Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an intriguing and underexplored topic by linking androgen receptor (AR) dysfunction to lean MASLD, illustrated through a clinical case of Kennedy’s disease. The premise is strong, and the integration of mechanistic review with a clinical vignette is potentially impactful. However, in its current form, the paper falls short of the rigor and clarity required for publication, and several critical revisions are needed.

The narrative contains excessive density, which results in repeated information. AR regulation of lipid metabolism, together with insulin sensitivity and mitochondrial function pathways, is repeated multiple times using equivalent wording. The repeated information weakens the main findings presented in the study. Each mechanistic theme should be introduced only once in a revised structure, before it undergoes clear development and connection to the central hypothesis. The paper's accessibility to outside readers from specific fields can be improved by removing duplicated sections.

The clinical case presents an interesting situation, but its presentation needs further development. The connection between Kennedy’s disease and lean MASLD requires more substantial evidence to establish a link between these conditions. The text implies a causal relationship between AR dysfunction and MASLD, but provides insufficient evidence to support this relationship. The case requires an explicit acknowledgment of its hypothesis-generating status, along with a discussion of possible alternative explanations for steatosis affecting this patient group, including genetic factors, dietary factors, or concurrent metabolic factors. Without proper equilibrium, the argument may seem overconfident.

The visual content employs basic descriptive figures rather than analytical ones. The liver and muscle metabolism diagrams presented by the text do not add new mechanistic information beyond what the text already explains. The figures should present specific molecular interactions and pathways, as well as organ cross-talk, in a visual format to demonstrate the unique AR–MASLD hypothesis. The addition of pathway-style schematic figures would enhance the manuscript's strength.

The therapeutic perspectives section contains confusing information that extends beyond specific boundaries. The section presents preclinical research alongside case studies and theoretical strategies, but fails to clarify the quality of the evidence. The combination of preliminary animal research with clinical effectiveness creates confusion for readers. The section requires reorganization to distinguish between preclinical data and clinical trial findings, while establishing an evidence-based structure. The proposed AR-targeted interventions require thorough evaluation regarding their translational potential, as well as their risks and off-target effects, and the challenges of controlling nuclear receptor signaling in human subjects.

The paper requires more direct clarification about classification problems. The classification of steatosis caused by AR dysfunction remains unclear because researchers debate whether it should be categorized under MASLD or established as a distinct genetic/metabolic liver disease. The discussion explores this matter but fails to provide a thorough analysis regarding its effects on diagnosis and treatment approaches. The review would gain significant value through the clarification of this conceptual framework.

Finally, the tone of the conclusions is too strong for the evidence presented. Assertions that AR dysfunction “explains” lean MASLD are premature, given that the data are primarily associative and based on a single illustrative case. The authors should temper their conclusions to emphasize that this is a plausible but unproven mechanism, requiring confirmation in larger cohorts and mechanistic studies.

Author Response

REVIEWER 1.  COMMENTS AND RESPONSES

General comment: The manuscript addresses an intriguing and underexplored topic by linking androgen receptor (AR) dysfunction to lean MASLD, illustrated through a clinical case of Kennedy’s disease. The premise is strong, and the integration of mechanistic review with a clinical vignette is potentially impactful. However, in its current form, the paper falls short of the rigor and clarity required for publication, and several critical revisions are needed.

Reply: Firstly, we would like to thank the Reviewer for his/her constructive and thorough examination of our manuscript, which helps us to improve it. The Manuscript is currently being revised at an English level. Please see below for detailed responses to his/her minor/major comments.

Comment 1. The narrative contains excessive density, which results in repeated information. AR regulation of lipid metabolism, together with insulin sensitivity and mitochondrial function pathways, is repeated multiple times using equivalent wording. The repeated information weakens the main findings presented in the study. Each mechanistic theme should be introduced only once in a revised structure, before it undergoes clear development and connection to the central hypothesis. The paper's accessibility to outside readers from specific fields can be improved by removing duplicated sections.

Reply: Thank you for bringing this issue to our attention. We revised the manuscript and removed the duplicated sections.  The introduction was reduced, and the paragraph on AR-disruption and its implications has been revised for greater clarity.  The part of the liver-muscle axis has also been more detailed and clarified.

Comment 2. The clinical case presents an interesting situation, but its presentation needs further development. The connection between Kennedy’s disease and lean MASLD requires more substantial evidence to establish a link between these conditions. The text implies a causal relationship between AR dysfunction and MASLD, but provides insufficient evidence to support this relationship. The case requires an explicit acknowledgment of its hypothesis-generating status, along with a discussion of possible alternative explanations for steatosis affecting this patient group, including genetic factors, dietary factors, or concurrent metabolic factors. Without proper equilibrium, the argument may seem overconfident.

Reply:  We thank the reviewer for this insightful comment. We agree that the current evidence is insufficient to establish a direct causal relationship between Kennedy’s disease/AR dysfunction and lean MASLD. In line with the suggestion, we have revised the manuscript to (i) explicitly acknowledge the hypothesis-generating nature of our case, (ii) emphasize that the observed association is exploratory rather than causal, and (iii) include a discussion of alternative explanations for steatosis in this patient population, such as genetic predisposition (e.g., PNPLA3, TM6SF2), dietary influences, and concurrent metabolic factors. These changes ensure a more balanced interpretation of our findings. The revisions can be found in the Discussion and Conclusion, as well as in the paragraph of the Case-report presentation.

Case report paragraph:

2.3 Hypothesis and diagnosis confirmation

Despite the patient's strict adherence to medical and lifestyle modifications, including a tailored diet and physical exercise plan, the drug response was suboptimal, and the persistence of ALT was noticeable.  This phenomenon raised our suspicions for a more complex molecular background of metabolic dysfunction and hepatic steatosis, in combination with chronic elevation of CPK: 1163 IU/L, which was irrelevant to statin intake or physical exercise intensity. Meanwhile, neurological evaluation excluded several types of myopathies or common neuromuscular disorders, including lipid myopathies (LPIN1 and carnitine palmitoyltransferase II deficiencies), Amyotrophic Lateral Sclerosis, progressive muscular atrophy, etc.

