalities.\nFurthermore, the cytogenetic abnormalities retained for the study should be detailed. This\ncomprehensive clinical and biological information would significantly enhance the value of\nTable 2 (responders vs. non-responders).\nMoreover, the classical G-MDSCs phenotypic profile is CD11b+CD14-CD15+HLA-\nDRlowCD66b+. Since the study did not evaluate CD11b or CD15, the relevance of the\nstudied population may be limited. Additionally, information regarding monocytic-MDSCs (M-\nMDSCs), which often maintain a balance with neutrophil-MDSCs, would be valuable.\nMinor corrections:\nLine 76: Correct \"aslo\" to \"also\"\nLine 83: Add a missing space.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03968-5	Reviewed - bmc_medicine	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 19 Oct 2024 Reviewer's report: In this study, the authors investigated the relationship between peripheral blood CD10 negative neutrophils and the prognosis of patients with B-cell acute lymphoblastic leukemia receiving CD19 CAR T cell therapy. They found that a high frequency of CD10 negative neutrophils (defined as #21.57%) was correlated with poor response, shorter relapse-free survival, and overall survival in patients who received CAR-T cell therapy. While intriguing, the major limitation of this paper is the small sample size and possibility of confounding. N=44 is too small for a satisfactory multivariable analysis, especially logistic regression which typically requires a large sample size. The authors state that they used stepwise regression where variables with a p value of < 0.05 on univariable analysis were included in multivariable analysis. However, in Figure 3, there were only 2 variables in the multivariable analysis. In Figure 4, the "multivariate" analysis only included 1 variable. In Figure 5, the multivariable analysis only included 2 variables.	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 0 Date: 19 Oct 2024 Reviewer's report: In this study, the authors investigated the relationship between peripheral blood CD10 negative neutrophils and the prognosis of patients with B-cell acute lymphoblastic leukemia receiving CD19 CAR T cell therapy. They found that a high frequency of CD10 negative neutrophils (defined as #21.57%) was correlated with poor response, shorter relapse-free survival, and overall survival in patients who received CAR-T cell therapy. While intriguing, the major limitation of this paper is the small sample size and possibility of confounding. N=44 is too small for a satisfactory multivariable analysis, especially logistic regression which typically requires a large sample size. The authors state that they used stepwise regression where variables with a p value of < 0.05 on univariable analysis were included in multivariable analysis. However, in Figure 3, there were only 2 variables in the multivariable analysis. In Figure 4, the "multivariate" analysis only included 1 variable. In Figure 5, the multivariable analysis only included 2 variables.	BMC	12916_2025_3968_ReviewerReport_V0_R1.pdf	{ "criticism": 2, "example": 3, "importance_and_relevance": 0, "materials_and_methods": 8, "praise": 0, "presentation_and_reporting": 1, "results_and_discussion": 2, "suggestion_and_solution": 0, "total": 8 }	{ "criticism": 0.25, "example": 0.375, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0.125, "results_and_discussion": 0.25, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19\nCAR T-cell therapy for B-cell acute lymphoblastic leukemia\nVersion: 0 Date: 19 Oct 2024\nReviewer's report:\nIn this study, the authors investigated the relationship between peripheral blood CD10 negative\nneutrophils and the prognosis of patients with B-cell acute lymphoblastic leukemia receiving\nCD19 CAR T cell therapy. They found that a high frequency of CD10 negative neutrophils\n(defined as #21.57%) was correlated with poor response, shorter relapse-free survival, and\noverall survival in patients who received CAR-T cell therapy.\nWhile intriguing, the major limitation of this paper is the small sample size and possibility\nof confounding. N=44 is too small for a satisfactory multivariable analysis, especially logistic\nregression which typically requires a large sample size.\nThe authors state that they used stepwise regression where variables with a p value of < 0.05\non univariable analysis were included in multivariable analysis. However, in Figure 3, there\nwere only 2 variables in the multivariable analysis. In Figure 4, the \"multivariate\" analysis only\nincluded 1 variable. In Figure 5, the multivariable analysis only included 2 variables.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03968-5	Reviewed - bmc_medicine	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 1 Date: 17 Jan 2025 Reviewer's report: The authors have adequately addressed the raised concerns. I concur with Reviewer #3 regarding the relatively small sample size (n=44) for multivariate analysis. The presence of cytogenetic/ molecular abnormalities in 33/44 patients (see Supplementary Data) may introduce potential confounders, potentially the results (associated with either good or poor prognosis outcomes. This potential confounding factor should be acknowledged and discussed in the manuscript. The English language used in the manuscript requires revision, for instance Line 31 : « There are evidences show that some neutrophils have… » Line 50 :« Moreover, the CD10- neuts levels in patients with non-responding to CAR T cells displayed vast higher than those in patients who acquired remission, … »	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 1 Date: 17 Jan 2025 Reviewer's report: The authors have adequately addressed the raised concerns. I concur with Reviewer #3 regarding the relatively small sample size (n=44) for multivariate analysis. The presence of cytogenetic/ molecular abnormalities in 33/44 patients (see Supplementary Data) may introduce potential confounders, potentially the results (associated with either good or poor prognosis outcomes. This potential confounding factor should be acknowledged and discussed in the manuscript. The English language used in the manuscript requires revision, for instance Line 31 : « There are evidences show that some neutrophils have… » Line 50 :« Moreover, the CD10- neuts levels in patients with non-responding to CAR T cells displayed vast higher than those in patients who acquired remission, … »	BMC	12916_2025_3968_ReviewerReport_V1_R3.pdf	{ "criticism": 0, "example": 1, "importance_and_relevance": 0, "materials_and_methods": 4, "praise": 0, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 2, "total": 5 }	{ "criticism": 0, "example": 0.2, "importance_and_relevance": 0, "materials_and_methods": 0.8, "praise": 0, "presentation_and_reporting": 0.2, "results_and_discussion": 0.2, "suggestion_and_solution": 0.4 }	1.8	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19\nCAR T-cell therapy for B-cell acute lymphoblastic leukemia\nVersion: 1 Date: 17 Jan 2025\nReviewer's report:\nThe authors have adequately addressed the raised concerns. I concur with Reviewer #3 regarding\nthe relatively small sample size (n=44) for multivariate analysis. The presence of cytogenetic/\nmolecular abnormalities in 33/44 patients (see Supplementary Data) may introduce potential\nconfounders, potentially the results (associated with either good or poor prognosis outcomes.\nThis potential confounding factor should be acknowledged and discussed in the manuscript.\nThe English language used in the manuscript requires revision, for instance\nLine 31 : « There are evidences show that some neutrophils have… »\nLine 50 :« Moreover, the CD10- neuts levels in patients with non-responding to CAR T cells\ndisplayed vast higher than those in patients who acquired remission, … »", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03968-5	Reviewed - bmc_medicine	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 1 Date: 22 Jan 2025 Reviewer's report: The authors provided adequate responses to my initial critiques along with updated analyses and figures to support their rebuttal.	Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia Version: 1 Date: 22 Jan 2025 Reviewer's report: The authors provided adequate responses to my initial critiques along with updated analyses and figures to support their rebuttal.	BMC	12916_2025_3968_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Elevated CD10- neutrophils correlate with non-response and poor prognosis of CD19\nCAR T-cell therapy for B-cell acute lymphoblastic leukemia\nVersion: 1 Date: 22 Jan 2025\nReviewer's report:\nThe authors provided adequate responses to my initial critiques along with updated analyses and\nfigures to support their rebuttal.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03957-8	Reviewed - bmc_medicine	Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Study Version: 1 Date: 19 Dec 2024 Reviewer's report: Peer review BMC Med Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Survey Yinyan Gao et al. The authors answered all reviewers’ comments and modified the manuscript accordingly Minor comment: The authors report the study as being a methodological survey in the title, abstract and text. The wording methodological study or methodological review would be more appropriate. Major comments: Sampling: The authors should avoid the wording ‘sample /sampled studies’. The studies assessed actually consist of all the studies fulfilling all the eligibility criteria and identified through the search strategy. It is not a sample or a random sample of these studies. The authors should clearly indicate in the abstract and in the text, their search strategy and eligibility criteria and clarify that they selected all studies fulfilling these eligibility criteria. Abstract: The abstract should be improved. Particularly, the authors should clarify the eligibility criteria and avoid the wording ‘sample’ They should indicate how the screening was done (duplicate independently). It would be useful to clarify the main categories and indicate whether they were prespecified or determined after reading the manuscripts. They should clarify what they mean by mutual adjustment. Introduction section: The introduction is clear Methods section: the sampling is unclear. Did the authors select all studies identified, a random sample, those published in specific journals? other approaches? Their answers to the reviewers clarify their approach but it could be more detailed in the text and in the abstract. Regarding the classification, please clarify in the text whether the classification was pre- specified before data extraction or was developed over time according to the methods used in the selected papers Results The authors focus on studies published in high impact factor journal. They should clarify in the methods and in the text what this sample represents. The reviewer 3 requested to distinguish hypothesis-generating and hypothesis-driven research. The authors should clearly make the distinction using this specific wording from the start in the methods and results sections.	Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Study Version: 1 Date: 19 Dec 2024 Reviewer's report: Peer review BMC Med Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Survey Yinyan Gao et al. The authors answered all reviewers’ comments and modified the manuscript accordingly Minor comment: The authors report the study as being a methodological survey in the title, abstract and text. The wording methodological study or methodological review would be more appropriate. Major comments: Sampling: The authors should avoid the wording ‘sample /sampled studies’. The studies assessed actually consist of all the studies fulfilling all the eligibility criteria and identified through the search strategy. It is not a sample or a random sample of these studies. The authors should clearly indicate in the abstract and in the text, their search strategy and eligibility criteria and clarify that they selected all studies fulfilling these eligibility criteria. Abstract: The abstract should be improved. Particularly, the authors should clarify the eligibility criteria and avoid the wording ‘sample’ They should indicate how the screening was done (duplicate independently). It would be useful to clarify the main categories and indicate whether they were prespecified or determined after reading the manuscripts. They should clarify what they mean by mutual adjustment. Introduction section: The introduction is clear Methods section: the sampling is unclear. Did the authors select all studies identified, a random sample, those published in specific journals? other approaches? Their answers to the reviewers clarify their approach but it could be more detailed in the text and in the abstract. Regarding the classification, please clarify in the text whether the classification was pre- specified before data extraction or was developed over time according to the methods used in the selected papers Results The authors focus on studies published in high impact factor journal. They should clarify in the methods and in the text what this sample represents. The reviewer 3 requested to distinguish hypothesis-generating and hypothesis-driven research. The authors should clearly make the distinction using this specific wording from the start in the methods and results sections.	BMC	12916_2025_3957_ReviewerReport_V1_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 15, "praise": 0, "presentation_and_reporting": 11, "results_and_discussion": 1, "suggestion_and_solution": 12, "total": 19 }	{ "criticism": 0.05263157894736842, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.7894736842105263, "praise": 0, "presentation_and_reporting": 0.5789473684210527, "results_and_discussion": 0.05263157894736842, "suggestion_and_solution": 0.631578947368421 }	2.105263	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A\nMethodological Study\nVersion: 1 Date: 19 Dec 2024\nReviewer's report:\nPeer review BMC Med\nConfounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A\nMethodological Survey\nYinyan Gao et al.\nThe authors answered all reviewers’ comments and modified the manuscript accordingly\nMinor comment:\nThe authors report the study as being a methodological survey in the title, abstract and text. The\nwording methodological study or methodological review would be more appropriate.\nMajor comments:\nSampling: The authors should avoid the wording ‘sample /sampled studies’.\nThe studies assessed actually consist of all the studies fulfilling all the eligibility criteria and\nidentified through the search strategy. It is not a sample or a random sample of these studies. The\nauthors should clearly indicate in the abstract and in the text, their search strategy and eligibility\ncriteria and clarify that they selected all studies fulfilling these eligibility criteria.\nAbstract:\nThe abstract should be improved.\nParticularly, the authors should clarify the eligibility criteria and avoid the wording ‘sample’\nThey should indicate how the screening was done (duplicate independently).\nIt would be useful to clarify the main categories and indicate whether they were prespecified or\ndetermined after reading the manuscripts.\nThey should clarify what they mean by mutual adjustment.\nIntroduction section: The introduction is clear\nMethods section: the sampling is unclear. Did the authors select all studies identified, a random\nsample, those published in specific journals? other approaches?\nTheir answers to the reviewers clarify their approach but it could be more detailed in the text\nand in the abstract.\nRegarding the classification, please clarify in the text whether the classification was pre-\nspecified before data extraction or was developed over time according to the methods used in\nthe selected papers\nResults\nThe authors focus on studies published in high impact factor journal. They should clarify in the\nmethods and in the text what this sample represents.\nThe reviewer 3 requested to distinguish hypothesis-generating and hypothesis-driven research.\nThe authors should clearly make the distinction using this specific wording from the start in the\nmethods and results sections.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03957-8	Reviewed - bmc_medicine	Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Study Version: 2 Date: 26 Jan 2025 Reviewer's report: The authors answered all my questions and took into account all my suggestions. I have no other comments and believe the manuscript is ready for publications	Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A Methodological Study Version: 2 Date: 26 Jan 2025 Reviewer's report: The authors answered all my questions and took into account all my suggestions. I have no other comments and believe the manuscript is ready for publications	BMC	12916_2025_3957_ReviewerReport_V2_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0.5, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Confounder Adjustment in Observational Studies Investigating Multiple Risk Factors: A\nMethodological Study\nVersion: 2 Date: 26 Jan 2025\nReviewer's report:\nThe authors answered all my questions and took into account all my suggestions.\nI have no other comments and believe the manuscript is ready for publications", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03972-9	Reviewed - bmc_medicine	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 0 Date: 31 Oct 2024 Reviewer: Nicholas Aderinto Reviewer's report: I want to thank the authors for this timely work. The topic represents a significant gap in the literature. Here are a few comments for the authors to consider. 1. The introduction should focus more on building a background for the topic. The current introduction broadly states what is known. Only the last paragraphs discuss the rationale for the study. These comments apply to the discussion section, too. There should be a discussion on the implications of this study. 2. Since the study focused on indirect costs, this should be stated as a limitation for future studies.	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 0 Date: 31 Oct 2024 Reviewer: Nicholas Aderinto Reviewer's report: I want to thank the authors for this timely work. The topic represents a significant gap in the literature. Here are a few comments for the authors to consider. 1. The introduction should focus more on building a background for the topic. The current introduction broadly states what is known. Only the last paragraphs discuss the rationale for the study. These comments apply to the discussion section, too. There should be a discussion on the implications of this study. 2. Since the study focused on indirect costs, this should be stated as a limitation for future studies.	BMC	12916_2025_3972_ReviewerReport_V0_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 3, "materials_and_methods": 2, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 2, "suggestion_and_solution": 5, "total": 11 }	{ "criticism": 0.09090909090909091, "example": 0, "importance_and_relevance": 0.2727272727272727, "materials_and_methods": 0.18181818181818182, "praise": 0.09090909090909091, "presentation_and_reporting": 0.09090909090909091, "results_and_discussion": 0.18181818181818182, "suggestion_and_solution": 0.45454545454545453 }	1.363636	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost-\nEffectiveness and Budget Impact Analysis\nVersion: 0 Date: 31 Oct 2024\nReviewer: Nicholas Aderinto\nReviewer's report:\nI want to thank the authors for this timely work. The topic represents a significant gap in the\nliterature. Here are a few comments for the authors to consider.\n1. The introduction should focus more on building a background for the topic. The current\nintroduction broadly states what is known. Only the last paragraphs discuss the rationale for the\nstudy. These comments apply to the discussion section, too. There should be a discussion on\nthe implications of this study.\n2. Since the study focused on indirect costs, this should be stated as a limitation for future studies.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03972-9	Reviewed - bmc_medicine	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 0 Date: 18 Nov 2024 Reviewer: Dezhi Cao Reviewer's report:	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 0 Date: 18 Nov 2024 Reviewer: Dezhi Cao Reviewer's report:	BMC	12916_2025_3972_ReviewerReport_V0_R4.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost-\nEffectiveness and Budget Impact Analysis\nVersion: 0 Date: 18 Nov 2024\nReviewer: Dezhi Cao\nReviewer's report:", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03972-9	Reviewed - bmc_medicine	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 1 Date: 05 Dec 2024 Reviewer: Nicholas Aderinto Reviewer's report: The authors have addressed my previous comments.	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 1 Date: 05 Dec 2024 Reviewer: Nicholas Aderinto Reviewer's report: The authors have addressed my previous comments.	BMC	12916_2025_3972_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost-\nEffectiveness and Budget Impact Analysis\nVersion: 1 Date: 05 Dec 2024\nReviewer: Nicholas Aderinto\nReviewer's report:\nThe authors have addressed my previous comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03972-9	Reviewed - bmc_medicine	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 1 Date: 08 Feb 2025 Reviewer: Dezhi Cao Reviewer's report: The study demonstrates robust methodological design but requires enhanced data transparency, terminology consistency, and language refinement. Implementing these revisions will strengthen scientific rigor, readability, and policy relevance. Post-revision, consider professional English editing and expanded documentation of key parameters.	Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost- Effectiveness and Budget Impact Analysis Version: 1 Date: 08 Feb 2025 Reviewer: Dezhi Cao Reviewer's report: The study demonstrates robust methodological design but requires enhanced data transparency, terminology consistency, and language refinement. Implementing these revisions will strengthen scientific rigor, readability, and policy relevance. Post-revision, consider professional English editing and expanded documentation of key parameters.	BMC	12916_2025_3972_ReviewerReport_V1_R4.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 2, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 3 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.3333333333333333, "materials_and_methods": 0.6666666666666666, "praise": 0.6666666666666666, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0, "suggestion_and_solution": 0.3333333333333333 }	2.333333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Value of Cannabidiol as Adjunctive Treatment for Lennox Gastaut syndrome: Cost-\nEffectiveness and Budget Impact Analysis\nVersion: 1 Date: 08 Feb 2025\nReviewer: Dezhi Cao\nReviewer's report:\nThe study demonstrates robust methodological design but requires enhanced data transparency,\nterminology consistency, and language refinement. Implementing these revisions will\nstrengthen scientific rigor, readability, and policy relevance. Post-revision, consider professional\nEnglish editing and expanded documentation of key parameters.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 10 Nov 2024 Reviewer's report: The authors report on a 8-week, multi-centred, double-blinded, randomized, and placebo controlled trial of adjunctive agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). The results suggest that agomelatine augmentation was not superior to placebo in terms of antidepressant efficacy in adults who had an inadequate response to 2 weeks of treatment with a SSRI or SNRI. The manuscript is appropriately presented and organized and easy to follow. I have several comments that require addressing prior to any publication: 1. In the Abstract and Introduction authors refer to agomelatine as a “novel” antidepressant. It has been around for several years and is not considered novel. Please revise. 2. The authors should justify why they used a 2-week time period to consider the initial antidepressant response as inadequate. Most assessments of treatment response are based on 4 to 8 weeks of antidepressant treatment at an adequate dose. 3. Why did the authors use an upper age limit cut-off of 60 years? 4. How many participants included in the study would meet traditional criteria for treatment resistant depression (i.e., inadequate response to 2 or more antidepressant treatments for current episode)? 5. Why did the authors choose not to standardize concomitant treatment? Augmenting to either a SSRI or SNRI adds substantial noise the sample. 6. Rephrase the term “agomelatine-assisted therapy group”. 7. The authors should discuss the trial setting (China) and any association with the results. They touch on this in the Discussion, stating that the medication provided for free may have contributed to the high rates of remission in both arms. Are there any other aspects that may have inflated the response? Access to care issues? Would the results generalize to other settings/ populations? 