Although initial neurological evaluation excluded common myopathies, the combination of mild neuromuscular symptoms and laboratory evidence of muscle involvement raised suspicion for androgen receptor (AR)-related neuromuscular dysfunction, prompting targeted genetic testing. More particularly, polymerase chain reaction (PCR)-based fragment analysis was performed, which demonstrated a pathogenic expansion of the CAG (≥38 repeats), whereas normal alleles present approximately 9–36 CAG repeats, which confirmed the diagnosis of AR dysfunction. All those above clinical (muscle weakness), laboratory (increased CPK, ALT, and normal testosterone), and imaging findings (hepatic steatosis), as well as the pathogenic expansion of CAG, led us to the diagnosis of Kennedy Disease (KD) or the so-called Spinal and Bulbar Muscular Atrophy (SBMA), which is a neuromuscular disorder that primarily affects male population, that includes a significant metabolic dysfunction, endocrinal symptoms and progressive loss of muscle strength [13-15]. Therefore, the metabolic and hepatic phenotype in this case was attributed to AR dysfunction, supporting the role of the liver–muscle axis in the pathophysiology of lean MASLD. Nevertheless, although this case highlights a possible mechanistic correlation between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating, with KD and lean MASLD concurrence in this patient cannot be considered as definitive causality, as further research is required to clarify this interplay. In Table 1, we summarize the laboratory and imaging findings at the time of diagnosis.

Comment 3: The visual content employs basic descriptive figures rather than analytical ones. The liver and muscle metabolism diagrams presented by the text do not add new mechanistic information beyond what the text already explains. The figures should present specific molecular interactions and pathways, as well as organ cross-talk, in a visual format to demonstrate the unique AR–MASLD hypothesis. The addition of pathway-style schematic figures would enhance the manuscript's strength.

Reply: We deleted figure 1 and 2 and we demonstrate a new figure that shows the molecular and signaling interactions in the liver-muscle axis and the AR-Masld hypothesis, as you suggested.

Comment 4: The therapeutic perspectives section contains confusing information that extends beyond specific boundaries. The section presents preclinical research alongside case studies and theoretical strategies, but fails to clarify the quality of the evidence. The combination of preliminary animal research with clinical effectiveness creates confusion for readers. The section requires reorganization to distinguish between preclinical data and clinical trial findings, while establishing an evidence-based structure. The proposed AR-targeted interventions require thorough evaluation regarding their translational potential, as well as their risks and off-target effects, and the challenges of controlling nuclear receptor signaling in human subjects.

Reply: We thank the reviewer for this insightful comment. We modified the manuscript accordingly. We modified the paragraph radically. We separated the clinical and preclinical studies, making it more reader-friendly.  We also deleted the previous tables and added a well-structured table for pharmacologic treatments, categorized by Drug/Class, Mechanism, Trial Status, and Limitations (including currently used agents, clinical trials, and preclinical studies).

 

Moreover, we added to our discussion. “Nevertheless, it is essential to note that the AR-targeted interventions are presented at the preclinical or early clinical stage. Their translational potential, safety profile, and risk of off-target effects require careful evaluation. In particular, modulating nuclear receptor signaling in humans presents inherent challenges, including tissue-specific effects and systemic hormonal impacts. These strategies are promising but remain experimental, and further mechanistic and clinical studies are necessary before routine therapeutic application.”

We added in conclusion: Lastly, AR-targeted interventions, the translational potential, safety profile, and risk of off-target effects of nuclear receptor signaling modulators, such as in the case of AR-targeted agents, require careful evaluation, as they are considered challenging due to their potential systemic hormonal impacts in humans.

Comment 4: The paper requires more direct clarification about classification problems. The classification of steatosis caused by AR dysfunction remains unclear because researchers debate whether it should be categorized under MASLD or established as a distinct genetic/metabolic liver disease. The discussion explores this matter but fails to provide a thorough analysis regarding its effects on diagnosis and treatment approaches. The review would gain significant value through the clarification of this conceptual framework.

Reply: We thank the reviewer for this insightful comment. We modified the manuscript accordingly.

Discussion: “Last but not least, although this case highlights a possible mechanistic interplay between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating. The co-occurrence of KD and lean MASLD in this patient does not establish a definitive causality, and further research is needed to clarify the nature of this relationship”.

Additionally, we mention that there is no other background of genetic-metabolic liver disease, as we excluded them.

We also added in discussion: “Last but not least, although this case highlights a possible mechanistic interplay between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating. The co-occurrence of KD and lean MASLD in this patient does not establish a definitive causality, and further research is needed to clarify the nature of this relationship. However, we consider AR dysfunction as the most possible mechanism, as other potential contributors to steatosis in this patient have been carefully excluded, including genetic variants, dietary patterns, and co-existing metabolic factors, that could independently or synergistically promote hepatic lipid accumulation.

 

Conclusion: “This case should be regarded as hypothesis-generating, underscoring the need for further studies to determine whether AR dysfunction contributes causally to lean MASLD or whether it represents one of multiple overlapping risk factors. Explicit recognition of alternative mechanisms is essential for balanced interpretation.”

 

Comment 5: Finally, the tone of the conclusions is too strong for the evidence presented. Assertions that AR dysfunction “explains” lean MASLD are premature, given that the data are primarily associative and based on a single illustrative case. The authors should temper their conclusions to emphasize that this is a plausible but unproven mechanism, requiring confirmation in larger cohorts and mechanistic studies.

Reply: Thank you for this comment. We modified the conclusion accordingly:

“This case-based review should be regarded as hypothesis-generating, underscoring the need for further studies to determine whether AR dysfunction contributes causally to lean MASLD or whether it represents one of multiple overlapping risk factors. Explicit recognition of alternative mechanisms is essential for balanced interpretation.AR dysfunction may contribute to lean MASLD, representing a plausible mechanism that warrants further investigation. However, these findings are primarily associative and based on a single illustrative case, and confirmation in larger cohorts and mechanistic studies is needed”.  