8. There are several typos throughout the manuscript that require revision – authors should carefully proofread prior to resubmission.	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 10 Nov 2024 Reviewer's report: The authors report on a 8-week, multi-centred, double-blinded, randomized, and placebo controlled trial of adjunctive agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). The results suggest that agomelatine augmentation was not superior to placebo in terms of antidepressant efficacy in adults who had an inadequate response to 2 weeks of treatment with a SSRI or SNRI. The manuscript is appropriately presented and organized and easy to follow. I have several comments that require addressing prior to any publication: 1. In the Abstract and Introduction authors refer to agomelatine as a “novel” antidepressant. It has been around for several years and is not considered novel. Please revise. 2. The authors should justify why they used a 2-week time period to consider the initial antidepressant response as inadequate. Most assessments of treatment response are based on 4 to 8 weeks of antidepressant treatment at an adequate dose. 3. Why did the authors use an upper age limit cut-off of 60 years? 4. How many participants included in the study would meet traditional criteria for treatment resistant depression (i.e., inadequate response to 2 or more antidepressant treatments for current episode)? 5. Why did the authors choose not to standardize concomitant treatment? Augmenting to either a SSRI or SNRI adds substantial noise the sample. 6. Rephrase the term “agomelatine-assisted therapy group”. 7. The authors should discuss the trial setting (China) and any association with the results. They touch on this in the Discussion, stating that the medication provided for free may have contributed to the high rates of remission in both arms. Are there any other aspects that may have inflated the response? Access to care issues? Would the results generalize to other settings/ populations? 8. There are several typos throughout the manuscript that require revision – authors should carefully proofread prior to resubmission.	BMC	12916_2025_3951_ReviewerReport_V0_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 9, "praise": 1, "presentation_and_reporting": 4, "results_and_discussion": 5, "suggestion_and_solution": 6, "total": 27 }	{ "criticism": 0.037037037037037035, "example": 0, "importance_and_relevance": 0.037037037037037035, "materials_and_methods": 0.3333333333333333, "praise": 0.037037037037037035, "presentation_and_reporting": 0.14814814814814814, "results_and_discussion": 0.18518518518518517, "suggestion_and_solution": 0.2222222222222222 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 0 Date: 10 Nov 2024\nReviewer's report:\nThe authors report on a 8-week, multi-centred, double-blinded, randomized, and placebo\ncontrolled trial of adjunctive agomelatine versus placebo in treating MDD patients who failed to\nrespond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake\ninhibitors (SNRIs). The results suggest that agomelatine augmentation was not superior to\nplacebo in terms of antidepressant efficacy in adults who had an inadequate response to 2 weeks\nof treatment with a SSRI or SNRI. The manuscript is appropriately presented and organized and\neasy to follow. I have several comments that require addressing prior to any publication:\n1. In the Abstract and Introduction authors refer to agomelatine as a “novel” antidepressant. It\nhas been around for several years and is not considered novel. Please revise.\n2. The authors should justify why they used a 2-week time period to consider the initial\nantidepressant response as inadequate. Most assessments of treatment response are based on 4\nto 8 weeks of antidepressant treatment at an adequate dose.\n3. Why did the authors use an upper age limit cut-off of 60 years?\n4. How many participants included in the study would meet traditional criteria for treatment\nresistant depression (i.e., inadequate response to 2 or more antidepressant treatments for current\nepisode)?\n5. Why did the authors choose not to standardize concomitant treatment? Augmenting to either\na SSRI or SNRI adds substantial noise the sample.\n6. Rephrase the term “agomelatine-assisted therapy group”.\n7. The authors should discuss the trial setting (China) and any association with the results.\nThey touch on this in the Discussion, stating that the medication provided for free may have\ncontributed to the high rates of remission in both arms. Are there any other aspects that may\nhave inflated the response? Access to care issues? Would the results generalize to other settings/\npopulations?\n8. There are several typos throughout the manuscript that require revision – authors should\ncarefully proofread prior to resubmission.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 02 Dec 2024 Reviewer's report: Thankyou for this relevant RCT of agomelatine adjunctive treatment to SSRI/SNRI treatment of MDD. Most comments are available in the attachment. In addition, the ms should be proof read for language errors.	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 02 Dec 2024 Reviewer's report: Thankyou for this relevant RCT of agomelatine adjunctive treatment to SSRI/SNRI treatment of MDD. Most comments are available in the attachment. In addition, the ms should be proof read for language errors.	BMC	12916_2025_3951_ReviewerReport_V0_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 1, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 3 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.3333333333333333, "praise": 0, "presentation_and_reporting": 0.3333333333333333, "results_and_discussion": 0, "suggestion_and_solution": 0.3333333333333333 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 0 Date: 02 Dec 2024\nReviewer's report:\nThankyou for this relevant RCT of agomelatine adjunctive treatment to SSRI/SNRI treatment\nof MDD. Most comments are available in the attachment.\nIn addition, the ms should be proof read for language errors.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 10 Dec 2024 Reviewer's report: In the manuscript entitled “Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial”, the authors conducted a randomized controlled trial to investigate the efficacy and safety of augmenting antidepressant treatment with agomelatine for patients with MDD who exhibited an insufficient response to SSRIs and SNRIs during the early phase of treatment.Additionally, the study explored the effects of augmenting antidepressant treatment with agomelatine on anxiety, anhedonia, sleep quality, social functioning, and cognitive function. The authors found no significant findings in favour of the augmentation effect of agomelation for MDD patients. Overall, the experiment follows the state of the art procedures of RCT, and the manuscript is clearly written while the hypotheses of the trial are well articulated. However, some concerns, including majors and minors should still be answered by the authors before the conclusion of this paper could be accepted. Major concerns: 1. “We aimed to recruit 60 participants in each group, giving 80% power to detect a standardized effect size (Cohen’s d) of 0·52 at a two sided 5% significance level. This would correspond to a difference of 2 to 3 points on the HAMD-17 between groups, which is considered clinically significant. Allowing for a 10% loss to follow-up, we planned to recruit 67 participants in each group.” The justification for the chosen effect size is not entirely convincing, particularly about the choice of effect size. The authors mentioned Minimal Important Differences (MID), which typically reflects modest but clinically meaningful changes. If authors intend to use MID as a reference for sample size calculation, a low effect size of 0.2 would be more appropriate than a moderate effect size of 0.5, as it aligns better with the concept of MID. Please better justify their choice of effect size or to provide an updated power calculation based on the current sample size. 2. SSRI and SNRI have distinct mechanisms of action, which might result in different effects. However, the allocation of SSRI and SNRI was not considered in the trial. For instance, among 12 patients administering duloxetine, 9 were assigned to the Agomelatine + SSRI or SNRI group, and 3 were assigned to the Placebo + SSRI or SNRI group. This variability in antidepressant type could influence the overall results. The authors should address this limitation and provide a discussion of its potential impact on the findings. Minor concerns: 1. In Figure 2 and Table 1, the group labels “agomelatine” and “placebo” are inconsistent with those used in Figure 1 and Table 2 , which include the suffix “+ SSRI or SNRI”. To avoid confusion, the authors should ensure consistent labeling throughout the manuscript.	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 0 Date: 10 Dec 2024 Reviewer's report: In the manuscript entitled “Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial”, the authors conducted a randomized controlled trial to investigate the efficacy and safety of augmenting antidepressant treatment with agomelatine for patients with MDD who exhibited an insufficient response to SSRIs and SNRIs during the early phase of treatment.Additionally, the study explored the effects of augmenting antidepressant treatment with agomelatine on anxiety, anhedonia, sleep quality, social functioning, and cognitive function. The authors found no significant findings in favour of the augmentation effect of agomelation for MDD patients. Overall, the experiment follows the state of the art procedures of RCT, and the manuscript is clearly written while the hypotheses of the trial are well articulated. However, some concerns, including majors and minors should still be answered by the authors before the conclusion of this paper could be accepted. Major concerns: 1. “We aimed to recruit 60 participants in each group, giving 80% power to detect a standardized effect size (Cohen’s d) of 0·52 at a two sided 5% significance level. This would correspond to a difference of 2 to 3 points on the HAMD-17 between groups, which is considered clinically significant. Allowing for a 10% loss to follow-up, we planned to recruit 67 participants in each group.” The justification for the chosen effect size is not entirely convincing, particularly about the choice of effect size. The authors mentioned Minimal Important Differences (MID), which typically reflects modest but clinically meaningful changes. If authors intend to use MID as a reference for sample size calculation, a low effect size of 0.2 would be more appropriate than a moderate effect size of 0.5, as it aligns better with the concept of MID. Please better justify their choice of effect size or to provide an updated power calculation based on the current sample size. 2. SSRI and SNRI have distinct mechanisms of action, which might result in different effects. However, the allocation of SSRI and SNRI was not considered in the trial. For instance, among 12 patients administering duloxetine, 9 were assigned to the Agomelatine + SSRI or SNRI group, and 3 were assigned to the Placebo + SSRI or SNRI group. This variability in antidepressant type could influence the overall results. The authors should address this limitation and provide a discussion of its potential impact on the findings. Minor concerns: 1. In Figure 2 and Table 1, the group labels “agomelatine” and “placebo” are inconsistent with those used in Figure 1 and Table 2 , which include the suffix “+ SSRI or SNRI”. To avoid confusion, the authors should ensure consistent labeling throughout the manuscript.	BMC	12916_2025_3951_ReviewerReport_V0_R3.pdf	{ "criticism": 5, "example": 1, "importance_and_relevance": 1, "materials_and_methods": 10, "praise": 1, "presentation_and_reporting": 4, "results_and_discussion": 7, "suggestion_and_solution": 5, "total": 20 }	{ "criticism": 0.25, "example": 0.05, "importance_and_relevance": 0.05, "materials_and_methods": 0.5, "praise": 0.05, "presentation_and_reporting": 0.2, "results_and_discussion": 0.35, "suggestion_and_solution": 0.25 }	1.7	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 0 Date: 10 Dec 2024\nReviewer's report:\nIn the manuscript entitled “Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major\nDepressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial”, the\nauthors conducted a randomized controlled trial to investigate the efficacy and safety of\naugmenting antidepressant treatment with agomelatine for patients with MDD who exhibited\nan insufficient response to SSRIs and SNRIs during the early phase of treatment.Additionally,\nthe study explored the effects of augmenting antidepressant treatment with agomelatine on\nanxiety, anhedonia, sleep quality, social functioning, and cognitive function. The authors found\nno significant findings in favour of the augmentation effect of agomelation for MDD patients.\nOverall, the experiment follows the state of the art procedures of RCT, and the manuscript is\nclearly written while the hypotheses of the trial are well articulated. However, some concerns,\nincluding majors and minors should still be answered by the authors before the conclusion of\nthis paper could be accepted.\nMajor concerns:\n1. “We aimed to recruit 60 participants in each group, giving 80% power to detect a standardized\neffect size (Cohen’s d) of 0·52 at a two sided 5% significance level. This would correspond to\na difference of 2 to 3 points on the HAMD-17 between groups, which is considered clinically\nsignificant. Allowing for a 10% loss to follow-up, we planned to recruit 67 participants in each\ngroup.” The justification for the chosen effect size is not entirely convincing, particularly about\nthe choice of effect size. The authors mentioned Minimal Important Differences (MID), which\ntypically reflects modest but clinically meaningful changes. If authors intend to use MID as a\nreference for sample size calculation, a low effect size of 0.2 would be more appropriate than a\nmoderate effect size of 0.5, as it aligns better with the concept of MID. Please better justify their\nchoice of effect size or to provide an updated power calculation based on the current sample size.\n2. SSRI and SNRI have distinct mechanisms of action, which might result in different effects.\nHowever, the allocation of SSRI and SNRI was not considered in the trial. For instance, among\n12 patients administering duloxetine, 9 were assigned to the Agomelatine + SSRI or SNRI group,\nand 3 were assigned to the Placebo + SSRI or SNRI group. This variability in antidepressant\ntype could influence the overall results. The authors should address this limitation and provide\na discussion of its potential impact on the findings.\nMinor concerns:\n1. In Figure 2 and Table 1, the group labels “agomelatine” and “placebo” are inconsistent with\nthose used in Figure 1 and Table 2 , which include the suffix “+ SSRI or SNRI”. To avoid\nconfusion, the authors should ensure consistent labeling throughout the manuscript.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 10 Jan 2025 Reviewer's report: I thank the authors for thoughtfully responding to my critiques, which have now been adequately addressed.	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 10 Jan 2025 Reviewer's report: I thank the authors for thoughtfully responding to my critiques, which have now been adequately addressed.	BMC	12916_2025_3951_ReviewerReport_V1_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 1 Date: 10 Jan 2025\nReviewer's report:\nI thank the authors for thoughtfully responding to my critiques, which have now been adequately\naddressed.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 14 Jan 2025 Reviewer's report: I think the authors have responded adequately to my comments. i think the manuscript could be accepted for publication.	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 14 Jan 2025 Reviewer's report: I think the authors have responded adequately to my comments. i think the manuscript could be accepted for publication.	BMC	12916_2025_3951_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0.5 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 1 Date: 14 Jan 2025\nReviewer's report:\nI think the authors have responded adequately to my comments. i think the manuscript could\nbe accepted for publication.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03951-0	Reviewed - bmc_medicine	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 23 Jan 2025 Reviewer's report: Thanks for the authors’ response. Could authors estimate the current effect size based on the existing sample size and present it in the Discussion, just like the paper you cited as the reference? “First, we calculated the sample size needed to detect a moderate effect size of 0·5 by referring to the largest RCT at the time. Therefore, we cannot rule out that tDCS had effects with smaller effect sizes. Because of the 95% CI of our results and the standard deviation of the MADRS score change in our sample, the effect size would not be larger than 0·35, which is equivalent to a difference of 2·88 MADRS score points.” (Burkhardt G, Kumpf U, Crispin A, et al. Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial. Lancet. Aug 12 2023;402(10401):545-554. doi:10.1016/S0140-6736(23)00640-2)	Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder: A multicentre, double-blind, randomized, placebo-controlled trial Version: 1 Date: 23 Jan 2025 Reviewer's report: Thanks for the authors’ response. Could authors estimate the current effect size based on the existing sample size and present it in the Discussion, just like the paper you cited as the reference? “First, we calculated the sample size needed to detect a moderate effect size of 0·5 by referring to the largest RCT at the time. Therefore, we cannot rule out that tDCS had effects with smaller effect sizes. Because of the 95% CI of our results and the standard deviation of the MADRS score change in our sample, the effect size would not be larger than 0·35, which is equivalent to a difference of 2·88 MADRS score points.” (Burkhardt G, Kumpf U, Crispin A, et al. Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial. Lancet. Aug 12 2023;402(10401):545-554. doi:10.1016/S0140-6736(23)00640-2)	BMC	12916_2025_3951_ReviewerReport_V1_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 5, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 4, "suggestion_and_solution": 1, "total": 8 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.625, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0.5, "suggestion_and_solution": 0.125 }	1.25	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Agomelatine as adjunctive therapy with SSRIs or SNRIs for Major Depressive Disorder:\nA multicentre, double-blind, randomized, placebo-controlled trial\nVersion: 1 Date: 23 Jan 2025\nReviewer's report:\nThanks for the authors’ response.\nCould authors estimate the current effect size based on the existing sample size and present it in\nthe Discussion, just like the paper you cited as the reference?\n“First, we calculated the sample size needed to detect a moderate effect size of 0·5 by referring\nto the largest RCT at the time. Therefore, we cannot rule out that tDCS had effects with smaller\neffect sizes. Because of the 95% CI of our results and the standard deviation of the MADRS\nscore change in our sample, the effect size would not be larger than 0·35, which is equivalent\nto a difference of 2·88 MADRS score points.”\n(Burkhardt G, Kumpf U, Crispin A, et al. Transcranial direct current stimulation as an additional\ntreatment to selective serotonin reuptake inhibitors in adults with major depressive disorder\nin Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.\nLancet. Aug 12 2023;402(10401):545-554. doi:10.1016/S0140-6736(23)00640-2)", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 04 Oct 2024 Reviewer: Ritha Njau Reviewer's report: The manuscript is concise and well written. However I have made some suggestions in order to improve the outcome of the work which the authors could consider.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 04 Oct 2024 Reviewer: Ritha Njau Reviewer's report: The manuscript is concise and well written. However I have made some suggestions in order to improve the outcome of the work which the authors could consider.	BMC	12916_2025_3902_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 1, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0.5, "presentation_and_reporting": 0.5, "results_and_discussion": 0.5, "suggestion_and_solution": 0.5 }	2.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 0 Date: 04 Oct 2024\nReviewer: Ritha Njau\nReviewer's report:\nThe manuscript is concise and well written. However I have made some suggestions in order to\nimprove the outcome of the work which the authors could consider.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 11 Oct 2024 Reviewer's report: Thank you for the opportunity to review this manuscript. It provides a comprehensive analysis of malaria trends in Indonesia, which is particularly valuable for a country aiming for malaria elimination. I found the study insightful, and I believe the authors have made significant contributions. My comments below are suggestions for the authors to consider. [Line 97] Could the authors elaborate on the rationale behind the two sets of age cutoffs (the second set further described in Figure 6B)? When referring to adults as 15+ years old and associating high incidence among “adult” males with "occupational risk", this may be an overgeneralization. Additional explanation would help clarify the choice and implications of these categories. [Line 144] Only Plasmodium vivax (Pv) cases were presented in this analysis when raw Plasmodium falciparum (Pf) cases were observed to be higher throughout the decade (Figure 1B). Could the authors clarify the reasoning behind this focus? [Line 147] In the text, it would improve readability to specify the age range/s when referring to the “youngest age groups.” [Line 166] The current phrasing (“no declining trend” in case-finding efforts) could be reframed in a more positive light. For example, describing it as “stable” might be more suitable. [Line 197] Consider adding the word “Finally” at the beginning of the sentence that introduces the last figure (Figure 6) for better flow. [Line 280] Could the authors provide examples of the ongoing barriers to progress referred to in Papua? Are there specific barriers unique to this region (e.g. poverty, conflict) that could explain the current situation? [Line 324] The terms “variations in climate factors” and “climate variability” used in the same sentence seem redundant. Consider rephrasing for clarity. [Line 508] In Figure 2A, it might be worth slightly adjusting the placement of the “A” label (currently too close to the year below it i.e. 2010). In Figure 2B, to clarify the category labels for API per 1,000, it may be helpful to indicate that these ranges are mutually exclusive, if that is the case. For instance, changing “5-50” to “>5-50” and “50-100” to “>50-100” could make this distinction clearer. Additionally in Figure 2B, the labels for the years (2010, 2015, 2019), appears to have some overlap with other objects, affecting the legibility of the top part of those year labels. [Line 509] The phrase “(from the top to the bottom row, respectively)” can be removed from the Figure 2A legend, as the figure is clear and self-explanatory. [Line 514] The font used in Figure 3D legend appears different from that used in other figures (also noted in Figure S1D). Consider standardizing the font style for consistency. [Discussion/Limitations] Discussing potential biases, gaps in data, or challenges in surveillance can help readers better understand the context of the findings, and if possible, provide implications for policy and practice to improve future research efforts on routine surveillance data. [Discussion/Conclusion] The importance of inter-district cooperation was emphasized. This could be expanded upon in both the discussion and conclusion sections, highlighting successful case studies or models from other regions that could be adapted for Indonesia.