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This case-based review describes a 34-year-old lean male with unexplained hypertransaminasemia, resistant dyslipidemia, and elevated creatine phosphokinase levels, ultimately diagnosed with Kennedy disease (spinal and bulbar muscular atrophy) linked to androgen receptor (AR) dysfunction. The authors argue that AR disruption contributes to metabolic and hepatic abnormalities, positioning it as a mechanistic link in lean-MASLD among men. They propose that AR dysfunction should be systematically considered in such cases, given its potential to influence both diagnosis and management strategies.

This is an interesting and well-written manuscript that highlights an underappreciated angle in lean MASLD. The case is clearly presented and the review component is thorough, combining molecular mechanisms of AR signaling with clinical implications. However, there are some areas requiring clarification and strengthening:

Genetic Evaluation Beyond AR: The authors correctly report exclusion of common polymorphisms including PNPLA3 and TM6SF2, but this is only briefly mentioned. Given that PNPLA3 is the strongest genetic determinant of lean NASH, especially in Asian populations, the paper should better explore its role in comparison to AR dysfunction. Without more explicit discussion, the reader may overestimate the primacy of AR in this phenotype. I strongly suggest a dedicated subsection contextualizing AR mutations alongside PNPLA3, TM6SF2, MBOAT7, and HSD17B13, with commentary on ethnic variability.

Factual Accuracy: Most affirmations are correct, but some are phrased too broadly. For instance, the claim that AR dysfunction “significantly modifies metabolic signaling pathways leading to drug resistance to lipid-lowering therapy" is plausible but not adequately evidenced; it should be reframed more cautiously, perhaps as “may contribute to reduced responsiveness.” Similarly, the suggestion that PCSK9 inhibitors are a “safer alternative” in Kennedy disease could be overstated since no controlled data exist—this should be clarified.

Overemphasis on AR: While AR dysfunction is central to the case, the text tends to present it as a near-exclusive explanation for lean-MASLD. A balanced review should highlight that lean MASLD is heterogeneous, with environmental, metabolic, and other genetic contributors. Otherwise, the narrative risks sounding too deterministic.

Clarity and Structure: The manuscript is dense, with long paragraphs that mix case detail, pathophysiology, and therapy. Breaking down sections into clearer subsections (Case, Differential Diagnoses Excluded, AR Pathophysiology, Therapeutic Implications) would improve readability. Figures are helpful but could be complemented by a concise table summarizing “Genetic and Non-Genetic Causes of Lean MASLD.”

Minor Issues: The manuscript states that “lean MASLD patients should not be screened unless metabolic dysfunction is present”; while technically correct per current guidelines, it would be useful to nuance this by stressing that incidental steatosis in lean individuals still warrants careful evaluation. There are several English typos and awkward phrasings (e.g., “lipid dysregulation aggrevation,” “hepatic parenchymal” instead of “hepatic parenchyma”), which should be corrected.

Please expand the discussion of PNPLA3 and other major polymorphisms as alternative or complementary drivers of lean MASLD, particularly given their prevalence in Asian populations. This will strengthen the scientific balance of your review.

Reconsider broad statements on therapy resistance and drug efficacy; reframe them with caution unless supported by clinical trial data.

Clarify that AR dysfunction is a novel but not exclusive mechanism in lean MASLD.

Author Response

 

REVIEWER 2 – ROUND 1

General comment:

This case-based review describes a 34-year-old lean male with unexplained hypertransaminasemia, resistant dyslipidemia, and elevated creatine phosphokinase levels, ultimately diagnosed with Kennedy disease (spinal and bulbar muscular atrophy) linked to androgen receptor (AR) dysfunction. The authors argue that AR disruption contributes to metabolic and hepatic abnormalities, positioning it as a mechanistic link in lean-MASLD among men. They propose that AR dysfunction should be systematically considered in such cases, given its potential to influence both diagnosis and management strategies. This is an interesting and well-written manuscript that highlights an underappreciated angle in lean MASLD. The case is clearly presented and the review component is thorough, combining molecular mechanisms of AR signaling with clinical implications. However, there are some areas requiring clarification and strengthening:

REPLY: Firstly, we would like to thank the Reviewer for his/her constructive and thorough examination of our manuscript, which helps us to improve it. The Manuscript is currently being revised at an English level. Please see below for detailed responses to his/her minor/major comments.

 

• Genetic Evaluation Beyond AR: The authors correctly report exclusion of common polymorphisms including PNPLA3 and TM6SF2, but this is only briefly mentioned. Given that PNPLA3 is the strongest genetic determinant of lean NASH, especially in Asian populations, the paper should better explore its role in comparison to AR dysfunction.

REPLY: We thank the reviewer for highlighting the importance of genetic determinants beyond AR dysfunction, particularly PNPLA3 (rs738409 I148M), which indeed represents the strongest and most consistently replicated risk allele for MASLD/MASH across diverse populations, with pronounced effects in lean individuals, especially in Asian cohorts.

 We agree that its role warrants fuller discussion. In our case, both PNPLA3 and TM6SF2 polymorphisms were evaluated and excluded, which strengthens the relevance of AR dysfunction as a primary contributor to the phenotype observed.

We have now expanded the discussion to compare the potential contribution of AR dysfunction with the established role of PNPLA3 in lean NASH, emphasizing that while PNPLA3 confers susceptibility via enhanced triglyceride retention in hepatocytes, AR dysfunction may act through distinct mechanisms involving androgen signaling, lipid oxidation, and metabolic regulation. This addition contextualizes our findings within the broader genetic landscape of lean MASLD.

 

 

• Without more explicit discussion, the reader may overestimate the primacy of AR in this phenotype. I strongly suggest a dedicated subsection contextualizing AR mutations alongside PNPLA3, TM6SF2, MBOAT7, and HSD17B13, with commentary on ethnic variability.

REPLY: Indeed, thank you for your valuable comment. We made several modifications. More particularly:

• We added the ethnicity of the patient: caucasian
• We made the additions that you suggested
  • Genetic causes of lean-MASLD

Genetic determinants of MASLD, particularly in lean individuals, have been extensively studied and have a pivotal role in disease progression, especially in specific ethnicities. Several gene polymorphisms have been identified as strong contributors to lean-MASLD and increased risk of fibrosis development, such as PNPLA3 rs738409 (I148M) polymorphism, which is considered the strongest genetic risk factor for hepatic steatosis and MASH, especially for the Hispanic and Asian population. Other variants include MBOAT7 (rs641738), TM6SF2 (E167K), and GCKR (P446L), as well as other loci such as APOC3 and LYPLAL1, which induce moderate effects.