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 11 Oct 2024 Reviewer's report: Thank you for the opportunity to review this manuscript. It provides a comprehensive analysis of malaria trends in Indonesia, which is particularly valuable for a country aiming for malaria elimination. I found the study insightful, and I believe the authors have made significant contributions. My comments below are suggestions for the authors to consider. [Line 97] Could the authors elaborate on the rationale behind the two sets of age cutoffs (the second set further described in Figure 6B)? When referring to adults as 15+ years old and associating high incidence among “adult” males with "occupational risk", this may be an overgeneralization. Additional explanation would help clarify the choice and implications of these categories. [Line 144] Only Plasmodium vivax (Pv) cases were presented in this analysis when raw Plasmodium falciparum (Pf) cases were observed to be higher throughout the decade (Figure 1B). Could the authors clarify the reasoning behind this focus? [Line 147] In the text, it would improve readability to specify the age range/s when referring to the “youngest age groups.” [Line 166] The current phrasing (“no declining trend” in case-finding efforts) could be reframed in a more positive light. For example, describing it as “stable” might be more suitable. [Line 197] Consider adding the word “Finally” at the beginning of the sentence that introduces the last figure (Figure 6) for better flow. [Line 280] Could the authors provide examples of the ongoing barriers to progress referred to in Papua? Are there specific barriers unique to this region (e.g. poverty, conflict) that could explain the current situation? [Line 324] The terms “variations in climate factors” and “climate variability” used in the same sentence seem redundant. Consider rephrasing for clarity. [Line 508] In Figure 2A, it might be worth slightly adjusting the placement of the “A” label (currently too close to the year below it i.e. 2010). In Figure 2B, to clarify the category labels for API per 1,000, it may be helpful to indicate that these ranges are mutually exclusive, if that is the case. For instance, changing “5-50” to “>5-50” and “50-100” to “>50-100” could make this distinction clearer. Additionally in Figure 2B, the labels for the years (2010, 2015, 2019), appears to have some overlap with other objects, affecting the legibility of the top part of those year labels. [Line 509] The phrase “(from the top to the bottom row, respectively)” can be removed from the Figure 2A legend, as the figure is clear and self-explanatory. [Line 514] The font used in Figure 3D legend appears different from that used in other figures (also noted in Figure S1D). Consider standardizing the font style for consistency. [Discussion/Limitations] Discussing potential biases, gaps in data, or challenges in surveillance can help readers better understand the context of the findings, and if possible, provide implications for policy and practice to improve future research efforts on routine surveillance data. [Discussion/Conclusion] The importance of inter-district cooperation was emphasized. This could be expanded upon in both the discussion and conclusion sections, highlighting successful case studies or models from other regions that could be adapted for Indonesia.	BMC	12916_2025_3902_ReviewerReport_V0_R2.pdf	{ "criticism": 2, "example": 13, "importance_and_relevance": 4, "materials_and_methods": 7, "praise": 2, "presentation_and_reporting": 12, "results_and_discussion": 4, "suggestion_and_solution": 15, "total": 28 }	{ "criticism": 0.07142857142857142, "example": 0.4642857142857143, "importance_and_relevance": 0.14285714285714285, "materials_and_methods": 0.25, "praise": 0.07142857142857142, "presentation_and_reporting": 0.42857142857142855, "results_and_discussion": 0.14285714285714285, "suggestion_and_solution": 0.5357142857142857 }	2.107143	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 0 Date: 11 Oct 2024\nReviewer's report:\nThank you for the opportunity to review this manuscript. It provides a comprehensive analysis\nof malaria trends in Indonesia, which is particularly valuable for a country aiming for malaria\nelimination. I found the study insightful, and I believe the authors have made significant\ncontributions. My comments below are suggestions for the authors to consider.\n[Line 97] Could the authors elaborate on the rationale behind the two sets of age cutoffs\n(the second set further described in Figure 6B)? When referring to adults as 15+ years old\nand associating high incidence among “adult” males with \"occupational risk\", this may be an\novergeneralization. Additional explanation would help clarify the choice and implications of\nthese categories.\n[Line 144] Only Plasmodium vivax (Pv) cases were presented in this analysis when raw\nPlasmodium falciparum (Pf) cases were observed to be higher throughout the decade (Figure\n1B). Could the authors clarify the reasoning behind this focus?\n[Line 147] In the text, it would improve readability to specify the age range/s when referring\nto the “youngest age groups.”\n[Line 166] The current phrasing (“no declining trend” in case-finding efforts) could be reframed\nin a more positive light. For example, describing it as “stable” might be more suitable.\n[Line 197] Consider adding the word “Finally” at the beginning of the sentence that introduces\nthe last figure (Figure 6) for better flow.\n[Line 280] Could the authors provide examples of the ongoing barriers to progress referred to in\nPapua? Are there specific barriers unique to this region (e.g. poverty, conflict) that could explain\nthe current situation?\n[Line 324] The terms “variations in climate factors” and “climate variability” used in the same\nsentence seem redundant. Consider rephrasing for clarity.\n[Line 508] In Figure 2A, it might be worth slightly adjusting the placement of the “A” label\n(currently too close to the year below it i.e. 2010). In Figure 2B, to clarify the category labels\nfor API per 1,000, it may be helpful to indicate that these ranges are mutually exclusive, if that\nis the case. For instance, changing “5-50” to “>5-50” and “50-100” to “>50-100” could make\nthis distinction clearer. Additionally in Figure 2B, the labels for the years (2010, 2015, 2019),\nappears to have some overlap with other objects, affecting the legibility of the top part of those\nyear labels.\n[Line 509] The phrase “(from the top to the bottom row, respectively)” can be removed from\nthe Figure 2A legend, as the figure is clear and self-explanatory.\n[Line 514] The font used in Figure 3D legend appears different from that used in other figures\n(also noted in Figure S1D). Consider standardizing the font style for consistency.\n[Discussion/Limitations] Discussing potential biases, gaps in data, or challenges in surveillance\ncan help readers better understand the context of the findings, and if possible, provide\nimplications for policy and practice to improve future research efforts on routine surveillance\ndata.\n[Discussion/Conclusion] The importance of inter-district cooperation was emphasized. This\ncould be expanded upon in both the discussion and conclusion sections, highlighting successful\ncase studies or models from other regions that could be adapted for Indonesia.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 24 Oct 2024 Reviewer: Ingrid Chen Reviewer's report: Shifts in Indonesia’s malaria landscape: an analysis of 2010-2019 routine surveillance data BMC Medicine peer review This paper is about Indonesia’s progress towards malaria elimination from 2010 to 2019. There is a lot of data here as well as the identification of the most challenging locations. I suggest some edits to emphasize the paper’s impact. Abstract: - Background – the 2013 detail is not necessary here. The point is that progress has plateaued, I think it’s better to leave it at that. - Methods – give a bit more detail on the stat methods used, including that you did modeling. - Results – please give numbers of cases identified and some stats to show the scope of what you have found. - Conclusion to focus on Papua can be more concise. Background: - This is well written and gives a good picture of the situation in Indonesia and some of the challenges. The last sentence can be clearer. “True picture” could be more specific without implying the picture at the moment is not true. Something about more detailed information, that can be used to develop targeted strategies. Tie this to plateaued progress and how this paper can help to address this. Methods: - Looks good, suggest some of this be worked into the abstract (see above). Results: - Very info rich and results are organized well with fitting tables and figures. Small formatting issue on page 10 (the lines look wider spaced), I think the proofing process can fix this though. - Figures are very nice. Discussion: - Line 243 should be “trial” not “trials” - Paragraph on tafenoquine vs primaquine needs some work. A few points: o Is the single RCT enough to say that tafenoquine with DP didn’t work? Why? Artemisnin resistance? Note that tafenoquine requires quantitative G6Pd testing, this needs to be mentioned and understood. o Short-course 7 day primaquine improves adherence? Compared to what, 14 days of PQ? This needs to be clarified, adherence is usually the issue with PQ for radical cure, which is the value of tafenoquine. I believe there are other options for tafenoquine – you can look into this – be it partner drugs or regimens. o Weekly primaquine can be used in G6PD deficient individuals. - No examination of zoonotic infections – this should be mentioned earlier, why this was not done and affiliated challenges. - Any thoughts on P ovale and P malariae? - This section goes in depth as to some reasons for heterogenous transmission, which his interesting. Would be great to get more recommendations on subnational tailoring. What should be done where? This is implied in different sections but can come together as ~3 main recommendations indicating who, what, where are the priority / most challenging locations based on your findings.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 0 Date: 24 Oct 2024 Reviewer: Ingrid Chen Reviewer's report: Shifts in Indonesia’s malaria landscape: an analysis of 2010-2019 routine surveillance data BMC Medicine peer review This paper is about Indonesia’s progress towards malaria elimination from 2010 to 2019. There is a lot of data here as well as the identification of the most challenging locations. I suggest some edits to emphasize the paper’s impact. Abstract: - Background – the 2013 detail is not necessary here. The point is that progress has plateaued, I think it’s better to leave it at that. - Methods – give a bit more detail on the stat methods used, including that you did modeling. - Results – please give numbers of cases identified and some stats to show the scope of what you have found. - Conclusion to focus on Papua can be more concise. Background: - This is well written and gives a good picture of the situation in Indonesia and some of the challenges. The last sentence can be clearer. “True picture” could be more specific without implying the picture at the moment is not true. Something about more detailed information, that can be used to develop targeted strategies. Tie this to plateaued progress and how this paper can help to address this. Methods: - Looks good, suggest some of this be worked into the abstract (see above). Results: - Very info rich and results are organized well with fitting tables and figures. Small formatting issue on page 10 (the lines look wider spaced), I think the proofing process can fix this though. - Figures are very nice. Discussion: - Line 243 should be “trial” not “trials” - Paragraph on tafenoquine vs primaquine needs some work. A few points: o Is the single RCT enough to say that tafenoquine with DP didn’t work? Why? Artemisnin resistance? Note that tafenoquine requires quantitative G6Pd testing, this needs to be mentioned and understood. o Short-course 7 day primaquine improves adherence? Compared to what, 14 days of PQ? This needs to be clarified, adherence is usually the issue with PQ for radical cure, which is the value of tafenoquine. I believe there are other options for tafenoquine – you can look into this – be it partner drugs or regimens. o Weekly primaquine can be used in G6PD deficient individuals. - No examination of zoonotic infections – this should be mentioned earlier, why this was not done and affiliated challenges. - Any thoughts on P ovale and P malariae? - This section goes in depth as to some reasons for heterogenous transmission, which his interesting. Would be great to get more recommendations on subnational tailoring. What should be done where? This is implied in different sections but can come together as ~3 main recommendations indicating who, what, where are the priority / most challenging locations based on your findings.	BMC	12916_2025_3902_ReviewerReport_V0_R4.pdf	{ "criticism": 0, "example": 2, "importance_and_relevance": 1, "materials_and_methods": 9, "praise": 5, "presentation_and_reporting": 16, "results_and_discussion": 5, "suggestion_and_solution": 18, "total": 33 }	{ "criticism": 0, "example": 0.06060606060606061, "importance_and_relevance": 0.030303030303030304, "materials_and_methods": 0.2727272727272727, "praise": 0.15151515151515152, "presentation_and_reporting": 0.48484848484848486, "results_and_discussion": 0.15151515151515152, "suggestion_and_solution": 0.5454545454545454 }	1.69697	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 0 Date: 24 Oct 2024\nReviewer: Ingrid Chen\nReviewer's report:\nShifts in Indonesia’s malaria landscape: an analysis of 2010-2019 routine surveillance data\nBMC Medicine peer review\nThis paper is about Indonesia’s progress towards malaria elimination from 2010 to 2019. There\nis a lot of data here as well as the identification of the most challenging locations. I suggest some\nedits to emphasize the paper’s impact.\nAbstract:\n- Background – the 2013 detail is not necessary here. The point is that progress has plateaued,\nI think it’s better to leave it at that.\n- Methods – give a bit more detail on the stat methods used, including that you did modeling.\n- Results – please give numbers of cases identified and some stats to show the scope of what\nyou have found.\n- Conclusion to focus on Papua can be more concise.\nBackground:\n- This is well written and gives a good picture of the situation in Indonesia and some of the\nchallenges. The last sentence can be clearer. “True picture” could be more specific without\nimplying the picture at the moment is not true. Something about more detailed information, that\ncan be used to develop targeted strategies. Tie this to plateaued progress and how this paper can\nhelp to address this.\nMethods:\n- Looks good, suggest some of this be worked into the abstract (see above).\nResults:\n- Very info rich and results are organized well with fitting tables and figures. Small formatting\nissue on page 10 (the lines look wider spaced), I think the proofing process can fix this though.\n- Figures are very nice.\nDiscussion:\n- Line 243 should be “trial” not “trials”\n- Paragraph on tafenoquine vs primaquine needs some work. A few points:\no Is the single RCT enough to say that tafenoquine with DP didn’t work? Why? Artemisnin\nresistance? Note that tafenoquine requires quantitative G6Pd testing, this needs to be mentioned\nand understood.\no Short-course 7 day primaquine improves adherence? Compared to what, 14 days of PQ? This\nneeds to be clarified, adherence is usually the issue with PQ for radical cure, which is the value\nof tafenoquine. I believe there are other options for tafenoquine – you can look into this – be\nit partner drugs or regimens.\no Weekly primaquine can be used in G6PD deficient individuals.\n- No examination of zoonotic infections – this should be mentioned earlier, why this was not\ndone and affiliated challenges.\n- Any thoughts on P ovale and P malariae?\n- This section goes in depth as to some reasons for heterogenous transmission, which his\ninteresting. Would be great to get more recommendations on subnational tailoring. What\nshould be done where? This is implied in different sections but can come together as ~3 main\nrecommendations indicating who, what, where are the priority / most challenging locations based\non your findings.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 21 Nov 2024 Reviewer: Ritha Njau Reviewer's report: The manuscript has taken into consideration all the reviewers concerns and is an excellent piece of work. I have very few editorials which I have done in track changes in the revised manuscript.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 21 Nov 2024 Reviewer: Ritha Njau Reviewer's report: The manuscript has taken into consideration all the reviewers concerns and is an excellent piece of work. I have very few editorials which I have done in track changes in the revised manuscript.	BMC	12916_2025_3902_ReviewerReport_V1_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0.5, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 1 Date: 21 Nov 2024\nReviewer: Ritha Njau\nReviewer's report:\nThe manuscript has taken into consideration all the reviewers concerns and is an excellent piece\nof work.\nI have very few editorials which I have done in track changes in the revised manuscript.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 26 Nov 2024 Reviewer: Ingrid Chen Reviewer's report: Thanks for your edits. Most of my points raised were well addressed. Quick suggestion: abstract conclusions are wordy and you say in results that cases in Papua are concentrated in children. You could jump to the point here - more efforts are needed in Papua, but your suggestions need to match your findings described in the abstract more so edit both accordingly. Everything else looks good.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 26 Nov 2024 Reviewer: Ingrid Chen Reviewer's report: Thanks for your edits. Most of my points raised were well addressed. Quick suggestion: abstract conclusions are wordy and you say in results that cases in Papua are concentrated in children. You could jump to the point here - more efforts are needed in Papua, but your suggestions need to match your findings described in the abstract more so edit both accordingly. Everything else looks good.	BMC	12916_2025_3902_ReviewerReport_V1_R4.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 2, "presentation_and_reporting": 3, "results_and_discussion": 2, "suggestion_and_solution": 2, "total": 5 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0.4, "presentation_and_reporting": 0.6, "results_and_discussion": 0.4, "suggestion_and_solution": 0.4 }	1.8	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 1 Date: 26 Nov 2024\nReviewer: Ingrid Chen\nReviewer's report:\nThanks for your edits. Most of my points raised were well addressed.\nQuick suggestion: abstract conclusions are wordy and you say in results that cases in Papua are\nconcentrated in children. You could jump to the point here - more efforts are needed in Papua,\nbut your suggestions need to match your findings described in the abstract more so edit both\naccordingly.\nEverything else looks good.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03902-9	Reviewed - bmc_medicine	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 07 Dec 2024 Reviewer's report: Thank you for the opportunity to review the revised manuscript titled Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019. The authors have addressed my comments and suggestions thoughtfully and comprehensively, including clarifying the API category levels in Figure 2B. I recommend double-checking the cutoff labels in Figure 2B to ensure they appear as intended. I am satisfied with the revisions and have no further comments. I recommend the manuscript for publication.	Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019 Version: 1 Date: 07 Dec 2024 Reviewer's report: Thank you for the opportunity to review the revised manuscript titled Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data 2010-2019. The authors have addressed my comments and suggestions thoughtfully and comprehensively, including clarifying the API category levels in Figure 2B. I recommend double-checking the cutoff labels in Figure 2B to ensure they appear as intended. I am satisfied with the revisions and have no further comments. I recommend the manuscript for publication.	BMC	12916_2025_3902_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 1, "importance_and_relevance": 0, "materials_and_methods": 2, "praise": 3, "presentation_and_reporting": 2, "results_and_discussion": 0, "suggestion_and_solution": 2, "total": 5 }	{ "criticism": 0.2, "example": 0.2, "importance_and_relevance": 0, "materials_and_methods": 0.4, "praise": 0.6, "presentation_and_reporting": 0.4, "results_and_discussion": 0, "suggestion_and_solution": 0.4 }	2.2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Spatiotemporal heterogeneity in malaria transmission across Indonesia: analysis of\nroutine surveillance data 2010-2019\nVersion: 1 Date: 07 Dec 2024\nReviewer's report:\nThank you for the opportunity to review the revised manuscript titled Spatiotemporal\nheterogeneity in malaria transmission across Indonesia: analysis of routine surveillance data\n2010-2019. The authors have addressed my comments and suggestions thoughtfully and\ncomprehensively, including clarifying the API category levels in Figure 2B. I recommend\ndouble-checking the cutoff labels in Figure 2B to ensure they appear as intended.\nI am satisfied with the revisions and have no further comments. I recommend the manuscript\nfor publication.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 04 Nov 2024 Reviewer's report: In this study, Yang and colleagues conducted proteomics and metabolomics analysis to study potential mechanisms of COVID-19 patients with prolonged symptoms up to three years after discharge. I have the following comments. 1) Proteomics and metabolomics analysis of patients with post-acute sequelae of COVID-19 (PASC) has been conducted in earlier studies. The authors should discuss the similarity and difference of the findings in this study and previous studies. 2) The description of “Proteomics analysis” is too brief and more information needs to be provided. For plasma proteomics, it’s quite common to do protein depletion, as the 22 most abundant proteins account for 99% of the protein content, which would prevent the detection of less abundant proteins. However, it’s not clear if the protein depletion step was done or not in “Proteomics analysis” 3) The description of “Metabolomics analysis” is also too brief and more information needs to be provided. Importantly, quality control (QC) samples (mixture of a small aliquot of all the samples) were not mentioned in the analysis. The performance of mass spec can drift along time, and it’s important to include QC samples in the analysis. Without QCs, it is difficult to determine the reliability of the data in this study. 4) Study Design: 23 patients were followed up for 3 years. Do these patients belong to nDLco or aDLco group, or a mixture from both groups? Meanwhile, “the plasma biomarker panel was then validated in a testing cohort”. The information of this testing cohort should be included in the “Patient Enrollment”. 5) Dynamics of Metabolomic Signature across 3-year After SARS-CoV-2 Infection: how was figure 4D prepared and is it to sum up like the peak area of all the fatty acyls? If so, not sure if this is a good way to present the data and it may amplify the difference among different groups. 6) Page 14, line 290: should “proteins” be “metabolites” here? Line 293: should Fig 6A should be 6B here? 7) Distinguish Individuals with Respiratory Sequelae From Controls at 6 Months: It is important to confirm the structure of the 2 metabolite biomarkers in the panel with chemical standards, considering the potential of their clinical application. Why is there a D8 in arachidonoyl EA and does it mean it’s a deuterated form? As it’s almost impossible to have a deuterated form of arachidonoyl EA in plasma of all these patients, it’s very likely to be a wrong identification. The authors should give more details on how the 7 metabolites used in the machine learning models were identified.	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 04 Nov 2024 Reviewer's report: In this study, Yang and colleagues conducted proteomics and metabolomics analysis to study potential mechanisms of COVID-19 patients with prolonged symptoms up to three years after discharge. I have the following comments. 1) Proteomics and metabolomics analysis of patients with post-acute sequelae of COVID-19 (PASC) has been conducted in earlier studies. The authors should discuss the similarity and difference of the findings in this study and previous studies. 2) The description of “Proteomics analysis” is too brief and more information needs to be provided. For plasma proteomics, it’s quite common to do protein depletion, as the 22 most abundant proteins account for 99% of the protein content, which would prevent the detection of less abundant proteins. However, it’s not clear if the protein depletion step was done or not in “Proteomics analysis” 3) The description of “Metabolomics analysis” is also too brief and more information needs to be provided. Importantly, quality control (QC) samples (mixture of a small aliquot of all the samples) were not mentioned in the analysis. The performance of mass spec can drift along time, and it’s important to include QC samples in the analysis. Without QCs, it is difficult to determine the reliability of the data in this study. 4) Study Design: 23 patients were followed up for 3 years. Do these patients belong to nDLco or aDLco group, or a mixture from both groups? Meanwhile, “the plasma biomarker panel was then validated in a testing cohort”. The information of this testing cohort should be included in the “Patient Enrollment”. 5) Dynamics of Metabolomic Signature across 3-year After SARS-CoV-2 Infection: how was figure 4D prepared and is it to sum up like the peak area of all the fatty acyls? If so, not sure if this is a good way to present the data and it may amplify the difference among different groups. 6) Page 14, line 290: should “proteins” be “metabolites” here? Line 293: should Fig 6A should be 6B here? 7) Distinguish Individuals with Respiratory Sequelae From Controls at 6 Months: It is important to confirm the structure of the 2 metabolite biomarkers in the panel with chemical standards, considering the potential of their clinical application. Why is there a D8 in arachidonoyl EA and does it mean it’s a deuterated form? As it’s almost impossible to have a deuterated form of arachidonoyl EA in plasma of all these patients, it’s very likely to be a wrong identification. The authors should give more details on how the 7 metabolites used in the machine learning models were identified.	BMC	12916_2025_3971_ReviewerReport_V0_R1.pdf	{ "criticism": 4, "example": 3, "importance_and_relevance": 0, "materials_and_methods": 16, "praise": 0, "presentation_and_reporting": 7, "results_and_discussion": 1, "suggestion_and_solution": 10, "total": 22 }	{ "criticism": 0.18181818181818182, "example": 0.13636363636363635, "importance_and_relevance": 0, "materials_and_methods": 0.7272727272727273, "praise": 0, "presentation_and_reporting": 0.3181818181818182, "results_and_discussion": 0.045454545454545456, "suggestion_and_solution": 0.45454545454545453 }	1.863636	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 0 Date: 04 Nov 2024\nReviewer's report:\nIn this study, Yang and colleagues conducted proteomics and metabolomics analysis to study\npotential mechanisms of COVID-19 patients with prolonged symptoms up to three years after\ndischarge. I have the following comments.\n1) Proteomics and metabolomics analysis of patients with post-acute sequelae of COVID-19\n(PASC) has been conducted in earlier studies. The authors should discuss the similarity and\ndifference of the findings in this study and previous studies.\n2) The description of “Proteomics analysis” is too brief and more information needs to be\nprovided. For plasma proteomics, it’s quite common to do protein depletion, as the 22 most\nabundant proteins account for 99% of the protein content, which would prevent the detection\nof less abundant proteins. However, it’s not clear if the protein depletion step was done or not\nin “Proteomics analysis”\n3) The description of “Metabolomics analysis” is also too brief and more information needs to\nbe provided. Importantly, quality control (QC) samples (mixture of a small aliquot of all the\nsamples) were not mentioned in the analysis. The performance of mass spec can drift along\ntime, and it’s important to include QC samples in the analysis. Without QCs, it is difficult to\ndetermine the reliability of the data in this study.\n4) Study Design: 23 patients were followed up for 3 years. Do these patients belong to nDLco\nor aDLco group, or a mixture from both groups? Meanwhile, “the plasma biomarker panel was\nthen validated in a testing cohort”. The information of this testing cohort should be included in\nthe “Patient Enrollment”.\n5) Dynamics of Metabolomic Signature across 3-year After SARS-CoV-2 Infection: how was\nfigure 4D prepared and is it to sum up like the peak area of all the fatty acyls? If so, not sure if\nthis is a good way to present the data and it may amplify the difference among different groups.\n6) Page 14, line 290: should “proteins” be “metabolites” here? Line 293: should Fig 6A should\nbe 6B here?\n7) Distinguish Individuals with Respiratory Sequelae From Controls at 6 Months: It is important\nto confirm the structure of the 2 metabolite biomarkers in the panel with chemical standards,\nconsidering the potential of their clinical application. Why is there a D8 in arachidonoyl EA\nand does it mean it’s a deuterated form? As it’s almost impossible to have a deuterated form\nof arachidonoyl EA in plasma of all these patients, it’s very likely to be a wrong identification.\nThe authors should give more details on how the 7 metabolites used in the machine learning\nmodels were identified.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 28 Dec 2024 Reviewer's report: Thank you for the opportunity to review the research article by Yang et al. The authors identified molecular sequela among COVID-19 convalescents across 3 years after infection and developed a novel model to predict the impairment of diffusion capacity. The longitudinal multi-omics analysis was applied in this study. The data demonstrate some key proteins and metabolites constitute a biomarker panel to predict the impairment of diffusion capacity. Overall, the topic and data are interesting and important, but I have some concerns regarding the analysis. I therefore suggest major revision of the manuscript. 1. Please add more details on the blood collection and processing. 2. The written informed consent should also be obtained from healthy controls. 3. The authors wrote “p-value” in different ways, including P-value, p-value, p in figure legends and results. 4. In figure 1A, the word “distarged” needs to be modified to “discharged”. In figure 7D, the red curve of Arachidonoyl-Ea(D8) is missing. 5. Proteomics and metabolomics data should be validated by different approaches, and if possible, additional samples. 6. The molecular mechanisms should be validated experimentally. 7. I am not convinced that the stepwise analysis, first analyzing all patients as one group and then separating for the individual disease types is the most powerful and correct way to analyze the different disease groups.	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 28 Dec 2024 Reviewer's report: Thank you for the opportunity to review the research article by Yang et al. The authors identified molecular sequela among COVID-19 convalescents across 3 years after infection and developed a novel model to predict the impairment of diffusion capacity. The longitudinal multi-omics analysis was applied in this study. The data demonstrate some key proteins and metabolites constitute a biomarker panel to predict the impairment of diffusion capacity. Overall, the topic and data are interesting and important, but I have some concerns regarding the analysis. I therefore suggest major revision of the manuscript. 1. Please add more details on the blood collection and processing. 2. The written informed consent should also be obtained from healthy controls. 3. The authors wrote “p-value” in different ways, including P-value, p-value, p in figure legends and results. 4. In figure 1A, the word “distarged” needs to be modified to “discharged”. In figure 7D, the red curve of Arachidonoyl-Ea(D8) is missing. 5. Proteomics and metabolomics data should be validated by different approaches, and if possible, additional samples. 6. The molecular mechanisms should be validated experimentally. 7. I am not convinced that the stepwise analysis, first analyzing all patients as one group and then separating for the individual disease types is the most powerful and correct way to analyze the different disease groups.	BMC	12916_2025_3971_ReviewerReport_V0_R2.pdf	{ "criticism": 3, "example": 2, "importance_and_relevance": 2, "materials_and_methods": 10, "praise": 1, "presentation_and_reporting": 3, "results_and_discussion": 1, "suggestion_and_solution": 6, "total": 21 }	{ "criticism": 0.14285714285714285, "example": 0.09523809523809523, "importance_and_relevance": 0.09523809523809523, "materials_and_methods": 0.47619047619047616, "praise": 0.047619047619047616, "presentation_and_reporting": 0.14285714285714285, "results_and_discussion": 0.047619047619047616, "suggestion_and_solution": 0.2857142857142857 }	1.333333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 0 Date: 28 Dec 2024\nReviewer's report:\nThank you for the opportunity to review the research article by Yang et al. The authors identified\nmolecular sequela among COVID-19 convalescents across 3 years after infection and developed\na novel model to predict the impairment of diffusion capacity. The longitudinal multi-omics\nanalysis was applied in this study. The data\ndemonstrate some key proteins and metabolites constitute a biomarker panel to predict the\nimpairment of diffusion capacity.\nOverall, the topic and data are interesting and important, but I have some concerns regarding\nthe analysis. I therefore suggest major revision of the manuscript.\n1. Please add more details on the blood collection and processing.\n2. The written informed consent should also be obtained from healthy controls.\n3. The authors wrote “p-value” in different ways, including P-value, p-value, p in figure legends\nand results.\n4. In figure 1A, the word “distarged” needs to be modified to “discharged”. In figure 7D, the\nred curve of Arachidonoyl-Ea(D8) is missing.\n5. Proteomics and metabolomics data should be validated by different approaches, and if\npossible, additional samples.\n6. The molecular mechanisms should be validated experimentally.\n7. I am not convinced that the stepwise analysis, first analyzing all patients as one group and\nthen separating for the individual disease types is the most powerful and correct way to analyze\nthe different disease groups.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 28 Dec 2024 Reviewer's report: This study is valuable and warrants publication, but certain revisions are recommended prior to acceptance: 1. The control group was recruited from a pre-COVID-19 physical examination cohort with a limited sample size. Given such constraints, potential confounding factors (e.g., environment, diet, vaccination status) are likely unavoidable. Has this limited the generalizability of the findings? Please discuss. 2. Although multi-omics approaches have identified candidate biomarkers, additional verification in an independent cohort is lacking. Is it feasible to conduct such a validation? If not, please include a discussion of its limitations. 3. In both the proteomic and metabolomic analyses, please provide a more detailed description of procedures such as sample handling and preparation. 4. The study reports molecular changes such as immunosuppression and impaired gas transport, which warrant further exploration. It is suggested that you expand the discussion by proposing possible molecular or cellular mechanisms. For example, how does SARS-CoV-2 infection interact with red blood cells or hemoglobin function? 5. In the figure legends, consider adding more intuitive indicators for each group, along with significance levels or fold-change values. 6. In the abstract, the statement of research objectives and primary findings is somewhat concise. Consider adding one or two sentences to clearly clarify the research background and main conclusions.	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 0 Date: 28 Dec 2024 Reviewer's report: This study is valuable and warrants publication, but certain revisions are recommended prior to acceptance: 1. The control group was recruited from a pre-COVID-19 physical examination cohort with a limited sample size. Given such constraints, potential confounding factors (e.g., environment, diet, vaccination status) are likely unavoidable. Has this limited the generalizability of the findings? Please discuss. 2. Although multi-omics approaches have identified candidate biomarkers, additional verification in an independent cohort is lacking. Is it feasible to conduct such a validation? If not, please include a discussion of its limitations. 3. In both the proteomic and metabolomic analyses, please provide a more detailed description of procedures such as sample handling and preparation. 4. The study reports molecular changes such as immunosuppression and impaired gas transport, which warrant further exploration. It is suggested that you expand the discussion by proposing possible molecular or cellular mechanisms. For example, how does SARS-CoV-2 infection interact with red blood cells or hemoglobin function? 5. In the figure legends, consider adding more intuitive indicators for each group, along with significance levels or fold-change values. 6. In the abstract, the statement of research objectives and primary findings is somewhat concise. Consider adding one or two sentences to clearly clarify the research background and main conclusions.	BMC	12916_2025_3971_ReviewerReport_V0_R6.pdf	{ "criticism": 3, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 8, "praise": 2, "presentation_and_reporting": 6, "results_and_discussion": 5, "suggestion_and_solution": 7, "total": 20 }	{ "criticism": 0.15, "example": 0, "importance_and_relevance": 0.05, "materials_and_methods": 0.4, "praise": 0.1, "presentation_and_reporting": 0.3, "results_and_discussion": 0.25, "suggestion_and_solution": 0.35 }	1.6	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 0 Date: 28 Dec 2024\nReviewer's report:\nThis study is valuable and warrants publication, but certain revisions are recommended prior\nto acceptance:\n1. The control group was recruited from a pre-COVID-19 physical examination cohort with a\nlimited sample size. Given such constraints, potential confounding factors (e.g., environment,\ndiet, vaccination status) are likely unavoidable. Has this limited the generalizability of the\nfindings? Please discuss.\n2. Although multi-omics approaches have identified candidate biomarkers, additional\nverification in an independent cohort is lacking. Is it feasible to conduct such a validation? If\nnot, please include a discussion of its limitations.\n3. In both the proteomic and metabolomic analyses, please provide a more detailed description\nof procedures such as sample handling and preparation.\n4. The study reports molecular changes such as immunosuppression and impaired gas transport,\nwhich warrant further exploration. It is suggested that you expand the discussion by proposing\npossible molecular or cellular mechanisms. For example, how does SARS-CoV-2 infection\ninteract with red blood cells or hemoglobin function?\n5. In the figure legends, consider adding more intuitive indicators for each group, along with\nsignificance levels or fold-change values.\n6. In the abstract, the statement of research objectives and primary findings is somewhat concise.\nConsider adding one or two sentences to clearly clarify the research background and main\nconclusions.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 02 Feb 2025 Reviewer's report: Based on the extensive revisions carried out by the authors in response to the reviewers’ comments, the manuscript now demonstrates significantly improved clarity in its experimental methods, data analyses, and discussion of findings. The additional details on methodology, the corrections made to previously unclear data points, and the enhanced exploration of underlying mechanisms all align with standard publication requirements. Therefore, I believe the revised manuscript is sufficiently robust and merits acceptance for publication.	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 02 Feb 2025 Reviewer's report: Based on the extensive revisions carried out by the authors in response to the reviewers’ comments, the manuscript now demonstrates significantly improved clarity in its experimental methods, data analyses, and discussion of findings. The additional details on methodology, the corrections made to previously unclear data points, and the enhanced exploration of underlying mechanisms all align with standard publication requirements. Therefore, I believe the revised manuscript is sufficiently robust and merits acceptance for publication.	BMC	12916_2025_3971_ReviewerReport_V1_R6.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 2, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 1, "suggestion_and_solution": 0, "total": 3 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.6666666666666666, "praise": 0.6666666666666666, "presentation_and_reporting": 0, "results_and_discussion": 0.3333333333333333, "suggestion_and_solution": 0 }	1.666667	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 1 Date: 02 Feb 2025\nReviewer's report:\nBased on the extensive revisions carried out by the authors in response to the reviewers’\ncomments, the manuscript now demonstrates significantly improved clarity in its experimental\nmethods, data analyses, and discussion of findings. The additional details on methodology, the\ncorrections made to previously unclear data points, and the enhanced exploration of underlying\nmechanisms all align with standard publication requirements. Therefore, I believe the revised\nmanuscript is sufficiently robust and merits acceptance for publication.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 05 Feb 2025 Reviewer's report: Thank you for the opportunity to review the research article. I have no other suggestions	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 05 Feb 2025 Reviewer's report: Thank you for the opportunity to review the research article. I have no other suggestions	BMC	12916_2025_3971_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0.5, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 1 Date: 05 Feb 2025\nReviewer's report:\nThank you for the opportunity to review the research article. I have no other suggestions", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03971-w	Reviewed - bmc_medicine	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 09 Feb 2025 Reviewer's report: All my comments have been satisfactorily addressed by the authors and I'd like to suggest acceptance of the manuscript	Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6-36 months after COVID-19 Version: 1 Date: 09 Feb 2025 Reviewer's report: All my comments have been satisfactorily addressed by the authors and I'd like to suggest acceptance of the manuscript	BMC	12916_2025_3971_ReviewerReport_V1_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 1 }	3	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae\n6-36 months after COVID-19\nVersion: 1 Date: 09 Feb 2025\nReviewer's report:\nAll my comments have been satisfactorily addressed by the authors and I'd like to suggest\nacceptance of the manuscript", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 28 Oct 2024 Reviewer's report: This manuscript explored the joint associations between accelerometer-measured physical activity and sedentary time with frailty status on mortality risk. Using data from UK Biobank participants without missing frailty scores, the authors conducted a survival analysis. Higher levels of physical activity were inversely associated with mortality risk across all frailty groups, whereas higher levels of sedentary time were positively associated with mortality risk across these groups. Individuals with both high sedentary time and high frailty had the highest mortality risk. An analysis of joint associations could inform targeted public health interventions to promote physical activity across population subgroups. However, some methodological details are quite sparse, and the authors failed to describe the existing field of evidence for the individual associations with mortality. Lastly, the authors frequently use causal language, despite this being an observational study. Please see the below suggestions for revisions: Suggestions for Revisions: 1. Since this is an observational study, causal language should be avoided throughout. Terms like "impact," "reduced risk," "benefits," or "linked" should be replaced with more accurate, non-causal phrasing. 2. Typos appear throughout the manuscript, especially with terms like "accelerometer- measured" and "accelerometer measured." Please ensure consistent use of hyphens. 3. In the Introduction, I suggest adding a few sentences describing what frailty is. 4. Page 4, Line 11: There is a typo with a missing word in "has documented." 5. Introduction, Paragraph 3 (Page 4, Line 20): This paragraph is repetitive. Additionally, in the sentence starting on Line 20, clarify the inverse association to specify whether higher or lower PA is being referenced. 6. Methods Section (Page 5): The second and third paragraphs seem out of order. Consider describing the accelerometer data collection first before discussing exclusion criteria. 7. More information about the variables used in the frailty index would be helpful on Page 6. The supplemental materials describe some health conditions, but it is unclear if these were self-reported or collected from hospital data. A general description of the information used to calculate the score would improve clarity. 8. Page 6, Line 24: The phrasing "ethnicity assumed not to have changed" does not seem correct; "self-reported ethnicity" would be clearer. 9. Page 6, Supplemental Figure 2: The description of covariate updates is unclear. Supplemental Figure 2 suggests that not all participants had data for all covariates and that visit 3 interview data collection overlapped with accelerometer data. I suggest that the authors clarify that most participants did not have updated variables, and that data was used from baseline (which of course could introduce bias). Also, I suggest the authors specify that covariates measured after accelerometer collection were not used, as this was not clear from the supplementary figure. 10. Page 8, Line 18: Provide more details on the "waking window" used and why it was defined this way. How did this treat participants who may have had waking hours outside this period (e.g., early risers, night shift workers) as this could bias results? Was this considered for the sensitive analysis? 11. Page 10, Line 28: If the authors did not conduct a systematic review, they should avoid claiming this study is the "first" of its kind. 12. Page 11, Line 17: The discussion of sex differences is interesting, but I recommend adding a comment on potential cause-specific mortality. Documented differences in causes of mortality for males and females could be relevant here. 13. In the Discussion section, consider referencing more prior studies on physical activity, sedentary behaviour, frailty, and mortality. The rationale for examining joint associations should be supported by previous research in this area, such as the work by Delgado-Velandia et al. (https://doi.org/10.1093/ageing/afad092), who conducted a similar analysis using a healthy living index, including physical activity, in the UK Biobank. 14. Nearly 14,000 individuals with missing frailty index data were excluded. I strongly suggest that the authors include a table comparing these individuals to the included participants would be helpful to assess potential selection bias. 15. In the Supplemental Materials, ensure all abbreviations are spelt out in each figure or table (e.g., ENMO). 16. Some citations appear incomplete, lacking details like authors (References 15, 17, 23). Ensure all references are complete. 17. Supplemental Figure 1: There is a note indicating that individuals with ENMO >10 mg were excluded. Based on other UK Biobank studies, this might be a typo, possibly meaning 100 mg. Please double-check this value. 18. Supplemental Figure 5: Align the x-axes across rows to facilitate easier comparisons across frailty categories. 19. Throughout the manuscript, the terms "male" and "men" as well as "female" and "women" are used interchangeably. Please clarify whether the study examines sex or gender and ensure consistent terminology. 20. Several supplemental materials are not mentioned in the main text (e.g., Supplemental Tables 5–12 and 20–23, and Supplemental Figures 3–5). If these tables and figures are not relevant to the manuscript, consider omitting them.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 28 Oct 2024 Reviewer's report: This manuscript explored the joint associations between accelerometer-measured physical activity and sedentary time with frailty status on mortality risk. Using data from UK Biobank participants without missing frailty scores, the authors conducted a survival analysis. Higher levels of physical activity were inversely associated with mortality risk across all frailty groups, whereas higher levels of sedentary time were positively associated with mortality risk across these groups. Individuals with both high sedentary time and high frailty had the highest mortality risk. An analysis of joint associations could inform targeted public health interventions to promote physical activity across population subgroups. However, some methodological details are quite sparse, and the authors failed to describe the existing field of evidence for the individual associations with mortality. Lastly, the authors frequently use causal language, despite this being an observational study. Please see the below suggestions for revisions: Suggestions for Revisions: 1. Since this is an observational study, causal language should be avoided throughout. Terms like "impact," "reduced risk," "benefits," or "linked" should be replaced with more accurate, non-causal phrasing. 2. Typos appear throughout the manuscript, especially with terms like "accelerometer- measured" and "accelerometer measured." Please ensure consistent use of hyphens. 