  Focusing on the implication of PNPLA3 rs738409 (I148M) polymorphism in disease progression, this variant significantly promotes TG storage in hepatocytes, via the impairment of TG hydrolysis, which eventually leads to steatosis development. It has to be underlined that the aforementioned phenomenon is independent of the obese phenotype, leading to steatosis even in lean individuals. Based on the epidemiological data, it is mostly identified in Latin America (50-63 %), in East (35-45%), and South Asia (24-30%), followed by Europe (23-38%), and Sub-Saharan Africa (12%). The predominance of PNPLA3 in the Asian population underlined the key role of this polymorphism in hepatic lipid metabolism dysregulation, rather than systemic metabolic dysfunction and obesity. Other variants, such as TM6SF2 (E167K), MBOAT7 (rs641738), and GCKR (P446L), also contribute to disease risk, though their distribution and clinical impact may differ across ethnic groups. MBOAT7 (rs641738) is related to proneness to steatosis and fibrosis development, as well as it is also correlated with the modified phospholipid remodeling mechanism, mostly in Europe and less frequently in East Asia. Moreover, TM6SF2 (E167K variant) is related to altered VLDL secretion; however, it is not considered as common compared to the other two aforementioned variants. GCKR (P446L variant) is related to increased hepatic glucose uptake and DNL, lower fasting plasma glucose, and higher TG. Interestingly, these patients have a lower risk of T2DM development.

 

• Non-genetic causes of lean MASLD

In addition to genetic predisposition, several non-genetic factors also contribute significantly to the development of lean-MASLD. Ethnicity has a crucial role in lean-MASLD development, with Asians showing a disproportionately higher prevalence despite normal BMI. Lifestyle and diet also influence disease progression, with physical inactivity and higher intake of carbohydrates and lipids enhancing hepatic glucose uptake, DNL, and insulin resistance, respectively. On top of that, certain medications, including methotrexate, corticosteroids, and tamoxifen, can induce iatrogenic steatosis, as well as endocrine disorders such as polycystic ovarian syndrome, hypothyroidism, and hypopituitarism. Moreover, alterations in the gut microbiome (dysbiosis) disrupt bile acid signaling and intestinal permeability, leading to bacterial translocation and hepatic inflammation. Finally, low muscle mass and sarcopenia are increasingly recognized as contributors, since they worsen insulin resistance and compound metabolic stress in lean individuals.

 

• Factual Accuracy: Most affirmations are correct, but some are phrased too broadly. For instance, the claim that AR dysfunction “significantly modifies metabolic signaling pathways leading to drug resistance to lipid-lowering therapy" is plausible but not adequately evidenced; it should be reframed more cautiously, perhaps as “may contribute to reduced responsiveness.”

REPLY: Thank you for this valuable comment. We modified the manuscript accordingly.

This case-based review should be regarded as hypothesis-generating, underscoring the need for further studies to determine whether AR dysfunction contributes causally to lean MASLD or whether it represents one of multiple overlapping risk factors. Explicit recognition of alternative mechanisms is essential for balanced interpretation.AR dysfunction may contribute to lean MASLD, representing a plausible mechanism that warrants further investigation. However, these findings are primarily associative and based on a single illustrative case. It has to be clarified that the potential contribution of AR dysfunction represents a distinct mechanistic pathway, underscoring the genetic heterogeneity underlying MASLD across populations.Confirmation in larger cohorts and mechanistic studies, which can molecularly evaluate lean-MASLD patients for AR-related abnormalities (cross-sectional and population cohort), is necessary, as this group is quite heterogeneous, especially for the estimation of prevalence. In addition, a subgroup analysis considering AR function, histological severity, and disease outcomes (prospective cohorts) will open new horizons for managing lean-MASLD patients based on the AR genetic variant.

• Similarly, the suggestion that PCSK9 inhibitors are a “safer alternative” in Kennedy disease could be overstated since no controlled data exist—this should be clarified.

REPLY: Thank you for this valuable comment. We modified the manuscript accordingly.

We hypothesized that modification of lipid treatment could be beneficial, including the initiation of a PCSK9 inhibitor in combination with ezetimibe and omega-3 fatty acids for a wider targeting of multiple lipid-lowering pathways and the cessation of statins due to several concerns about their utilization, as possible statin-associated muscle symptoms (SAMs) could aggravate the AR dysfunction-related neuromuscular manifestations, like in KD. However, the safety and efficacy of statins' utilization have not been widely and systematically studied in KD. At the same time, there is no general contraindication to statin prescription in all neuromuscular pathologies, except for autoimmune myopathies and some specific genetic muscle diseases [15,16]. Additionally, PCSK9 inhibitors were chosen as they are generally well-tolerated based on clinical trial data, with a very low incidence of hepatic and muscle toxicity and reduced risk of T2DM development, compared to statins. Inclisiran (siRNA-based PCSK9 inhibitor) can potentially have one side effect, which constitutes injection site reactions (5%), which are not severe and can be decreased after repeated administrations, in comparison to other agents of this drug family. On top of that, there is no reported specific interaction based on the available literature between the aforementioned combination of drugs (Inclisiran, ezetimibe, and Omega-3), which could, unlikely, cause major pharmacokinetic issues.  The combination of Inclisiran and ezetimibe provides a positive additive pharmacodynamic effect for LDL reduction, whereas omega-3 works on triglycerides. Another benefit of Inclisiran that was taken into consideration is that nucleases metabolize it to inactive nucleotides and do not constitute a substrate of cytochrome P450 (CYP) isozymes or other transporters. Therefore, Inclisiran is not expected to cause drug interactions since it does not interfere with the CYP enzyme system or drug transporters, which makes it ideal for patients who are receiving multiple medications. 