3. In the Introduction, I suggest adding a few sentences describing what frailty is. 4. Page 4, Line 11: There is a typo with a missing word in "has documented." 5. Introduction, Paragraph 3 (Page 4, Line 20): This paragraph is repetitive. Additionally, in the sentence starting on Line 20, clarify the inverse association to specify whether higher or lower PA is being referenced. 6. Methods Section (Page 5): The second and third paragraphs seem out of order. Consider describing the accelerometer data collection first before discussing exclusion criteria. 7. More information about the variables used in the frailty index would be helpful on Page 6. The supplemental materials describe some health conditions, but it is unclear if these were self-reported or collected from hospital data. A general description of the information used to calculate the score would improve clarity. 8. Page 6, Line 24: The phrasing "ethnicity assumed not to have changed" does not seem correct; "self-reported ethnicity" would be clearer. 9. Page 6, Supplemental Figure 2: The description of covariate updates is unclear. Supplemental Figure 2 suggests that not all participants had data for all covariates and that visit 3 interview data collection overlapped with accelerometer data. I suggest that the authors clarify that most participants did not have updated variables, and that data was used from baseline (which of course could introduce bias). Also, I suggest the authors specify that covariates measured after accelerometer collection were not used, as this was not clear from the supplementary figure. 10. Page 8, Line 18: Provide more details on the "waking window" used and why it was defined this way. How did this treat participants who may have had waking hours outside this period (e.g., early risers, night shift workers) as this could bias results? Was this considered for the sensitive analysis? 11. Page 10, Line 28: If the authors did not conduct a systematic review, they should avoid claiming this study is the "first" of its kind. 12. Page 11, Line 17: The discussion of sex differences is interesting, but I recommend adding a comment on potential cause-specific mortality. Documented differences in causes of mortality for males and females could be relevant here. 13. In the Discussion section, consider referencing more prior studies on physical activity, sedentary behaviour, frailty, and mortality. The rationale for examining joint associations should be supported by previous research in this area, such as the work by Delgado-Velandia et al. (https://doi.org/10.1093/ageing/afad092), who conducted a similar analysis using a healthy living index, including physical activity, in the UK Biobank. 14. Nearly 14,000 individuals with missing frailty index data were excluded. I strongly suggest that the authors include a table comparing these individuals to the included participants would be helpful to assess potential selection bias. 15. In the Supplemental Materials, ensure all abbreviations are spelt out in each figure or table (e.g., ENMO). 16. Some citations appear incomplete, lacking details like authors (References 15, 17, 23). Ensure all references are complete. 17. Supplemental Figure 1: There is a note indicating that individuals with ENMO >10 mg were excluded. Based on other UK Biobank studies, this might be a typo, possibly meaning 100 mg. Please double-check this value. 18. Supplemental Figure 5: Align the x-axes across rows to facilitate easier comparisons across frailty categories. 19. Throughout the manuscript, the terms "male" and "men" as well as "female" and "women" are used interchangeably. Please clarify whether the study examines sex or gender and ensure consistent terminology. 20. Several supplemental materials are not mentioned in the main text (e.g., Supplemental Tables 5–12 and 20–23, and Supplemental Figures 3–5). If these tables and figures are not relevant to the manuscript, consider omitting them.	BMC	12916_2025_3960_ReviewerReport_V0_R1.pdf	{ "criticism": 8, "example": 16, "importance_and_relevance": 2, "materials_and_methods": 23, "praise": 1, "presentation_and_reporting": 30, "results_and_discussion": 5, "suggestion_and_solution": 25, "total": 67 }	{ "criticism": 0.11940298507462686, "example": 0.23880597014925373, "importance_and_relevance": 0.029850746268656716, "materials_and_methods": 0.34328358208955223, "praise": 0.014925373134328358, "presentation_and_reporting": 0.44776119402985076, "results_and_discussion": 0.07462686567164178, "suggestion_and_solution": 0.373134328358209 }	1.641791	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 0 Date: 28 Oct 2024\nReviewer's report:\nThis manuscript explored the joint associations between accelerometer-measured physical\nactivity and sedentary time with frailty status on mortality risk. Using data from UK Biobank\nparticipants without missing frailty scores, the authors conducted a survival analysis. Higher\nlevels of physical activity were inversely associated with mortality risk across all frailty groups,\nwhereas higher levels of sedentary time were positively associated with mortality risk across\nthese groups. Individuals with both high sedentary time and high frailty had the highest mortality\nrisk. An analysis of joint associations could inform targeted public health interventions to\npromote physical activity across population subgroups. However, some methodological details\nare quite sparse, and the authors failed to describe the existing field of evidence for the individual\nassociations with mortality. Lastly, the authors frequently use causal language, despite this being\nan observational study.\nPlease see the below suggestions for revisions:\nSuggestions for Revisions:\n1. Since this is an observational study, causal language should be avoided throughout. Terms\nlike \"impact,\" \"reduced risk,\" \"benefits,\" or \"linked\" should be replaced with more accurate,\nnon-causal phrasing.\n2. Typos appear throughout the manuscript, especially with terms like \"accelerometer-\nmeasured\" and \"accelerometer measured.\" Please ensure consistent use of hyphens.\n3. In the Introduction, I suggest adding a few sentences describing what frailty is.\n4. Page 4, Line 11: There is a typo with a missing word in \"has documented.\"\n5. Introduction, Paragraph 3 (Page 4, Line 20): This paragraph is repetitive. Additionally, in the\nsentence starting on Line 20, clarify the inverse association to specify whether higher or lower\nPA is being referenced.\n6. Methods Section (Page 5): The second and third paragraphs seem out of order. Consider\ndescribing the accelerometer data collection first before discussing exclusion criteria.\n7. More information about the variables used in the frailty index would be helpful on Page\n6. The supplemental materials describe some health conditions, but it is unclear if these were\nself-reported or collected from hospital data. A general description of the information used to\ncalculate the score would improve clarity.\n8. Page 6, Line 24: The phrasing \"ethnicity assumed not to have changed\" does not seem correct;\n\"self-reported ethnicity\" would be clearer.\n9. Page 6, Supplemental Figure 2: The description of covariate updates is unclear. Supplemental\nFigure 2 suggests that not all participants had data for all covariates and that visit 3 interview\ndata collection overlapped with accelerometer data. I suggest that the authors clarify that most\nparticipants did not have updated variables, and that data was used from baseline (which of\ncourse could introduce bias). Also, I suggest the authors specify that covariates measured after\naccelerometer collection were not used, as this was not clear from the supplementary figure.\n10. Page 8, Line 18: Provide more details on the \"waking window\" used and why it was defined\nthis way. How did this treat participants who may have had waking hours outside this period\n(e.g., early risers, night shift workers) as this could bias results? Was this considered for the\nsensitive analysis?\n11. Page 10, Line 28: If the authors did not conduct a systematic review, they should avoid\nclaiming this study is the \"first\" of its kind.\n12. Page 11, Line 17: The discussion of sex differences is interesting, but I recommend adding a\ncomment on potential cause-specific mortality. Documented differences in causes of mortality\nfor males and females could be relevant here.\n13. In the Discussion section, consider referencing more prior studies on physical activity,\nsedentary behaviour, frailty, and mortality. The rationale for examining joint associations should\nbe supported by previous research in this area, such as the work by Delgado-Velandia et\nal. (https://doi.org/10.1093/ageing/afad092), who conducted a similar analysis using a healthy\nliving index, including physical activity, in the UK Biobank.\n14. Nearly 14,000 individuals with missing frailty index data were excluded. I strongly suggest\nthat the authors include a table comparing these individuals to the included participants would\nbe helpful to assess potential selection bias.\n15. In the Supplemental Materials, ensure all abbreviations are spelt out in each figure or table\n(e.g., ENMO).\n16. Some citations appear incomplete, lacking details like authors (References 15, 17, 23).\nEnsure all references are complete.\n17. Supplemental Figure 1: There is a note indicating that individuals with ENMO >10 mg were\nexcluded. Based on other UK Biobank studies, this might be a typo, possibly meaning 100 mg.\nPlease double-check this value.\n18. Supplemental Figure 5: Align the x-axes across rows to facilitate easier comparisons across\nfrailty categories.\n19. Throughout the manuscript, the terms \"male\" and \"men\" as well as \"female\" and \"women\"\nare used interchangeably. Please clarify whether the study examines sex or gender and ensure\nconsistent terminology.\n20. Several supplemental materials are not mentioned in the main text (e.g., Supplemental Tables\n5–12 and 20–23, and Supplemental Figures 3–5). If these tables and figures are not relevant to\nthe manuscript, consider omitting them.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 08 Nov 2024 Reviewer's report: Thank you for the opportunity to review this article. The current study addresses an important research topic within the scope of BMC Medicine and is generally well-written. However, there are a few minor points that may benefit from further consideration before publication: 1#The following paper is closely related to your research. Please consider citing it, and also check whether there are other similar studies that might be relevant: Watanabe et al., 2023 [PMID: 36726206]. 2#Please indicate the reference values for each physical activity and sedentary time in the spline curves to clarify the interpretation of your results. 3#Supplementary Figure 3 shows correlations between physical activity and sedentary time variables. Given this, please consider whether including other physical activity and sedentary time variables in the Cox models would affect your current results. Additionally, please expand on how unadjusted results should be interpreted in the main text.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 08 Nov 2024 Reviewer's report: Thank you for the opportunity to review this article. The current study addresses an important research topic within the scope of BMC Medicine and is generally well-written. However, there are a few minor points that may benefit from further consideration before publication: 1#The following paper is closely related to your research. Please consider citing it, and also check whether there are other similar studies that might be relevant: Watanabe et al., 2023 [PMID: 36726206]. 2#Please indicate the reference values for each physical activity and sedentary time in the spline curves to clarify the interpretation of your results. 3#Supplementary Figure 3 shows correlations between physical activity and sedentary time variables. Given this, please consider whether including other physical activity and sedentary time variables in the Cox models would affect your current results. Additionally, please expand on how unadjusted results should be interpreted in the main text.	BMC	12916_2025_3960_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 1, "importance_and_relevance": 1, "materials_and_methods": 3, "praise": 1, "presentation_and_reporting": 5, "results_and_discussion": 4, "suggestion_and_solution": 5, "total": 8 }	{ "criticism": 0, "example": 0.125, "importance_and_relevance": 0.125, "materials_and_methods": 0.375, "praise": 0.125, "presentation_and_reporting": 0.625, "results_and_discussion": 0.5, "suggestion_and_solution": 0.625 }	2.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 0 Date: 08 Nov 2024\nReviewer's report:\nThank you for the opportunity to review this article. The current study addresses an important\nresearch topic within the scope of BMC Medicine and is generally well-written. However, there\nare a few minor points that may benefit from further consideration before publication:\n1#The following paper is closely related to your research. Please consider citing it, and also\ncheck whether there are other similar studies that might be relevant: Watanabe et al., 2023\n[PMID: 36726206].\n2#Please indicate the reference values for each physical activity and sedentary time in the spline\ncurves to clarify the interpretation of your results.\n3#Supplementary Figure 3 shows correlations between physical activity and sedentary time\nvariables. Given this, please consider whether including other physical activity and sedentary\ntime variables in the Cox models would affect your current results. Additionally, please expand\non how unadjusted results should be interpreted in the main text.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 22 Nov 2024 Reviewer's report: The present manuscript aimed to investigate interactive effects of accelerometer-measured PA with frailty on all-cause mortality and life expectancy based on participants from the UK Biobank. The authors conclude that promoting physical activity (PA) and reducing sedentary behavior across the frailty spectrum improves life expectancy. The manuscript is overall well- written and benefits from its large study sample and objective assessment of physical activity. However, I have some concerns regarding operationalization of frailty status and handling of physical activity variables that the authors hopefully could address. - Frailty status is based on a 49-item index comprising a wide array of risk indicators and disease states. I have a few questions regarding this index: Given the wide array of different items, each implicated with different levels of severity for health, a question is how these items are weighted together to form the FI score? For example, individuals with the same number of deficits will belong to the same category (e.g. frail category), while the type of deficits will create different impacts on the life expectancy (e.g., being diagnosed with multiple cancers vs. hearing difficulty or occasional sleeping problems). Could the authors please explain whether or not the ‘severity level’ of each item is adjusted for in some way. Loss of muscle mass and muscle strength is a well-evidenced age-related process, which can lead to sarcopenia and related loss of independence in older adults. What is the rationale behind not including information about body composition and muscle strength in the FI? - The introduction of the manuscript questions whether PA might be less effective or feasible a health-enhancing factor for those in advanced stages of frailty. Therefore, the aim is to investigate the effects of PA with frailty on all-cause mortality and life expectancy. However, the analysis is based on several PA variables, total volume and time spent in different intensities of PA (LPA and MVPA) as well as sedentary time. Each variable contains different types of information, but the authors make no hypotheses about whether different intensities of PA will have different impacts on the outcome variables. Thus, it is currently not clear why information about PA besides total volume is necessary in order to address the study aim as it is currently formulated. Can the authors please justify the necessity of analyzing time spent in different intensities by providing a rationale in the introduction, as this is currently lacking. - Also related to the previous comment about PA variables: Implications of the findings regarding time spent in different intensities versus total PA volume are sparsely addressed in the discussion of the study findings. For example, the authors write “we found that being physically active and less sedentary was linked to even greater gains in life expectancy among people with frailty”. What does it mean to be physically active in this context and how is it determined? A lot of time in LPA? Time in MVPA? Simply a large PA volume, regardless of the intensity? Please include a discussion paragraph evaluating the importance of PA volume vs. intensity-specific PA time with a clearer message about the implications of the study findings to the reader. - As the awake time is calculated to a finite number of hours, an increase in time in one intensity category inevitably leads to a decrease in another. Currently, it is not clear in the manuscript how time in PA (LPA and MVPA) was controlled for when investigating effects by sedentary time or vice versa. For example, individuals who spend a large portion of daily time in sedentary behaviors may still accumulate health-enhancing amounts of MVPA (e.g. 150 min/week), which has been shown to attenuate detrimental effects by ST. Hence, without proper adjustment for this issue, it becomes difficult to conclude whether sedentary time per se is detrimental to health or simply a reflection of variations in time spent in higher PA intensities. Of course, this issue is solved if the authors only use total PA volume, which in my opinion would suffice to answer to the aim as it is currently formulated. However, if the aim should include investigations of intensity-specific effects, this issue needs to be addressed. - Please add references to support the following proposed explanations behind the study findings. “This phenomenon warrants further investigation into the underlying mechanisms. One possible explanation is that men, typically having higher muscle mass and oxygen uptake capacity, might experience a more significant impact from the decline in physical function. Additionally, men's tendency towards more vigorous exercise could mean that any reduction in their activity levels might result in more pronounced changes compared to women”. (page 11, rows 19-24). - Although the objective assessment of PA is a strength of the study, the fact that variations in energy cost during certain types of PA, e.g., stair climbing, bicycling, load carrying and many non-ambulatory muscle-strengthening activities cannot be reliably detected by the monitor may be acknowledged in the limitations section.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 0 Date: 22 Nov 2024 Reviewer's report: The present manuscript aimed to investigate interactive effects of accelerometer-measured PA with frailty on all-cause mortality and life expectancy based on participants from the UK Biobank. The authors conclude that promoting physical activity (PA) and reducing sedentary behavior across the frailty spectrum improves life expectancy. The manuscript is overall well- written and benefits from its large study sample and objective assessment of physical activity. However, I have some concerns regarding operationalization of frailty status and handling of physical activity variables that the authors hopefully could address. - Frailty status is based on a 49-item index comprising a wide array of risk indicators and disease states. I have a few questions regarding this index: Given the wide array of different items, each implicated with different levels of severity for health, a question is how these items are weighted together to form the FI score? For example, individuals with the same number of deficits will belong to the same category (e.g. frail category), while the type of deficits will create different impacts on the life expectancy (e.g., being diagnosed with multiple cancers vs. hearing difficulty or occasional sleeping problems). Could the authors please explain whether or not the ‘severity level’ of each item is adjusted for in some way. Loss of muscle mass and muscle strength is a well-evidenced age-related process, which can lead to sarcopenia and related loss of independence in older adults. What is the rationale behind not including information about body composition and muscle strength in the FI? - The introduction of the manuscript questions whether PA might be less effective or feasible a health-enhancing factor for those in advanced stages of frailty. Therefore, the aim is to investigate the effects of PA with frailty on all-cause mortality and life expectancy. However, the analysis is based on several PA variables, total volume and time spent in different intensities of PA (LPA and MVPA) as well as sedentary time. Each variable contains different types of information, but the authors make no hypotheses about whether different intensities of PA will have different impacts on the outcome variables. Thus, it is currently not clear why information about PA besides total volume is necessary in order to address the study aim as it is currently formulated. Can the authors please justify the necessity of analyzing time spent in different intensities by providing a rationale in the introduction, as this is currently lacking. - Also related to the previous comment about PA variables: Implications of the findings regarding time spent in different intensities versus total PA volume are sparsely addressed in the discussion of the study findings. For example, the authors write “we found that being physically active and less sedentary was linked to even greater gains in life expectancy among people with frailty”. What does it mean to be physically active in this context and how is it determined? A lot of time in LPA? Time in MVPA? Simply a large PA volume, regardless of the intensity? Please include a discussion paragraph evaluating the importance of PA volume vs. intensity-specific PA time with a clearer message about the implications of the study findings to the reader. - As the awake time is calculated to a finite number of hours, an increase in time in one intensity category inevitably leads to a decrease in another. Currently, it is not clear in the manuscript how time in PA (LPA and MVPA) was controlled for when investigating effects by sedentary time or vice versa. For example, individuals who spend a large portion of daily time in sedentary behaviors may still accumulate health-enhancing amounts of MVPA (e.g. 150 min/week), which has been shown to attenuate detrimental effects by ST. Hence, without proper adjustment for this issue, it becomes difficult to conclude whether sedentary time per se is detrimental to health or simply a reflection of variations in time spent in higher PA intensities. Of course, this issue is solved if the authors only use total PA volume, which in my opinion would suffice to answer to the aim as it is currently formulated. However, if the aim should include investigations of intensity-specific effects, this issue needs to be addressed. - Please add references to support the following proposed explanations behind the study findings. “This phenomenon warrants further investigation into the underlying mechanisms. One possible explanation is that men, typically having higher muscle mass and oxygen uptake capacity, might experience a more significant impact from the decline in physical function. Additionally, men's tendency towards more vigorous exercise could mean that any reduction in their activity levels might result in more pronounced changes compared to women”. (page 11, rows 19-24). - Although the objective assessment of PA is a strength of the study, the fact that variations in energy cost during certain types of PA, e.g., stair climbing, bicycling, load carrying and many non-ambulatory muscle-strengthening activities cannot be reliably detected by the monitor may be acknowledged in the limitations section.	BMC	12916_2025_3960_ReviewerReport_V0_R4.pdf	{ "criticism": 5, "example": 3, "importance_and_relevance": 1, "materials_and_methods": 13, "praise": 2, "presentation_and_reporting": 6, "results_and_discussion": 8, "suggestion_and_solution": 6, "total": 37 }	{ "criticism": 0.13513513513513514, "example": 0.08108108108108109, "importance_and_relevance": 0.02702702702702703, "materials_and_methods": 0.35135135135135137, "praise": 0.05405405405405406, "presentation_and_reporting": 0.16216216216216217, "results_and_discussion": 0.21621621621621623, "suggestion_and_solution": 0.16216216216216217 }	1.189189	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 0 Date: 22 Nov 2024\nReviewer's report:\nThe present manuscript aimed to investigate interactive effects of accelerometer-measured PA\nwith frailty on all-cause mortality and life expectancy based on participants from the UK\nBiobank. The authors conclude that promoting physical activity (PA) and reducing sedentary\nbehavior across the frailty spectrum improves life expectancy. The manuscript is overall well-\nwritten and benefits from its large study sample and objective assessment of physical activity.\nHowever, I have some concerns regarding operationalization of frailty status and handling of\nphysical activity variables that the authors hopefully could address.\n- Frailty status is based on a 49-item index comprising a wide array of risk indicators and disease\nstates. I have a few questions regarding this index:\nGiven the wide array of different items, each implicated with different levels of severity for\nhealth, a question is how these items are weighted together to form the FI score?\nFor example, individuals with the same number of deficits will belong to the same category (e.g.\nfrail category), while the type of deficits will create different impacts on the life expectancy (e.g.,\nbeing diagnosed with multiple cancers vs. hearing difficulty or occasional sleeping problems).\nCould the authors please explain whether or not the ‘severity level’ of each item is adjusted for\nin some way.\nLoss of muscle mass and muscle strength is a well-evidenced age-related process, which can\nlead to sarcopenia and related loss of independence in older adults. What is the rationale behind\nnot including information about body composition and muscle strength in the FI?\n- The introduction of the manuscript questions whether PA might be less effective or feasible\na health-enhancing factor for those in advanced stages of frailty. Therefore, the aim is to\ninvestigate the effects of PA with frailty on all-cause mortality and life expectancy. However,\nthe analysis is based on several PA variables, total volume and time spent in different intensities\nof PA (LPA and MVPA) as well as sedentary time. Each variable contains different types of\ninformation, but the authors make no hypotheses about whether different intensities of PA will\nhave different impacts on the outcome variables. Thus, it is currently not clear why information\nabout PA besides total volume is necessary in order to address the study aim as it is currently\nformulated. Can the authors please justify the necessity of analyzing time spent in different\nintensities by providing a rationale in the introduction, as this is currently lacking.\n- Also related to the previous comment about PA variables: Implications of the findings\nregarding time spent in different intensities versus total PA volume are sparsely addressed in the\ndiscussion of the study findings. For example, the authors write “we found that being physically\nactive and less sedentary was linked to even greater gains in life expectancy among people with\nfrailty”. What does it mean to be physically active in this context and how is it determined? A lot\nof time in LPA? Time in MVPA? Simply a large PA volume, regardless of the intensity? Please\ninclude a discussion paragraph evaluating the importance of PA volume vs. intensity-specific\nPA time with a clearer message about the implications of the study findings to the reader.\n- As the awake time is calculated to a finite number of hours, an increase in time in one intensity\ncategory inevitably leads to a decrease in another. Currently, it is not clear in the manuscript\nhow time in PA (LPA and MVPA) was controlled for when investigating effects by sedentary\ntime or vice versa. For example, individuals who spend a large portion of daily time in sedentary\nbehaviors may still accumulate health-enhancing amounts of MVPA (e.g. 150 min/week), which\nhas been shown to attenuate detrimental effects by ST. Hence, without proper adjustment for\nthis issue, it becomes difficult to conclude whether sedentary time per se is detrimental to health\nor simply a reflection of variations in time spent in higher PA intensities. Of course, this issue\nis solved if the authors only use total PA volume, which in my opinion would suffice to answer\nto the aim as it is currently formulated. However, if the aim should include investigations of\nintensity-specific effects, this issue needs to be addressed.\n- Please add references to support the following proposed explanations behind the study findings.\n“This phenomenon warrants further investigation into the underlying mechanisms. One possible\nexplanation is that men, typically having higher muscle mass and oxygen uptake capacity, might\nexperience a more significant impact from the decline in physical function. Additionally, men's\ntendency towards more vigorous exercise could mean that any reduction in their activity levels\nmight result in more pronounced changes compared to women”. (page 11, rows 19-24).\n- Although the objective assessment of PA is a strength of the study, the fact that variations in\nenergy cost during certain types of PA, e.g., stair climbing, bicycling, load carrying and many\nnon-ambulatory muscle-strengthening activities cannot be reliably detected by the monitor may\nbe acknowledged in the limitations section.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 14 Jan 2025 Reviewer's report: The authors have addressed all issues previously raised and improved the quality of the manuscript. I congratulate the authors for a nice work. I have no further comments.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 14 Jan 2025 Reviewer's report: The authors have addressed all issues previously raised and improved the quality of the manuscript. I congratulate the authors for a nice work. I have no further comments.	BMC	12916_2025_3960_ReviewerReport_V1_R4.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 3 }	{ "criticism": 0.3333333333333333, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.3333333333333333, "praise": 0.6666666666666666, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1.333333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 1 Date: 14 Jan 2025\nReviewer's report:\nThe authors have addressed all issues previously raised and improved the quality of the\nmanuscript. I congratulate the authors for a nice work. I have no further comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 21 Jan 2025 Reviewer's report: Thank you very much for your response to my review. I have no further comments.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 21 Jan 2025 Reviewer's report: Thank you very much for your response to my review. I have no further comments.	BMC	12916_2025_3960_ReviewerReport_V1_R3.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0.5, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 1 Date: 21 Jan 2025\nReviewer's report:\nThank you very much for your response to my review. I have no further comments.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03960-z	Reviewed - bmc_medicine	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 25 Jan 2025 Reviewer's report: Thank you for the opportunity to review this manuscript regarding the joint associations between accelerometer-measured physical activity, sedentary time, frailty status, and mortality risk. I appreciate the authors' revisions and believe they have adequately addressed my feedback. The manuscript is well-written, and the authors accurately describe the study and its limitations. The new sensitivity analyses and additional details about their methods have strengthened the manuscript. I have no further edits at this time.	Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life expectancy among middle-aged and older adults: a UK Biobank longitudinal study Version: 1 Date: 25 Jan 2025 Reviewer's report: Thank you for the opportunity to review this manuscript regarding the joint associations between accelerometer-measured physical activity, sedentary time, frailty status, and mortality risk. I appreciate the authors' revisions and believe they have adequately addressed my feedback. The manuscript is well-written, and the authors accurately describe the study and its limitations. The new sensitivity analyses and additional details about their methods have strengthened the manuscript. I have no further edits at this time.	BMC	12916_2025_3960_ReviewerReport_V1_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 2, "praise": 3, "presentation_and_reporting": 2, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 5 }	{ "criticism": 0.2, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.4, "praise": 0.6, "presentation_and_reporting": 0.4, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1.6	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Accelerometer-measured physical activity, frailty, and all-cause mortality and life\nexpectancy among middle-aged and older adults: a UK Biobank longitudinal study\nVersion: 1 Date: 25 Jan 2025\nReviewer's report:\nThank you for the opportunity to review this manuscript regarding the joint associations between\naccelerometer-measured physical activity, sedentary time, frailty status, and mortality risk. I\nappreciate the authors' revisions and believe they have adequately addressed my feedback. The\nmanuscript is well-written, and the authors accurately describe the study and its limitations.\nThe new sensitivity analyses and additional details about their methods have strengthened the\nmanuscript. I have no further edits at this time.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03954-x	Reviewed - bmc_medicine	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 0 Date: 12 Nov 2024 Reviewer's report:	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 0 Date: 12 Nov 2024 Reviewer's report:	BMC	12916_2025_3954_ReviewerReport_V0_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case\ncontrol study\nVersion: 0 Date: 12 Nov 2024\nReviewer's report:", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03954-x	Reviewed - bmc_medicine	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 0 Date: 24 Nov 2024 Reviewer's report: Dear authors, this is an interesting paper on potential use of vulvar smears in diagnosis of vulvar pre invasive lesions. I have some comments on it: Line 36: please unify terminology throughout manuscript according to LAST/ISSVD: VHSIL or dVIN LINE 41: same for lichen sclerosUs. Lichen ruber should be renamed lichen planus line 59: I would unify terminology and use Squamous Intraepithelial Lesion (SIL) instead of VIN Line 62-63: ignorer to stress the difference in oncogenic potential, I would cite the difference in progression risk of dVIN, that can be as high as 43.2% after treatment (please cite 10.1111/ aogs.14814) Line 64-66: I would rephrase: VHSIL is treated in order to exclude foci of invasion and lower the risk of progression to cancer Line 71: dysplasia free margin is not an absolute target in VHSIL treatment, please refer to Preti M, Joura E, Vieira-Baptista P, et al The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) consensus statements on pre-invasive vulvar lesions International Journal of Gynecologic Cancer 2022;32:830-845. Line 328 what is PAPIIID2? I would discuss limitations of the present study: no follow up, limited case numbers, etc Really interesting conclusion, this is an exploratory analysis that can open a new issue in vulvar pathology and diagnosis.	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 0 Date: 24 Nov 2024 Reviewer's report: Dear authors, this is an interesting paper on potential use of vulvar smears in diagnosis of vulvar pre invasive lesions. I have some comments on it: Line 36: please unify terminology throughout manuscript according to LAST/ISSVD: VHSIL or dVIN LINE 41: same for lichen sclerosUs. Lichen ruber should be renamed lichen planus line 59: I would unify terminology and use Squamous Intraepithelial Lesion (SIL) instead of VIN Line 62-63: ignorer to stress the difference in oncogenic potential, I would cite the difference in progression risk of dVIN, that can be as high as 43.2% after treatment (please cite 10.1111/ aogs.14814) Line 64-66: I would rephrase: VHSIL is treated in order to exclude foci of invasion and lower the risk of progression to cancer Line 71: dysplasia free margin is not an absolute target in VHSIL treatment, please refer to Preti M, Joura E, Vieira-Baptista P, et al The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) consensus statements on pre-invasive vulvar lesions International Journal of Gynecologic Cancer 2022;32:830-845. Line 328 what is PAPIIID2? I would discuss limitations of the present study: no follow up, limited case numbers, etc Really interesting conclusion, this is an exploratory analysis that can open a new issue in vulvar pathology and diagnosis.	BMC	12916_2025_3954_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 3, "importance_and_relevance": 2, "materials_and_methods": 2, "praise": 1, "presentation_and_reporting": 2, "results_and_discussion": 1, "suggestion_and_solution": 3, "total": 5 }	{ "criticism": 0, "example": 0.6, "importance_and_relevance": 0.4, "materials_and_methods": 0.4, "praise": 0.2, "presentation_and_reporting": 0.4, "results_and_discussion": 0.2, "suggestion_and_solution": 0.6 }	2.8	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case\ncontrol study\nVersion: 0 Date: 24 Nov 2024\nReviewer's report:\nDear authors, this is an interesting paper on potential use of vulvar smears in diagnosis of vulvar\npre invasive lesions. I have some comments on it:\nLine 36: please unify terminology throughout manuscript according to LAST/ISSVD: VHSIL\nor dVIN\nLINE 41: same for lichen sclerosUs. Lichen ruber should be renamed lichen planus\nline 59: I would unify terminology and use Squamous Intraepithelial Lesion (SIL) instead of VIN\nLine 62-63: ignorer to stress the difference in oncogenic potential, I would cite the difference\nin progression risk of dVIN, that can be as high as 43.2% after treatment (please cite 10.1111/\naogs.14814)\nLine 64-66: I would rephrase: VHSIL is treated in order to exclude foci of invasion and lower\nthe risk of progression to cancer\nLine 71: dysplasia free margin is not an absolute target in VHSIL treatment, please refer to\nPreti M, Joura E, Vieira-Baptista P, et al The European Society of Gynaecological Oncology\n(ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European\nCollege for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy\n(EFC) consensus statements on pre-invasive vulvar lesions International Journal of Gynecologic\nCancer 2022;32:830-845.\nLine 328 what is PAPIIID2?\nI would discuss limitations of the present study: no follow up, limited case numbers, etc\nReally interesting conclusion, this is an exploratory analysis that can open a new issue in vulvar\npathology and diagnosis.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03954-x	Reviewed - bmc_medicine	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 1 Date: 06 Jan 2025 Reviewer's report: Dear Authors, Thank you for the submitted updated review report. You have addressed specifically and thoroughly all the points raised. The paper has been updated tremendously, and now deserves publication. Thank you for this interesting addition to literature.	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 1 Date: 06 Jan 2025 Reviewer's report: Dear Authors, Thank you for the submitted updated review report. You have addressed specifically and thoroughly all the points raised. The paper has been updated tremendously, and now deserves publication. Thank you for this interesting addition to literature.	BMC	12916_2025_3954_ReviewerReport_V1_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 4 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0.25, "materials_and_methods": 0.25, "praise": 0.5, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case\ncontrol study\nVersion: 1 Date: 06 Jan 2025\nReviewer's report:\nDear Authors,\nThank you for the submitted updated review report. You have addressed specifically and\nthoroughly all the points raised. The paper has been updated tremendously, and now deserves\npublication. Thank you for this interesting addition to literature.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03954-x	Reviewed - bmc_medicine	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 1 Date: 07 Jan 2025 Reviewer's report: The current revisions have significantly improved the manuscript. However, further enhancements are necessary for it to be suitable for publication. Result section: Firstly, it is customary to begin the Results section with an overview of the patient population, including the total number of patients, their diagnoses, the number of FFPE samples collected, and the number of vulvar smears, before proceeding to subsections (e.g., 3.1, 3.2). Figure S3: The addition of Figure S3 has improved the interpretation of the results pertaining vulvar dysplasia independent of the threshold set for cervical dysplasia. However, currently Figure S3 is very difficult to read due to the presence of too many boxplots within a single figure and the use of identical hatching patterns for different diagnoses in the legend, making them indistinguishable. I recommend splitting both Figure S3A and S3B into six smaller figures (12 smaller figures in total), each displaying the methylation levels (on the y-axis) for the different diagnoses (on the x-axis). Assigning each marker its own figure will facilitate easier comparison of methylation levels across diagnoses for every marker. Ideally, the boxplots should exhibit a stairway-like pattern indicating increasing disease severity for most of the six markers. Additionally, should the authors be interested in adjusting the current threshold to vulvar dysplasia instead of cervical dysplasia, this could be achieved by establishing a threshold based on Youden's index (i.e., maximum sensitivity and specificity) through multivariate logistic regression, incorporating the current markers from GynTect®. line 594: remove 'not ' line 649: change 'lichen' to 'lichen sclerosus' (or lichen sclerosus and planus)	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 1 Date: 07 Jan 2025 Reviewer's report: The current revisions have significantly improved the manuscript. However, further enhancements are necessary for it to be suitable for publication. Result section: Firstly, it is customary to begin the Results section with an overview of the patient population, including the total number of patients, their diagnoses, the number of FFPE samples collected, and the number of vulvar smears, before proceeding to subsections (e.g., 3.1, 3.2). Figure S3: The addition of Figure S3 has improved the interpretation of the results pertaining vulvar dysplasia independent of the threshold set for cervical dysplasia. However, currently Figure S3 is very difficult to read due to the presence of too many boxplots within a single figure and the use of identical hatching patterns for different diagnoses in the legend, making them indistinguishable. I recommend splitting both Figure S3A and S3B into six smaller figures (12 smaller figures in total), each displaying the methylation levels (on the y-axis) for the different diagnoses (on the x-axis). Assigning each marker its own figure will facilitate easier comparison of methylation levels across diagnoses for every marker. Ideally, the boxplots should exhibit a stairway-like pattern indicating increasing disease severity for most of the six markers. Additionally, should the authors be interested in adjusting the current threshold to vulvar dysplasia instead of cervical dysplasia, this could be achieved by establishing a threshold based on Youden's index (i.e., maximum sensitivity and specificity) through multivariate logistic regression, incorporating the current markers from GynTect®. line 594: remove 'not ' line 649: change 'lichen' to 'lichen sclerosus' (or lichen sclerosus and planus)	BMC	12916_2025_3954_ReviewerReport_V1_R2.pdf	{ "criticism": 1, "example": 4, "importance_and_relevance": 0, "materials_and_methods": 5, "praise": 2, "presentation_and_reporting": 4, "results_and_discussion": 2, "suggestion_and_solution": 7, "total": 10 }	{ "criticism": 0.1, "example": 0.4, "importance_and_relevance": 0, "materials_and_methods": 0.5, "praise": 0.2, "presentation_and_reporting": 0.4, "results_and_discussion": 0.2, "suggestion_and_solution": 0.7 }	2.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case\ncontrol study\nVersion: 1 Date: 07 Jan 2025\nReviewer's report:\nThe current revisions have significantly improved the manuscript. However, further\nenhancements are necessary for it to be suitable for publication.\nResult section: Firstly, it is customary to begin the Results section with an overview of the patient\npopulation, including the total number of patients, their diagnoses, the number of FFPE samples\ncollected, and the number of vulvar smears, before proceeding to subsections (e.g., 3.1, 3.2).\nFigure S3: The addition of Figure S3 has improved the interpretation of the results pertaining\nvulvar dysplasia independent of the threshold set for cervical dysplasia. However, currently\nFigure S3 is very difficult to read due to the presence of too many boxplots within a single figure\nand the use of identical hatching patterns for different diagnoses in the legend, making them\nindistinguishable. I recommend splitting both Figure S3A and S3B into six smaller figures (12\nsmaller figures in total), each displaying the methylation levels (on the y-axis) for the different\ndiagnoses (on the x-axis). Assigning each marker its own figure will facilitate easier comparison\nof methylation levels across diagnoses for every marker. Ideally, the boxplots should exhibit a\nstairway-like pattern indicating increasing disease severity for most of the six markers.\nAdditionally, should the authors be interested in adjusting the current threshold to vulvar\ndysplasia instead of cervical dysplasia, this could be achieved by establishing a threshold based\non Youden's index (i.e., maximum sensitivity and specificity) through multivariate logistic\nregression, incorporating the current markers from GynTect®.\nline 594: remove 'not '\nline 649: change 'lichen' to 'lichen sclerosus' (or lichen sclerosus and planus)", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03954-x	Reviewed - bmc_medicine	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 2 Date: 14 Jan 2025 Reviewer's report: Dear Authors, Thank you for submitting the revised manuscript and implementing the suggested modifications. I believe the manuscript has been significantly improved, and I find Figure S3 to be very clear, providing a comprehensive overview of the raw results. The manuscript is now well-suited for publication, and I look forward to its final publication. Best regards	Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case control study Version: 2 Date: 14 Jan 2025 Reviewer's report: Dear Authors, Thank you for submitting the revised manuscript and implementing the suggested modifications. I believe the manuscript has been significantly improved, and I find Figure S3 to be very clear, providing a comprehensive overview of the raw results. The manuscript is now well-suited for publication, and I look forward to its final publication. Best regards	BMC	12916_2025_3954_ReviewerReport_V2_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 1, "total": 4 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.25, "praise": 0.5, "presentation_and_reporting": 0.25, "results_and_discussion": 0.25, "suggestion_and_solution": 0.25 }	1.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Non-invasive diagnosis of vulvar dysplasia using cervical methylation markers - a case\ncontrol study\nVersion: 2 Date: 14 Jan 2025\nReviewer's report:\nDear Authors,\nThank you for submitting the revised manuscript and implementing the suggested modifications.\nI believe the manuscript has been significantly improved, and I find Figure S3 to be very clear,\nproviding a comprehensive overview of the raw results. The manuscript is now well-suited for\npublication, and I look forward to its final publication.\nBest regards", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03945-y	Reviewed - bmc_medicine	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 0 Date: 21 Oct 2024 Reviewer's report: In this article, the authors explore osteoclastogenesis and bone loss in rheumatoid arthritis in terms of MTHFD2 by enhancing CKMT1-mediated oxidative phosphorylation. And suggest that, in the future, MTHFD2 can be targeted to provide a strategy for the treatment of rheumatoid arthritis. I have the following comments/suggestions for authors to take into consideration. Below are the specific comments related to the manuscript: 1. As you mentioned, evidence suggests a correlation between 1C metabolism and RA. However, what criteria led you to select MTHFD2 as your research focus among the numerous enzymes involved in 1C metabolism? 2. What factors lead CD14+ monocytes to preferentially select human sources, while BMMs exhibit a preference for mouse sources? 3. As mentioned above, MTHFD2 usually promotes RANKL-induced osteoclast-related gene expression. However, in figure 3G, why are Tnfrsf11a and Nfatc1 expressed in OE-MTHFD2 group lower than in OE-NC group? 