Considering that non-adherence, improper diet, and underdosing or genetic dyslipidemia and other comorbidities (e.g., diabetes, hypothyroidism, obesity, etc.) were excluded, we observed that the patient presented a suboptimal response to lipid-lowering therapy with statins, combined with ezetimibe and Ωmega-3. Meanwhile, we suspected an alternative signaling pathway implicated in dyslipidemia, also taking into consideration the involvement of muscle. Therefore, the hypothesis that AR dysfunction could contribute to the suboptimal response to the lipid-lowering regimen, as AR is implicated in liver-muscle axis regulation.

 

 

 

• Overemphasis on AR: While AR dysfunction is central to the case, the text tends to present it as a near-exclusive explanation for lean-MASLD. A balanced review should highlight that lean MASLD is heterogeneous, with environmental, metabolic, and other genetic contributors. Otherwise, the narrative risks sounding too deterministic.

REPLY: Indeed, we totally agree with your comment. We excluded a wide spectrum of etiologies.

We added in our manuscript this part in the discussion and in the conclusion:

Last but not least, although this case highlights a possible mechanistic interplay between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating. The co-occurrence of KD and lean MASLD in this patient does not establish a definitive causality, and further research is needed to clarify the nature of this relationship. However, we consider AR dysfunction as the most possible mechanism, as other potential contributors to steatosis in this patient have been carefully excluded, including genetic variants, dietary patterns, and co-existing metabolic factors, that could independently or synergistically promote hepatic lipid accumulation.

 

1. Conclusion and Future Perspectives

This case-based review should be regarded as hypothesis-generating, underscoring the need for further studies to determine whether AR dysfunction contributes causally to lean MASLD or whether it represents one of multiple overlapping risk factors. Explicit recognition of alternative mechanisms is essential for balanced interpretation.AR dysfunction may contribute to lean MASLD, representing a plausible mechanism that warrants further investigation. However, these findings are primarily associative and based on a single illustrative case. However, these findings are primarily associative and based on a single illustrative case. It has to be clarified that the potential contribution of AR dysfunction represents a distinct mechanistic pathway, underscoring the genetic heterogeneity underlying MASLD across populations.Confirmation in larger cohorts and mechanistic studies, which can molecularly evaluate lean-MASLD patients for AR-related abnormalities (cross-sectional and population cohort), is necessary, as this group is quite heterogeneous, especially for the estimation of prevalence. In addition, a subgroup analysis considering AR function, histological severity, and disease outcomes (prospective cohorts) will open new horizons for managing lean-MASLD patients based on the AR genetic variant. Lastly, AR-targeted interventions, the translational potential, safety profile, and risk of off-target effects of nuclear receptor signaling modulators, such as in the case of AR-targeted agents, require careful evaluation, as they are considered challenging due to their potential systemic hormonal impacts in humans.

 

• Clarity and Structure: The manuscript is dense, with long paragraphs that mix case detail, pathophysiology, and therapy. Breaking down sections into clearer subsections (Case, Differential Diagnoses Excluded, AR Pathophysiology, Therapeutic Implications) would improve readability.

REPLY:  We modified the manuscript’s skeleton as you suggested.

• Figures are helpful but could be complemented by a concise table summarizing “Genetic and Non-Genetic Causes of Lean MASLD.”

Reply: We deleted figures 1 and 2, and we demonstrate a new figure that shows the molecular and signaling interactions in the liver-muscle axis and the AR-Masld hypothesis. We have added the table you suggested (Table 4.)

• Minor Issues: The manuscript states that “lean MASLD patients should not be screened unless metabolic dysfunction is present”; while technically correct per current guidelines, it would be useful to nuance this by stressing that incidental steatosis in lean individuals still warrants careful evaluation.

REPLY: Indeed, thank you for this precious comment. We modified the manuscript accordingly.

• There are several English typos and awkward phrasings (e.g., “lipid dysregulation aggravation,” “hepatic parenchymal” instead of “hepatic parenchyma”), which should be corrected.

REPLY: The Manuscript is currently being revised at an English level.

 

• Please expand the discussion of PNPLA3and other major polymorphisms as alternative or complementary drivers of lean MASLD, particularly given their prevalence in Asian populations. This will strengthen the scientific balance of your review.

REPLY: We added information regarding the genetic polymorphism as you suggested in the paragraph on Lean MASLD.  

 

 

• Reconsider broad statements on therapy resistance and drug efficacy; reframe them with caution unless supported by clinical trial data.

REPLY: Thank you for this precious comment. We modified the manuscript accordingly.

 

We hypothesized that modification of lipid treatment could be beneficial, including the initiation of a PCSK9 inhibitor in combination with ezetimibe and omega-3 fatty acids for a wider targeting of multiple lipid-lowering pathways and the cessation of statins due to several concerns about their utilization, as possible statin-associated muscle symptoms (SAMs) could aggravate the AR dysfunction-related neuromuscular manifestations, like in KD. However, the safety and efficacy of statins' utilization have not been widely and systematically studied in KD. At the same time, there is no general contraindication to statin prescription in all neuromuscular pathologies, except for autoimmune myopathies and some specific genetic muscle diseases [16,17]. Additionally, PCSK9 inhibitors were chosen as they are generally well-tolerated based on clinical trial data, with a very low incidence of hepatic and muscle toxicity and reduced risk of T2DM development, compared to statins. Inclisiran (siRNA-based PCSK9 inhibitor) can potentially have one side effect, which constitutes injection site reactions (5%), which are not severe and can be decreased after repeated administrations, in comparison to other agents of this drug family [18]. On top of that, there is no reported specific interaction based on the available literature between the aforementioned combination of drugs (Inclisiran, ezetimibe, and Omega-3), which could, unlikely, cause major pharmacokinetic issues.  The combination of Inclisiran and ezetimibe provides a positive additive pharmacodynamic effect for LDL reduction, whereas omega-3 works on triglycerides. Another benefit of Inclisiran that was taken into consideration is that nucleases metabolize it to inactive nucleotides and do not constitute a substrate of cytochrome P450 (CYP) isozymes or other transporters. Therefore, Inclisiran is not expected to cause drug interactions since it does not interfere with the CYP enzyme system or drug transporters, which makes it ideal for patients who are receiving multiple medications [18,19].  Considering that non-adherence, improper diet, and underdosing or genetic dyslipidemia and other comorbidities (e.g., diabetes, hypothyroidism, obesity, etc.) were excluded, we observed that the patient presented a suboptimal response to lipid-lowering therapy with statins, combined with ezetimibe and Ωmega-3. Meanwhile, we suspected an alternative signaling pathway, such as AR signaling, being implicated in dyslipidemia, also taking into consideration the involvement of muscle [19-21].

 

• Sun L, Wolska A, Amar M, Zubirán R, Remaley AT. Approach to the Patient With a Suboptimal Statin Response: Causes and Algorithm for Clinical Management. J Clin Endocrinol Metab. 2023 Aug 18;108(9):2424-2434. doi: 10.1210/clinem/dgad153. PMID: 36929838; PMCID: PMC10438872.
• Stoll F, Eidam A, Michael L, Bauer JM, Haefeli WE. Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents. Drugs Aging. 2022 Apr;39(4):251-256. doi: 10.1007/s40266-022-00928-z. Epub 2022 Mar 12. PMID: 35278206; PMCID: PMC8995260. “Generally, the profile and frequencies of adverse events reported in the ORION trials were similar in the actively treated and placebo groups and increased with age, indicating that they were not caused by the active compound [24]. The summary of product characteristics lists injection site reactions (including erythema, pain, rash) as the only but common adverse reaction related to inclisiran [23]. In contrast to the unrelated adverse events, injection site reactions were more frequent in patients aged < 65 years than in older patients [24]. Mild elevations of serum hepatic transaminases (below the threefold of the upper limit of normal usually judged as clinically relevant) were observed under inclisiran treatment [23]. Inclisiran did not induce an adverse immunological reaction as measured by platelet counts, lymphocyte, monocyte, neutrophil counts, tumor necrosis factor-α, interleukin-6, and antidrug antibodies [27]. Because inclisiran is metabolized by nucleases to inactive nucleotides, it is not likely to be a substrate of common transporters or cytochrome P450 (CYP) isozymes [23]. Moreover, it is not targeting relevant structures of drug elimination pathways or their expression. Therefore, inclisiran-induced drug interactions are not expected.” (Based on the aforementioned reference)

 

 

• Clarify that AR dysfunction is a novel but not exclusive mechanism in lean MASLD.

REPLY: We added this clarification to our manuscript. Thank you for this precious comment.

Among these, androgen receptor (AR) signaling is in the spotlight of liver-steatosis related studies, as regulator of mitochondrial function, glucose, and lipid hepatic metabolism, with its functional disturbance leading to hepatic steatosis development, with or without the presence of cardiometabolic factors, making the diagnosis and the disease management quite challenging for physicians, especially in cases of lean patients, as AR dysfunction is mostly associated with visceral obesity[3-6]. However, it is essential to note that AR dysfunction constitutes a rare but not exclusive mechanism in lean MASLD. Prompted by a diagnostically challenging case of a lean young male with persistent ALT elevation, unexplained dyslipidemia, and chronically high CPK, we shed light on the role of androgen receptor (AR) dysfunction and its implication in liver–muscle crosstalk. At the same time, we emphasize the importance of its evaluation, particularly in lean patients with hepatic steatosis, when other common genetic and non-genetic causes are excluded.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This case-based review presents a compelling case of a 34-year-old lean male with Kennedy Disease (KD) manifesting as metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the underrecognized role of androgen receptor (AR) dysfunction in the liver-muscle axis. The manuscript provides a comprehensive overview of AR's role in hepatic metabolism and its dysfunction as a potential mechanism for lean-MASLD.

Major Concerns

1. Case Documentation

• The genetic testing methodology needs more detail. Please specify the exact sequencing platform used and the precise number of CAG repeats detected.
• Include baseline laboratory values before any treatment initiation for better context.
• The timeline between symptom onset, diagnosis, and treatment response should be clarified.

2. Structural and Organizational Issues

• The manuscript lacks clear transitions between sections, making it challenging to follow the logical flow.
• Section 3 titled "An overview of the current literature" immediately jumps to section 4.1, creating confusion about the manuscript structure.
• The extensive use of abbreviations, while defined, makes certain passages difficult to read.

3. Mechanistic Clarity

• The distinction between AR dysfunction effects and general testosterone deficiency needs better delineation.
• The specific mechanisms by which CAG repeat expansion leads to metabolic dysfunction versus neuromuscular symptoms require clearer explanation.

Minor Concerns

1. Writing and Presentation

• Numerous grammatical errors and awkward phrasings throughout (e.g., "muscle force impairment" should be "impaired muscle force").
• Inconsistent formatting in citations and references.
• Tables 1-3 could be consolidated or reorganized for better readability.

2. Figure Quality

• Figures 1 and 2 appear to be schematic representations but lack sufficient detail and professional quality expected for publication.
• Figure legends need expansion to stand alone without requiring extensive text reading.

3. Literature Gaps

• Limited discussion of other genetic causes of lean-MASLD beyond AR dysfunction.
• Insufficient coverage of potential drug-drug interactions in the proposed therapeutic combinations.
• The prevalence of AR dysfunction in lean-MASLD populations is not adequately addressed.

Author Response

REVIEWER 3.  COMMENTS AND RESPONSES

General comment: This case-based review presents a compelling case of a 34-year-old lean male with Kennedy Disease (KD) manifesting as metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the underrecognized role of androgen receptor (AR) dysfunction in the liver-muscle axis. The manuscript provides a comprehensive overview of AR's role in hepatic metabolism and its dysfunction as a potential mechanism for lean-MASLD.

Reply: Firstly, we would like to thank the Reviewer for his/her constructive and thorough examination of our manuscript, which helps us to improve it. The Manuscript is currently being revised at an English level. Please see below for detailed responses to his/her minor/major comments.

 

Major Concerns

1. Case Documentation

• The genetic testing methodology needs more detail. Please specify the exact sequencing platform used and the precise number of CAG repeats detected.
• Include baseline laboratory values before any treatment initiation for better context.
• The timeline between symptom onset, diagnosis, and treatment response should be clarified.