4.Some details in the paper are not perfect. For example, the meaning of **** in Figure1A is not expressed in figure legends, and the legend title is Figure while the text is figure. In addition, there is redundancy between 41 and 42 and between 51 and 52 in references.	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 0 Date: 21 Oct 2024 Reviewer's report: In this article, the authors explore osteoclastogenesis and bone loss in rheumatoid arthritis in terms of MTHFD2 by enhancing CKMT1-mediated oxidative phosphorylation. And suggest that, in the future, MTHFD2 can be targeted to provide a strategy for the treatment of rheumatoid arthritis. I have the following comments/suggestions for authors to take into consideration. Below are the specific comments related to the manuscript: 1. As you mentioned, evidence suggests a correlation between 1C metabolism and RA. However, what criteria led you to select MTHFD2 as your research focus among the numerous enzymes involved in 1C metabolism? 2. What factors lead CD14+ monocytes to preferentially select human sources, while BMMs exhibit a preference for mouse sources? 3. As mentioned above, MTHFD2 usually promotes RANKL-induced osteoclast-related gene expression. However, in figure 3G, why are Tnfrsf11a and Nfatc1 expressed in OE-MTHFD2 group lower than in OE-NC group? 4.Some details in the paper are not perfect. For example, the meaning of **** in Figure1A is not expressed in figure legends, and the legend title is Figure while the text is figure. In addition, there is redundancy between 41 and 42 and between 51 and 52 in references.	BMC	12916_2025_3945_ReviewerReport_V0_R2.pdf	{ "criticism": 2, "example": 2, "importance_and_relevance": 2, "materials_and_methods": 4, "praise": 0, "presentation_and_reporting": 3, "results_and_discussion": 1, "suggestion_and_solution": 1, "total": 14 }	{ "criticism": 0.14285714285714285, "example": 0.14285714285714285, "importance_and_relevance": 0.14285714285714285, "materials_and_methods": 0.2857142857142857, "praise": 0, "presentation_and_reporting": 0.21428571428571427, "results_and_discussion": 0.07142857142857142, "suggestion_and_solution": 0.07142857142857142 }	1.071429	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing\nCKMT1-mediated oxidative phosphorylation\nVersion: 0 Date: 21 Oct 2024\nReviewer's report:\nIn this article, the authors explore osteoclastogenesis and bone loss in rheumatoid arthritis in\nterms of MTHFD2 by enhancing CKMT1-mediated oxidative phosphorylation. And suggest\nthat, in the future, MTHFD2 can be targeted to provide a strategy for the treatment of rheumatoid\narthritis. I have the following comments/suggestions for authors to take into consideration.\nBelow are the specific comments related to the manuscript:\n1. As you mentioned, evidence suggests a correlation between 1C metabolism and RA. However,\nwhat criteria led you to select MTHFD2 as your research focus among the numerous enzymes\ninvolved in 1C metabolism?\n2. What factors lead CD14+ monocytes to preferentially select human sources, while BMMs\nexhibit a preference for mouse sources?\n3. As mentioned above, MTHFD2 usually promotes RANKL-induced osteoclast-related gene\nexpression. However, in figure 3G, why are Tnfrsf11a and Nfatc1 expressed in OE-MTHFD2\ngroup lower than in OE-NC group?\n4.Some details in the paper are not perfect. For example, the meaning of **** in Figure1A is not\nexpressed in figure legends, and the legend title is Figure while the text is figure. In addition,\nthere is redundancy between 41 and 42 and between 51 and 52 in references.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03945-y	Reviewed - bmc_medicine	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 0 Date: 29 Nov 2024 Reviewer's report:	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 0 Date: 29 Nov 2024 Reviewer's report:	BMC	12916_2025_3945_ReviewerReport_V0_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	0	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing\nCKMT1-mediated oxidative phosphorylation\nVersion: 0 Date: 29 Nov 2024\nReviewer's report:", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03945-y	Reviewed - bmc_medicine	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 1 Date: 08 Jan 2025 Reviewer's report: Authors have carefully addressed all the comments arisen from the reviewers. The revised manuscript can be considered for acceptance and publication.	Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation Version: 1 Date: 08 Jan 2025 Reviewer's report: Authors have carefully addressed all the comments arisen from the reviewers. The revised manuscript can be considered for acceptance and publication.	BMC	12916_2025_3945_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 2, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 1, "total": 2 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0.5 }	1.5	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing\nCKMT1-mediated oxidative phosphorylation\nVersion: 1 Date: 08 Jan 2025\nReviewer's report:\nAuthors have carefully addressed all the comments arisen from the reviewers. The revised\nmanuscript can be considered for acceptance and publication.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 06 Dec 2024 Reviewer: Tomoya Yokota Reviewer's report: This is a phase 2 trial to evaluate the efficacy and safety of induction chemotherapy plus camrelizumab followed by concurrent chemoradiotherapy (CCRT) for patients with locoregionally advanced NPC in non-endemic areas. In this study, they used 2 cycles of ICT and a reduced-dose and reduced-course of cisplatin was administrated in the concurrent phase. The primary endpoint of 3-year disease-free survival (DFS) rate was 83.5%. The AEs were well- tolerated and manageable, and the combination regimen did not result in any unexpected grade 3 or 4 TRAEs. I need to point out the following questions. Major points: 1. Please explain the precise statistical setting of DFS. What is the threshold of DFS and the lower limit of 95%(?) confident interval? These factors are associated with whether the trial is positive or negative. 2. Although this trial focused on NPC in non-endemic areas, positive EBV serostatuses were included in 30.9%, which does not seem to be specific in non-endemic area. 3. Several AEs listed up in Table 3 are not always specific for induction phase and concurrent CRT phase. For instance, hypothyroidism may happen not only in induction phase but also in concurrent CRT phase or after the treatment. Xerostomia, oral mucositis, dermatitis, weight loss, dental disorders and hypogeusia are late toxicities induced by CRT. There is no nausea event in Table 3. 4. In the Discussion section, the efficacy of this trial was too exaggerated in the comparison of other trials. For instance, “Compared with the historical ORR of 90% for IC, the ORR in the current study reached a numerically higher rate of 92.8%, indicating a favorable antitumor activity besides chemotherapy alone” in page 13. This is misleading, because difference in ORR between studies is only 2.8%. 5. In the Conclusion section, I cannot agree with you that significant improvement of survival outcome is conclusive in such non-randomized trial. 6. In the Results section and page 15, you mention camrelizumab maintenance led to “remarkable improvements in disease control and survival.” However, this trial did not intend to compare no adjuvant versus adjuvant group. Therefore, these expressions are inappropriate in this single arm study. Minor points: 1. Was this trial conducted in a single center or multicenter? 2. In line 9 to 11 of page 14 of the Discussion section, you describe that three-weekly cisplatin has significantly fewer acute and late-onset auditory loss toxicities than weekly cisplatin, but is this correct? In general, three-weekly cisplatin has more auditory loss toxicities than weekly cisplatin.	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 06 Dec 2024 Reviewer: Tomoya Yokota Reviewer's report: This is a phase 2 trial to evaluate the efficacy and safety of induction chemotherapy plus camrelizumab followed by concurrent chemoradiotherapy (CCRT) for patients with locoregionally advanced NPC in non-endemic areas. In this study, they used 2 cycles of ICT and a reduced-dose and reduced-course of cisplatin was administrated in the concurrent phase. The primary endpoint of 3-year disease-free survival (DFS) rate was 83.5%. The AEs were well- tolerated and manageable, and the combination regimen did not result in any unexpected grade 3 or 4 TRAEs. I need to point out the following questions. Major points: 1. Please explain the precise statistical setting of DFS. What is the threshold of DFS and the lower limit of 95%(?) confident interval? These factors are associated with whether the trial is positive or negative. 2. Although this trial focused on NPC in non-endemic areas, positive EBV serostatuses were included in 30.9%, which does not seem to be specific in non-endemic area. 3. Several AEs listed up in Table 3 are not always specific for induction phase and concurrent CRT phase. For instance, hypothyroidism may happen not only in induction phase but also in concurrent CRT phase or after the treatment. Xerostomia, oral mucositis, dermatitis, weight loss, dental disorders and hypogeusia are late toxicities induced by CRT. There is no nausea event in Table 3. 4. In the Discussion section, the efficacy of this trial was too exaggerated in the comparison of other trials. For instance, “Compared with the historical ORR of 90% for IC, the ORR in the current study reached a numerically higher rate of 92.8%, indicating a favorable antitumor activity besides chemotherapy alone” in page 13. This is misleading, because difference in ORR between studies is only 2.8%. 5. In the Conclusion section, I cannot agree with you that significant improvement of survival outcome is conclusive in such non-randomized trial. 6. In the Results section and page 15, you mention camrelizumab maintenance led to “remarkable improvements in disease control and survival.” However, this trial did not intend to compare no adjuvant versus adjuvant group. Therefore, these expressions are inappropriate in this single arm study. Minor points: 1. Was this trial conducted in a single center or multicenter? 2. In line 9 to 11 of page 14 of the Discussion section, you describe that three-weekly cisplatin has significantly fewer acute and late-onset auditory loss toxicities than weekly cisplatin, but is this correct? In general, three-weekly cisplatin has more auditory loss toxicities than weekly cisplatin.	BMC	12916_2025_3964_ReviewerReport_V0_R1.pdf	{ "criticism": 6, "example": 3, "importance_and_relevance": 0, "materials_and_methods": 15, "praise": 2, "presentation_and_reporting": 3, "results_and_discussion": 5, "suggestion_and_solution": 2, "total": 31 }	{ "criticism": 0.1935483870967742, "example": 0.0967741935483871, "importance_and_relevance": 0, "materials_and_methods": 0.4838709677419355, "praise": 0.06451612903225806, "presentation_and_reporting": 0.0967741935483871, "results_and_discussion": 0.16129032258064516, "suggestion_and_solution": 0.06451612903225806 }	1.16129	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 0 Date: 06 Dec 2024\nReviewer: Tomoya Yokota\nReviewer's report:\nThis is a phase 2 trial to evaluate the efficacy and safety of induction chemotherapy\nplus camrelizumab followed by concurrent chemoradiotherapy (CCRT) for patients with\nlocoregionally advanced NPC in non-endemic areas. In this study, they used 2 cycles of ICT and\na reduced-dose and reduced-course of cisplatin was administrated in the concurrent phase. The\nprimary endpoint of 3-year disease-free survival (DFS) rate was 83.5%. The AEs were well-\ntolerated and manageable, and the combination regimen did not result in any unexpected grade\n3 or 4 TRAEs. I need to point out the following questions.\nMajor points:\n1. Please explain the precise statistical setting of DFS. What is the threshold of DFS and the\nlower limit of 95%(?) confident interval? These factors are associated with whether the trial is\npositive or negative.\n2. Although this trial focused on NPC in non-endemic areas, positive EBV serostatuses were\nincluded in 30.9%, which does not seem to be specific in non-endemic area.\n3. Several AEs listed up in Table 3 are not always specific for induction phase and concurrent\nCRT phase. For instance, hypothyroidism may happen not only in induction phase but also in\nconcurrent CRT phase or after the treatment. Xerostomia, oral mucositis, dermatitis, weight loss,\ndental disorders and hypogeusia are late toxicities induced by CRT. There is no nausea event\nin Table 3.\n4. In the Discussion section, the efficacy of this trial was too exaggerated in the comparison\nof other trials. For instance, “Compared with the historical ORR of 90% for IC, the ORR in\nthe current study reached a numerically higher rate of 92.8%, indicating a favorable antitumor\nactivity besides chemotherapy alone” in page 13. This is misleading, because difference in ORR\nbetween studies is only 2.8%.\n5. In the Conclusion section, I cannot agree with you that significant improvement of survival\noutcome is conclusive in such non-randomized trial.\n6. In the Results section and page 15, you mention camrelizumab maintenance led to “remarkable\nimprovements in disease control and survival.” However, this trial did not intend to compare\nno adjuvant versus adjuvant group. Therefore, these expressions are inappropriate in this single\narm study.\nMinor points:\n1. Was this trial conducted in a single center or multicenter?\n2. In line 9 to 11 of page 14 of the Discussion section, you describe that three-weekly cisplatin\nhas significantly fewer acute and late-onset auditory loss toxicities than weekly cisplatin, but\nis this correct? In general, three-weekly cisplatin has more auditory loss toxicities than weekly\ncisplatin.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 17 Dec 2024 Reviewer: Yoshinori Imamura Reviewer's report: The study presents a highly interesting approach to evaluating the efficacy and safety of induction chemotherapy combined with camrelizumab followed by concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) in non-endemic areas. The findings are noteworthy; however, several critical issues must be addressed before the manuscript can be considered further. First, it seems inappropriate to limit the analysis to only the 55 patients who completed CCRT. Safety evaluations should include all 59 patients who received at least one dose of treatment (or 57 patients if accounting for complete withdrawal). Second, there is a discrepancy regarding the description of maintenance therapy. The protocol specifies 12 cycles, but the manuscript states 1 year (18 cycles). Even when factoring in two cycles of induction chemotherapy and two cycles during CCRT, the numbers remain inconsistent. Third, the fact that less than half of the patients completed maintenance therapy raises concerns about the overall quality of the trial. That said, it is intriguing that the findings suggest maintenance therapy may be necessary. This observation aligns with global trends in other cancer types and is a far more compelling avenue to explore than adjusting cisplatin dosage alone. Fourth, additional information on the patients' smoking history is required, as this remains an important factor influencing prognosis and outcomes. Furthermore, although this study is set in a non-endemic area, it is notable that non-keratinising undifferentiated cases accounted for more than half of the cohort, and the overall outcomes appear remarkably favorable. This point warrants further discussion. Fifth, the cutoff for plasma EBV DNA positivity is not clearly stated. Clarification on this is essential for interpreting the results appropriately. Sixth, the choice of the docetaxel-cisplatin (DC) regimen over gemcitabine-cisplatin (GC) and the reduced cumulative cisplatin dose (<200 mg/m²) during radiotherapy may have contributed to the poorer outcomes observed in T4/N3 cases. While this possibility should be acknowledged, it may not be overly concerning. A discussion on this point would strengthen the manuscript. Addressing these issues will significantly enhance the manuscript's clarity, rigor, and overall impact.	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 17 Dec 2024 Reviewer: Yoshinori Imamura Reviewer's report: The study presents a highly interesting approach to evaluating the efficacy and safety of induction chemotherapy combined with camrelizumab followed by concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) in non-endemic areas. The findings are noteworthy; however, several critical issues must be addressed before the manuscript can be considered further. First, it seems inappropriate to limit the analysis to only the 55 patients who completed CCRT. Safety evaluations should include all 59 patients who received at least one dose of treatment (or 57 patients if accounting for complete withdrawal). Second, there is a discrepancy regarding the description of maintenance therapy. The protocol specifies 12 cycles, but the manuscript states 1 year (18 cycles). Even when factoring in two cycles of induction chemotherapy and two cycles during CCRT, the numbers remain inconsistent. Third, the fact that less than half of the patients completed maintenance therapy raises concerns about the overall quality of the trial. That said, it is intriguing that the findings suggest maintenance therapy may be necessary. This observation aligns with global trends in other cancer types and is a far more compelling avenue to explore than adjusting cisplatin dosage alone. Fourth, additional information on the patients' smoking history is required, as this remains an important factor influencing prognosis and outcomes. Furthermore, although this study is set in a non-endemic area, it is notable that non-keratinising undifferentiated cases accounted for more than half of the cohort, and the overall outcomes appear remarkably favorable. This point warrants further discussion. Fifth, the cutoff for plasma EBV DNA positivity is not clearly stated. Clarification on this is essential for interpreting the results appropriately. Sixth, the choice of the docetaxel-cisplatin (DC) regimen over gemcitabine-cisplatin (GC) and the reduced cumulative cisplatin dose (<200 mg/m²) during radiotherapy may have contributed to the poorer outcomes observed in T4/N3 cases. While this possibility should be acknowledged, it may not be overly concerning. A discussion on this point would strengthen the manuscript. Addressing these issues will significantly enhance the manuscript's clarity, rigor, and overall impact.	BMC	12916_2025_3964_ReviewerReport_V0_R2.pdf	{ "criticism": 4, "example": 0, "importance_and_relevance": 3, "materials_and_methods": 9, "praise": 4, "presentation_and_reporting": 3, "results_and_discussion": 8, "suggestion_and_solution": 6, "total": 19 }	{ "criticism": 0.21052631578947367, "example": 0, "importance_and_relevance": 0.15789473684210525, "materials_and_methods": 0.47368421052631576, "praise": 0.21052631578947367, "presentation_and_reporting": 0.15789473684210525, "results_and_discussion": 0.42105263157894735, "suggestion_and_solution": 0.3157894736842105 }	1.947368	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 0 Date: 17 Dec 2024\nReviewer: Yoshinori Imamura\nReviewer's report:\nThe study presents a highly interesting approach to evaluating the efficacy and\nsafety of induction chemotherapy combined with camrelizumab followed by concurrent\nchemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal\ncarcinoma (NPC) in non-endemic areas. The findings are noteworthy; however, several critical\nissues must be addressed before the manuscript can be considered further.\nFirst, it seems inappropriate to limit the analysis to only the 55 patients who completed CCRT.\nSafety evaluations should include all 59 patients who received at least one dose of treatment (or\n57 patients if accounting for complete withdrawal).\nSecond, there is a discrepancy regarding the description of maintenance therapy. The protocol\nspecifies 12 cycles, but the manuscript states 1 year (18 cycles). Even when factoring in\ntwo cycles of induction chemotherapy and two cycles during CCRT, the numbers remain\ninconsistent.\nThird, the fact that less than half of the patients completed maintenance therapy raises concerns\nabout the overall quality of the trial. That said, it is intriguing that the findings suggest\nmaintenance therapy may be necessary. This observation aligns with global trends in other\ncancer types and is a far more compelling avenue to explore than adjusting cisplatin dosage\nalone.\nFourth, additional information on the patients' smoking history is required, as this remains an\nimportant factor influencing prognosis and outcomes. Furthermore, although this study is set\nin a non-endemic area, it is notable that non-keratinising undifferentiated cases accounted for\nmore than half of the cohort, and the overall outcomes appear remarkably favorable. This point\nwarrants further discussion.\nFifth, the cutoff for plasma EBV DNA positivity is not clearly stated. Clarification on this is\nessential for interpreting the results appropriately.\nSixth, the choice of the docetaxel-cisplatin (DC) regimen over gemcitabine-cisplatin (GC) and\nthe reduced cumulative cisplatin dose (<200 mg/m²) during radiotherapy may have contributed\nto the poorer outcomes observed in T4/N3 cases. While this possibility should be acknowledged,\nit may not be overly concerning. A discussion on this point would strengthen the manuscript.\nAddressing these issues will significantly enhance the manuscript's clarity, rigor, and overall\nimpact.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 18 Dec 2024 Reviewer: Mu-Hung Tsai Reviewer's report: This was a well-written manuscript on a important study. I commend the authors for completing this study and sharing it with the scientific community. Overall, I recommend publication of this study. I have only a few minor questions. 1) There was a discrepancy between the protocol stated in manuscript/protocol and the record posted on https://clinicaltrials.gov/study/NCT04782765. The dose for cisplatin during the IC phase was listed cisplatin 25 mg/m2 intravenously on days 2–4 in the manuscript but Cisplatin 20mg/m2, Day 1-3 on NCT04782765. 2) Please define the criteria for positive plasma EBV DNA, including the cut-off and type of assay used. Most kits sometimes report trace amounts of EBV DNA, are these considered positive or negative? 3) The authors have detailed accounts of acute adverse events, described as treatment-related AEs (TRAEs) in the manuscript. Data on late toxicity (usually defined as > 3 months) is also of interest to the readers. In particular, if the deaths due to nasopharyngeal necrosis were attributed to camrelizumab, this may be a worrisome late toxicity. 4) What was the time to developing ulcerated/bleeding lesions in the nasopharynx (Supplementary Figure 4)? Were these the same patients with the 3 that died of nasopharyngeal necrosis and massive hemorrhage? The time to nasopharyngeal necrosis and massive hemorrhage (9-15 months) was described in the discussions, consider moving this information to the results section. 5) There were a few typos in the manuscript. For example, in the Declarations section: "The trial protocol was approved by the Written informed consent was obtained from all participating patients before enrollment." 6) I suggest revising the conclusions. For a phase 2 trial without a comparator arm, it is difficult to assess "significantly improved survival outcomes".	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 0 Date: 18 Dec 2024 Reviewer: Mu-Hung Tsai Reviewer's report: This was a well-written manuscript on a important study. I commend the authors for completing this study and sharing it with the scientific community. Overall, I recommend publication of this study. I have only a few minor questions. 1) There was a discrepancy between the protocol stated in manuscript/protocol and the record posted on https://clinicaltrials.gov/study/NCT04782765. The dose for cisplatin during the IC phase was listed cisplatin 25 mg/m2 intravenously on days 2–4 in the manuscript but Cisplatin 20mg/m2, Day 1-3 on NCT04782765. 2) Please define the criteria for positive plasma EBV DNA, including the cut-off and type of assay used. Most kits sometimes report trace amounts of EBV DNA, are these considered positive or negative? 3) The authors have detailed accounts of acute adverse events, described as treatment-related AEs (TRAEs) in the manuscript. Data on late toxicity (usually defined as > 3 months) is also of interest to the readers. In particular, if the deaths due to nasopharyngeal necrosis were attributed to camrelizumab, this may be a worrisome late toxicity. 4) What was the time to developing ulcerated/bleeding lesions in the nasopharynx (Supplementary Figure 4)? Were these the same patients with the 3 that died of nasopharyngeal necrosis and massive hemorrhage? The time to nasopharyngeal necrosis and massive hemorrhage (9-15 months) was described in the discussions, consider moving this information to the results section. 