 

Reply: Thank you for your suggestions. First of all, we have added a description of the genetic sequencing method (next-generation sequencing (NGS) ), which was employed. We included the baseline labs and the timelines as you suggested

2. Structural and Organizational Issues

• The manuscript lacks clear transitions between sections, making it challenging to follow the logical flow.
• Section 3 titled "An overview of the current literature" immediately jumps to section 4.1, creating confusion about the manuscript structure.
• The extensive use of abbreviations, while defined, makes certain passages difficult to read.

Reply We modified the manuscript as you suggested

3. Mechanistic Clarity

• The distinction between AR dysfunction effects and general testosterone deficiency needs better delineation.
• The specific mechanisms by which CAG repeat expansion leads to metabolic dysfunction versus neuromuscular symptoms require clearer explanation.

Reply: we clarified these parts as you suggested

Minor Concerns

1. Writing and Presentation

• Numerous grammatical errors and awkward phrasings throughout (e.g., "muscle force impairment" should be "impaired muscle force").
• Inconsistent formatting in citations and references.
• Tables 1-3 could be consolidated or reorganized for better readability.

 

Reply: We modified these parts accordingly. Extensive English language polishing was performed.

2. Figure Quality

• Figures 1 and 2 appear to be schematic representations but lack sufficient detail and professional quality expected for publication.
• Figure legends need expansion to stand alone without requiring extensive text

reading.

Reply: We completely modified the figures, as you and other reviewers suggested, and we focused on the metabolic pathways.

3. Literature Gaps

• Limited discussion of other genetic causes of lean-MASLD beyond AR dysfunction.
• Insufficient coverage of potential drug-drug interactions in the proposed therapeutic combinations.
• The prevalence of AR dysfunction in lean-MASLD populations is not adequately addressed.

Reply: We modified the manuscript and added the proper information as you suggested.

 

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The work submitted by authors covered underexplored topic of AR dysfunction in lean MASLD, however, some revisions are needed to make it more clear and scientifically sound.

1. The abstract seems to be too long and elaborative, it is suggestive to shorten the abstract.
2. Use of “Lean MASLD among male patients” in introduction section, line 15-20 is ambiguous, authors should clarify whether they want to refer this in the terms of prevalence data or presented case only.
3. It is better to put all the laboratory investigations values in the form of a small table on page 3.
4. Author should mention the sequence method used to evaluate genetic AR function.
5. Author should add appropriate reference with diagnosis of Kennedy Disease.
6. Authors should add more consensus paper and guidelines to support the discussion related to classification of AR dysfunction under SLD vs MASLD.
7. Authors should maintain same reference formatting on page 6
8. Author should make a well-structured table for pharmacologic treatments using Drug/Class, Mechanism, Trial Status, Limitations.
9. Mention safety concern for Inclisiran and PCSK9 inhibitors.
10. In conclusion section, specify which studies large studies are needed.
11. Multiple references are appeared to be duplicate, thoroughly check all references especially 63, and 67 also.

Author Response

REVIEWER 4- ROUND 1

 

General comment: The work submitted by authors covered underexplored topic of AR dysfunction in lean MASLD, however, some revisions are needed to make it more clear and scientifically sound.

Reply: Firstly, we would like to thank the Reviewer for his/her constructive and thorough examination of our manuscript, which helps us to improve it. The Manuscript is currently being revised at an English level. Please see below for detailed responses to his/her minor/major comments.

Comment 1: The abstract seems to be too long and elaborative, it is suggestive to shorten the abstract.

Reply: We modified the abstract as you suggested.

 

Comment 2: “Use of ‘Lean MASLD among male patients’ in introduction section, line 15-20 is ambiguous, authors should clarify whether they want to refer this in the terms of prevalence data or presented case only.”
Response:

Reply: We have modified the sentence. Among male was deleted

Comment 3: “It is better to put all the laboratory investigations values in the form of a small table on page 3.”
Response:
We have converted all laboratory investigation values into a concise table format on page 3, including units and reference ranges for better readability. We completely changed the skeleton of this paragraph.

 

Comment 4: “Author should mention the sequence method used to evaluate genetic AR function.”
Response:
We have added a description of the method that patient’s AR function was evaluated, while we added a special paragraph that describes all the possible methodologies for AR function evaluation.

Paragraph 2 :  Case report: Although initial neurological evaluation excluded common myopathies, the combination of mild neuromuscular symptoms and laboratory evidence of muscle involvement raised suspicion for androgen receptor (AR)-related neuromuscular dysfunction, prompting targeted genetic testing. More particularly, polymerase chain reaction (PCR)-based fragment analysis was performed, which demonstrated a pathogenic expansion of the CAG (≥38 repeats), whereas normal alleles present approximately 9–36 CAG repeats, which confirmed the diagnosis of AR dysfunction. All those above clinical (muscle weakness), laboratory (increased CPK, ALT, and normal testosterone), and imaging findings (hepatic steatosis), as well as the pathogenic expansion of CAG, led us to the diagnosis of Kennedy Disease (KD) or the so-called Spinal and Bulbar Muscular Atrophy (SBMA), which is a neuromuscular disorder that primarily affects male population, that includes a significant metabolic dysfunction, endocrinal symptoms and progressive loss of muscle strength [13-15]. Therefore, the metabolic and hepatic phenotype in this case was attributed to AR dysfunction, supporting the role of the liver–muscle axis in the pathophysiology of lean MASLD. Nevertheless, although this case highlights a possible mechanistic correlation between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating, with KD and lean MASLD concurrence in this patient cannot be considered as definitive causality, as further research is required to clarify this interplay. In Table 1, we summarize the laboratory and imaging findings at the time of diagnosis.

 

 

Comment 5: “Author should add appropriate reference with diagnosis of Kennedy Disease.”
Response:
We have included an appropriate reference supporting the diagnostic criteria for Kennedy Disease, including clinical and molecular confirmation.