5) There were a few typos in the manuscript. For example, in the Declarations section: "The trial protocol was approved by the Written informed consent was obtained from all participating patients before enrollment." 6) I suggest revising the conclusions. For a phase 2 trial without a comparator arm, it is difficult to assess "significantly improved survival outcomes".	BMC	12916_2025_3964_ReviewerReport_V0_R3.pdf	{ "criticism": 4, "example": 2, "importance_and_relevance": 2, "materials_and_methods": 9, "praise": 4, "presentation_and_reporting": 3, "results_and_discussion": 2, "suggestion_and_solution": 4, "total": 18 }	{ "criticism": 0.2222222222222222, "example": 0.1111111111111111, "importance_and_relevance": 0.1111111111111111, "materials_and_methods": 0.5, "praise": 0.2222222222222222, "presentation_and_reporting": 0.16666666666666666, "results_and_discussion": 0.1111111111111111, "suggestion_and_solution": 0.2222222222222222 }	1.666667	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 0 Date: 18 Dec 2024\nReviewer: Mu-Hung Tsai\nReviewer's report:\nThis was a well-written manuscript on a important study. I commend the authors for completing\nthis study and sharing it with the scientific community. Overall, I recommend publication of this\nstudy. I have only a few minor questions.\n1) There was a discrepancy between the protocol stated in manuscript/protocol and the record\nposted on https://clinicaltrials.gov/study/NCT04782765. The dose for cisplatin during the IC\nphase was listed cisplatin 25 mg/m2 intravenously on days 2–4 in the manuscript but Cisplatin\n20mg/m2, Day 1-3 on NCT04782765.\n2) Please define the criteria for positive plasma EBV DNA, including the cut-off and type\nof assay used. Most kits sometimes report trace amounts of EBV DNA, are these considered\npositive or negative?\n3) The authors have detailed accounts of acute adverse events, described as treatment-related\nAEs (TRAEs) in the manuscript. Data on late toxicity (usually defined as > 3 months) is also of\ninterest to the readers. In particular, if the deaths due to nasopharyngeal necrosis were attributed\nto camrelizumab, this may be a worrisome late toxicity.\n4) What was the time to developing ulcerated/bleeding lesions in the nasopharynx\n(Supplementary Figure 4)? Were these the same patients with the 3 that died of nasopharyngeal\nnecrosis and massive hemorrhage? The time to nasopharyngeal necrosis and massive\nhemorrhage (9-15 months) was described in the discussions, consider moving this information\nto the results section.\n5) There were a few typos in the manuscript. For example, in the Declarations section: \"The\ntrial protocol was approved by the Written informed consent was obtained from all participating\npatients before enrollment.\"\n6) I suggest revising the conclusions. For a phase 2 trial without a comparator arm, it is difficult\nto assess \"significantly improved survival outcomes\".", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 27 Jan 2025 Reviewer: Tomoya Yokota Reviewer's report: The revised manuscript satisfied the requirement from us.	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 27 Jan 2025 Reviewer: Tomoya Yokota Reviewer's report: The revised manuscript satisfied the requirement from us.	BMC	12916_2025_3964_ReviewerReport_V1_R1.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 1 Date: 27 Jan 2025\nReviewer: Tomoya Yokota\nReviewer's report:\nThe revised manuscript satisfied the requirement from us.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 27 Jan 2025 Reviewer: Yoshinori Imamura Reviewer's report: The document now reflects that the manuscript is deemed ready for publication following thorough responses to the concerns.	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 27 Jan 2025 Reviewer: Yoshinori Imamura Reviewer's report: The document now reflects that the manuscript is deemed ready for publication following thorough responses to the concerns.	BMC	12916_2025_3964_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	2	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 1 Date: 27 Jan 2025\nReviewer: Yoshinori Imamura\nReviewer's report:\nThe document now reflects that the manuscript is deemed ready for publication following\nthorough responses to the concerns.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03964-9	Reviewed - bmc_medicine	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 31 Jan 2025 Reviewer: Mu-Hung Tsai Reviewer's report: The authors have addressed the concerns raised in the previous round of review.	Title: Induction chemotherapy plus camrelizumab combined with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic areas: a phase 2 clinical trial in North China Version: 1 Date: 31 Jan 2025 Reviewer: Mu-Hung Tsai Reviewer's report: The authors have addressed the concerns raised in the previous round of review.	BMC	12916_2025_3964_ReviewerReport_V1_R3.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Induction chemotherapy plus camrelizumab combined with concurrent\nchemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma in non-endemic\nareas: a phase 2 clinical trial in North China\nVersion: 1 Date: 31 Jan 2025\nReviewer: Mu-Hung Tsai\nReviewer's report:\nThe authors have addressed the concerns raised in the previous round of review.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 30 Aug 2024 Reviewer: Paul R. M. van Dijkman Reviewer's report: This is a very interesting study to show a significant relationship between CAC and prevalence of diastolic dysfunction in a population-based cohort study. It is a well-performed and important study for which the authors are to be congratulated. It is excellently written in correct English. I have a few remarks: 1. Page 7: 'Study Population': what kind of population participated in this study? Who were invited to participate in this Health Promotion Study? 2. page 7: 'available systems': change into 'availabe system'. 3. Page 8: visual estimation of LVEF is not acceptable, because it is highly subject to variation. Better to change in "not easy to measure"? 4. Page 8: the sentence 'Each DD index was also evaluated as a continuous variable to complement the binary assessment of DD using previously determind cutoffs'. is unclear to me. Please explain better. 5. Page 8: Coronary CT scans. It seems that no second CAC was performed, although a second ultrasound was often performed. A second CAC would have given information about progression of coronary atherosclerosis in relation to change of DD. I believe this should be discussed in the limitations. 6. Page 10: only CAC >=100 was used as parameter. It would also be interesting to study the group with CAC >= 400 (or 300), which means an extra high risk group. Page 13: "Central Illustration": where is that illustration (or am I missing something?).	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 30 Aug 2024 Reviewer: Paul R. M. van Dijkman Reviewer's report: This is a very interesting study to show a significant relationship between CAC and prevalence of diastolic dysfunction in a population-based cohort study. It is a well-performed and important study for which the authors are to be congratulated. It is excellently written in correct English. I have a few remarks: 1. Page 7: 'Study Population': what kind of population participated in this study? Who were invited to participate in this Health Promotion Study? 2. page 7: 'available systems': change into 'availabe system'. 3. Page 8: visual estimation of LVEF is not acceptable, because it is highly subject to variation. Better to change in "not easy to measure"? 4. Page 8: the sentence 'Each DD index was also evaluated as a continuous variable to complement the binary assessment of DD using previously determind cutoffs'. is unclear to me. Please explain better. 5. Page 8: Coronary CT scans. It seems that no second CAC was performed, although a second ultrasound was often performed. A second CAC would have given information about progression of coronary atherosclerosis in relation to change of DD. I believe this should be discussed in the limitations. 6. Page 10: only CAC >=100 was used as parameter. It would also be interesting to study the group with CAC >= 400 (or 300), which means an extra high risk group. Page 13: "Central Illustration": where is that illustration (or am I missing something?).	BMC	12916_2025_3956_ReviewerReport_V0_R1.pdf	{ "criticism": 2, "example": 7, "importance_and_relevance": 2, "materials_and_methods": 7, "praise": 3, "presentation_and_reporting": 7, "results_and_discussion": 1, "suggestion_and_solution": 6, "total": 24 }	{ "criticism": 0.08333333333333333, "example": 0.2916666666666667, "importance_and_relevance": 0.08333333333333333, "materials_and_methods": 0.2916666666666667, "praise": 0.125, "presentation_and_reporting": 0.2916666666666667, "results_and_discussion": 0.041666666666666664, "suggestion_and_solution": 0.25 }	1.458333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 0 Date: 30 Aug 2024\nReviewer: Paul R. M. van Dijkman\nReviewer's report:\nThis is a very interesting study to show a significant relationship between CAC and prevalence\nof diastolic dysfunction in a population-based cohort study. It is a well-performed and important\nstudy for which the authors are to be congratulated. It is excellently written in correct English.\nI have a few remarks:\n1. Page 7: 'Study Population': what kind of population participated in this study? Who were\ninvited to participate in this Health Promotion Study?\n2. page 7: 'available systems': change into 'availabe system'.\n3. Page 8: visual estimation of LVEF is not acceptable, because it is highly subject to variation.\nBetter to change in \"not easy to measure\"?\n4. Page 8: the sentence 'Each DD index was also evaluated as a continuous variable to\ncomplement the binary assessment of DD using previously determind cutoffs'. is unclear to me.\nPlease explain better.\n5. Page 8: Coronary CT scans. It seems that no second CAC was performed, although a\nsecond ultrasound was often performed. A second CAC would have given information about\nprogression of coronary atherosclerosis in relation to change of DD. I believe this should be\ndiscussed in the limitations.\n6. Page 10: only CAC >=100 was used as parameter. It would also be interesting to study the\ngroup with CAC >= 400 (or 300), which means an extra high risk group.\nPage 13: \"Central Illustration\": where is that illustration (or am I missing something?).", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 16 Sep 2024 Reviewer's report: In this study, the authors examined the CAC and diastolic dysfunction in a large-scale health screening population, as well as their longitudinal association with the risk of mortality. This study has significant clinical implications. The authors mentioned that all the proportional hazards models were adjusted for age, sex, BMI, smoking status, alcohol consumption, diabetes, hypertension, hyperlipidemia, statin use, and aspirin use. They also mentioned that this is the first study to confirm that significant CAC affects the progression of DD independently of other clinical factors. However, in previous population screening studies, the impact of conditions such as diabetes and hypertension on long- term adverse outcomes has also been observed. What might be the reasons for these differences? Perhaps further presentation of relevant results in tables is needed. 1. Regarding the 'Effects of CAC and DD on Mortality,' the authors generated four groups: CAC <100 without definite DD, CAC <100 with definite DD, CAC #100 without definite DD, and CAC #100 with definite DD. How did you define 100 as the basis for grouping CAC? Why not include CAC=0 as a reference group in the proportional hazards model? Additionally, separating CAC and DD groups for risk model analysis may provide more explanatory value for the correlation between CAC and DD in poor prognosis. 2. Did these subjects undergo coronary CT scans again during follow-up, and if changes in CAC variables were assessed, this could further explain the association with diastolic dysfunction and adverse events. 3. Given that there were 117 deaths in this study with a sample size of 15,193, it would be beneficial to distinguish cardiovascular deaths or add MACE as an end-point, and indicate the proportion of the population concerned. 4. The expression of values in the table 1 is confused, and it is not clear whether it is the median (IQR) or number (%) 5. The description of Table 1 states, 'All P values for trends comparing baseline characteristics of the three groups were < 0.05.' This could lead to misunderstanding, as we can see that at least LVEF is almost consistent among the three groups. Please verify or correct this. 6. In terms of medication, it would be beneficial to include antihypertensive agents or antidiabetic drugs, and if possible, specify the category for better detail. 7. The statement 'Age, male, current smoker, and metabolically unhealthy were positively associated with CAC' in the first paragraph of the results section cannot be concluded from Table 1. 8. Table 2 should include the total number of Definite DD and Definite or probable DD cases. 9. In the discussion section, under 'Progression of DD According to Presence of CAC,' the sentence 'This was 2.0 and 1.5 times more frequent compared to participants without DD, respectively' cannot be found in the results section or in the charts. Please check for accuracy.	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 16 Sep 2024 Reviewer's report: In this study, the authors examined the CAC and diastolic dysfunction in a large-scale health screening population, as well as their longitudinal association with the risk of mortality. This study has significant clinical implications. The authors mentioned that all the proportional hazards models were adjusted for age, sex, BMI, smoking status, alcohol consumption, diabetes, hypertension, hyperlipidemia, statin use, and aspirin use. They also mentioned that this is the first study to confirm that significant CAC affects the progression of DD independently of other clinical factors. However, in previous population screening studies, the impact of conditions such as diabetes and hypertension on long- term adverse outcomes has also been observed. What might be the reasons for these differences? Perhaps further presentation of relevant results in tables is needed. 1. Regarding the 'Effects of CAC and DD on Mortality,' the authors generated four groups: CAC <100 without definite DD, CAC <100 with definite DD, CAC #100 without definite DD, and CAC #100 with definite DD. How did you define 100 as the basis for grouping CAC? Why not include CAC=0 as a reference group in the proportional hazards model? Additionally, separating CAC and DD groups for risk model analysis may provide more explanatory value for the correlation between CAC and DD in poor prognosis. 2. Did these subjects undergo coronary CT scans again during follow-up, and if changes in CAC variables were assessed, this could further explain the association with diastolic dysfunction and adverse events. 3. Given that there were 117 deaths in this study with a sample size of 15,193, it would be beneficial to distinguish cardiovascular deaths or add MACE as an end-point, and indicate the proportion of the population concerned. 4. The expression of values in the table 1 is confused, and it is not clear whether it is the median (IQR) or number (%) 5. The description of Table 1 states, 'All P values for trends comparing baseline characteristics of the three groups were < 0.05.' This could lead to misunderstanding, as we can see that at least LVEF is almost consistent among the three groups. Please verify or correct this. 6. In terms of medication, it would be beneficial to include antihypertensive agents or antidiabetic drugs, and if possible, specify the category for better detail. 7. The statement 'Age, male, current smoker, and metabolically unhealthy were positively associated with CAC' in the first paragraph of the results section cannot be concluded from Table 1. 8. Table 2 should include the total number of Definite DD and Definite or probable DD cases. 9. In the discussion section, under 'Progression of DD According to Presence of CAC,' the sentence 'This was 2.0 and 1.5 times more frequent compared to participants without DD, respectively' cannot be found in the results section or in the charts. Please check for accuracy.	BMC	12916_2025_3956_ReviewerReport_V0_R3.pdf	{ "criticism": 3, "example": 3, "importance_and_relevance": 1, "materials_and_methods": 11, "praise": 1, "presentation_and_reporting": 8, "results_and_discussion": 4, "suggestion_and_solution": 9, "total": 30 }	{ "criticism": 0.1, "example": 0.1, "importance_and_relevance": 0.03333333333333333, "materials_and_methods": 0.36666666666666664, "praise": 0.03333333333333333, "presentation_and_reporting": 0.26666666666666666, "results_and_discussion": 0.13333333333333333, "suggestion_and_solution": 0.3 }	1.333333	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 0 Date: 16 Sep 2024\nReviewer's report:\nIn this study, the authors examined the CAC and diastolic dysfunction in a large-scale health\nscreening population, as well as their longitudinal association with the risk of mortality. This\nstudy has significant clinical implications.\nThe authors mentioned that all the proportional hazards models were adjusted for age, sex, BMI,\nsmoking status, alcohol consumption, diabetes, hypertension, hyperlipidemia, statin use, and\naspirin use. They also mentioned that this is the first study to confirm that significant CAC\naffects the progression of DD independently of other clinical factors. However, in previous\npopulation screening studies, the impact of conditions such as diabetes and hypertension on long-\nterm adverse outcomes has also been observed. What might be the reasons for these differences?\nPerhaps further presentation of relevant results in tables is needed.\n1. Regarding the 'Effects of CAC and DD on Mortality,' the authors generated four groups:\nCAC <100 without definite DD, CAC <100 with definite DD, CAC #100 without definite DD,\nand CAC #100 with definite DD. How did you define 100 as the basis for grouping CAC?\nWhy not include CAC=0 as a reference group in the proportional hazards model? Additionally,\nseparating CAC and DD groups for risk model analysis may provide more explanatory value\nfor the correlation between CAC and DD in poor prognosis.\n2. Did these subjects undergo coronary CT scans again during follow-up, and if changes in CAC\nvariables were assessed, this could further explain the association with diastolic dysfunction and\nadverse events.\n3. Given that there were 117 deaths in this study with a sample size of 15,193, it would be\nbeneficial to distinguish cardiovascular deaths or add MACE as an end-point, and indicate the\nproportion of the population concerned.\n4. The expression of values in the table 1 is confused, and it is not clear whether it is the median\n(IQR) or number (%)\n5. The description of Table 1 states, 'All P values for trends comparing baseline characteristics\nof the three groups were < 0.05.' This could lead to misunderstanding, as we can see that at least\nLVEF is almost consistent among the three groups. Please verify or correct this.\n6. In terms of medication, it would be beneficial to include antihypertensive agents or\nantidiabetic drugs, and if possible, specify the category for better detail.\n7. The statement 'Age, male, current smoker, and metabolically unhealthy were positively\nassociated with CAC' in the first paragraph of the results section cannot be concluded from\nTable 1.\n8. Table 2 should include the total number of Definite DD and Definite or probable DD cases.\n9. In the discussion section, under 'Progression of DD According to Presence of CAC,' the\nsentence 'This was 2.0 and 1.5 times more frequent compared to participants without DD,\nrespectively' cannot be found in the results section or in the charts. Please check for accuracy.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 08 Nov 2024 Reviewer's report: The manuscript is well-written, well-researched, well-documented with so many references. Please ask the authors to truncate the discussion. Overall to reduce the references to the most current ones. The discussion was redundant and could be shortened. The methods are impressive well documented.	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 0 Date: 08 Nov 2024 Reviewer's report: The manuscript is well-written, well-researched, well-documented with so many references. Please ask the authors to truncate the discussion. Overall to reduce the references to the most current ones. The discussion was redundant and could be shortened. The methods are impressive well documented.	BMC	12916_2025_3956_ReviewerReport_V0_R2.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 1, "praise": 2, "presentation_and_reporting": 4, "results_and_discussion": 2, "suggestion_and_solution": 3, "total": 5 }	{ "criticism": 0.2, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0.2, "praise": 0.4, "presentation_and_reporting": 0.8, "results_and_discussion": 0.4, "suggestion_and_solution": 0.6 }	2.6	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 0 Date: 08 Nov 2024\nReviewer's report:\nThe manuscript is well-written, well-researched, well-documented with so many references.\nPlease ask the authors to truncate the discussion. Overall to reduce the references to the most\ncurrent ones.\nThe discussion was redundant and could be shortened.\nThe methods are impressive well documented.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 24 Nov 2024 Reviewer's report: That's a good response. I don't have any more comments	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 24 Nov 2024 Reviewer's report: That's a good response. I don't have any more comments	BMC	12916_2025_3956_ReviewerReport_V1_R3.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 1, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 2 }	{ "criticism": 0.5, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0.5, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	1	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 1 Date: 24 Nov 2024\nReviewer's report:\nThat's a good response. I don't have any more comments", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 26 Nov 2024 Reviewer: Paul R. M. van Dijkman Reviewer's report: This is a an improved version of an interesting study. As already stated by me it is well written. An important addition was my request about data of repeated calciumscore measurements and about CA>400. However, the consequences of these are not discussed further in the discussion. I would like to hear the views of the authors on this additional data.	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 26 Nov 2024 Reviewer: Paul R. M. van Dijkman Reviewer's report: This is a an improved version of an interesting study. As already stated by me it is well written. An important addition was my request about data of repeated calciumscore measurements and about CA>400. However, the consequences of these are not discussed further in the discussion. I would like to hear the views of the authors on this additional data.	BMC	12916_2025_3956_ReviewerReport_V1_R1.pdf	{ "criticism": 1, "example": 0, "importance_and_relevance": 1, "materials_and_methods": 2, "praise": 2, "presentation_and_reporting": 1, "results_and_discussion": 1, "suggestion_and_solution": 1, "total": 5 }	{ "criticism": 0.2, "example": 0, "importance_and_relevance": 0.2, "materials_and_methods": 0.4, "praise": 0.4, "presentation_and_reporting": 0.2, "results_and_discussion": 0.2, "suggestion_and_solution": 0.2 }	1.8	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 1 Date: 26 Nov 2024\nReviewer: Paul R. M. van Dijkman\nReviewer's report:\nThis is a an improved version of an interesting study. As already stated by me it is well written.\nAn important addition was my request about data of repeated calciumscore measurements and\nabout CA>400.\nHowever, the consequences of these are not discussed further in the discussion. I would like to\nhear the views of the authors on this additional data.", "role": "assistant" } ]	2,025
Review for 10.1186/s12916-025-03956-9	Reviewed - bmc_medicine	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 04 Dec 2024 Reviewer's report:	Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort Study Version: 1 Date: 04 Dec 2024 Reviewer's report:	BMC	12916_2025_3956_ReviewerReport_V1_R2.pdf	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0, "total": 1 }	{ "criticism": 0, "example": 0, "importance_and_relevance": 0, "materials_and_methods": 0, "praise": 0, "presentation_and_reporting": 0, "results_and_discussion": 0, "suggestion_and_solution": 0 }	0	[ { "content": "Please review this paper.", "role": "user" }, { "content": "Title: Impact of Coronary Artery Calcium on Progression of Diastolic Dysfunction: A Cohort\nStudy\nVersion: 1 Date: 04 Dec 2024\nReviewer's report:", "role": "assistant" } ]	2,025

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