15. Pradat, P. F.; Bernard, E.; Corcia, P.; et al. The French National Protocol for Kennedy’s Disease (SBMA): Consensus Diagnostic and Management Recommendations. Orphanet J. Rare Dis. 2020, 15, 90. https://doi.org/10.1186/s13023-020-01366-z

Comment 6: “Authors should add more consensus paper and guidelines to support the discussion related to classification of AR dysfunction under SLD vs MASLD.”
Response: We have included the appropriate references such as

Our references were

1. Rinella, M. E.; et al. A Multisociety Delphi Consensus Statement on New Fatty Liver Disease Nomenclature. J. Hepatol. 2024, 79(6), 1542–1556.
2. Tacke, F.; Horn, P.; Wong, V. W.; Ratziu, V.; Bugianesi, E.; Francque, S.; Zelber-Sagi, S.; Valenti, L.; Roden, M.; Schick, F.; Yki-Järvinen, H.; Gastaldelli, A.; Vettor, R.; Frühbeck, G.; Dicker, D. EASL–EASD–EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). J. Hepatol. 2024, 81(3), 492–542. https://doi.org/10.1016/j.jhep.2024.04.031

 

EASL-EASD-EASO Clinical Practice Guidelines recommend that routine laboratory and/or imaging testing, including liver enzymes and abdominal ultrasound, be performed in patients with metabolic syndrome or obesity for steatosis screening and early management [11].

12. Wattacheril, J. J.; Loomba, R.; Rinella, M. E.; et al. AGA Clinical Practice Update on the Role of Noninvasive Tests in the Diagnosis and Management of Nonalcoholic Fatty Liver Disease. Gastroenterology 2023, 165 (1), 1–15. https://doi.org/10.1053/j.gastro.2023.03.001

 

We added :

• Younossi, Z. M.; Kanwal, F.; Wong, V. W.; Romero, D.; Bugianesi, E.; Mantovani, A.; Rinella, M. E.; Sanyal, A. J. Global Consensus Recommendations on the Nomenclature and Definition of Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD). Lancet Gastroenterol. Hepatol. 2024, 9 (8), 720–732. https://doi.org/10.1016/S2468-1253(24)00093-4.
• Korean Association for the Study of the Liver (KASL). KASL Clinical Practice Guideline for the Management of MASLD and MetALD. Mol. Hepatol. 2025, 31 (2), 101–130. https://doi.org/10.3350/cmh.2025.0032.

Based on all the aformentioned references and SLD vs MASLD criteria we expressed the dillema regarding the proper classifiaction of AR-related hepatic steatosis.

We also added to the discussion

 

“Last but not least, although this case highlights a possible mechanistic interplay between AR dysfunction and hepatic steatosis, the evidence remains hypothesis-generating. The co-occurrence of KD and lean MASLD in this patient does not establish a definitive causality, and further research is needed to clarify the nature of this relationship. However, we consider AR dysfunction as the most possible mechanism, as other potential contributors to steatosis in this patient have been carefully excluded, including genetic variants, dietary patterns, and co-existing metabolic factors, that could independently or synergistically promote hepatic lipid accumulation”.

 

Comment 7: “Authors should maintain same reference formatting on page 6
Response:

 

Comment 8: Author should make a well-structured table for pharmacologic treatments using Drug/Class, Mechanism, Trial Status, Limitations.

Reply: We thank the reviewer for this insightful comment. We modified the manuscript accordingly. We modified the paragraph radically. We separated the clinical and preclinical studies, making it more reader-friendly. We modified the table accordingly. We separated preclinical, clinical studies and the agents are currently used. We used the titles that you suggested for the columns of this table.

Comment 9: “Mention safety concern for Inclisiran and PCSK9 inhibitors.”
Response:
We have added details on safety concerns for Inclisiran and other PCSK9 inhibitors, including potential injection-site reactions, cost considerations, and general long-term safety monitoring, while noting that these agents are generally well tolerated in statin-intolerant patients.

2.2 Therapeutic and lifestyle management

“We hypothesized that modification of lipid treatment could be beneficial, including the initiation of a PCSK9 inhibitor in combination with ezetimibe and omega-3 fatty acids for a wider targeting of multiple lipid-lowering pathways and the cessation of statins due to several concerns about their utilization, as possible statin-associated muscle symptoms (SAMs) could aggravate the AR dysfunction-related neuromuscular manifestations, like in KD. However, the safety and efficacy of statins' utilization have not been widely and systematically studied in KD. At the same time, there is no general contraindication to statin prescription in all neuromuscular pathologies, except for autoimmune myopathies and some specific genetic muscle diseases [15,16]. Additionally, PCSK9 inhibitors were chosen as they are generally well-tolerated based on clinical trial data, with a very low incidence of hepatic and muscle toxicity and reduced risk of T2DM development, compared to statins. Inclisiran (siRNA-based PCSK9 inhibitor) has only one side effect, which constitutes injection site reactions (5%), which are not severe and can be decreased after repeated administrations, in comparison to other agents of this drug family. On top of that, there is no reported specific interaction based on the available literature between the aforementioned combination of drugs (Inclisiran, ezetimibe, and Omega-3), which could, unlikely, cause major pharmacokinetic issues.  The combination of Inclisiran and ezetimibe provides a positive additive pharmacodynamic effect for LDL reduction, whereas omega-3 works on triglycerides. Another benefit of Inclisiran that was taken into consideration is that nucleases metabolize it to inactive nucleotides and do not constitute a substrate of cytochrome P450 (CYP) isozymes or other transporters. Therefore, Inclisiran is not expected to cause drug interactions since it does not interfere with the CYP enzyme system or drug transporters, which makes it ideal for patients who are receiving multiple medications”.

Comment 10: “In conclusion section, specify which studies large studies are needed.”
Response:
We have revised the conclusion to clearly indicate that large cohort studies.

     Conclusion and Future Perspectives

“This case-based review should be regarded as hypothesis-generating, underscoring the need for further studies to determine whether AR dysfunction contributes causally to lean MASLD or whether it represents one of multiple overlapping risk factors. Explicit recognition of alternative mechanisms is essential for balanced interpretation.AR dysfunction may contribute to lean MASLD, representing a plausible mechanism that warrants further investigation. However, these findings are primarily associative and based on a single illustrative case. Confirmation in larger cohorts and mechanistic studies, which can molecularly evaluate lean-MASLD patients for AR-related abnormalities (cross-sectional and population cohort), is necessary, as this group is quite heterogeneous, especially for the estimation of prevalence. In addition, a subgroup analysis considering AR function, histological severity, and disease outcomes (prospective cohorts) will open new horizons for managing lean-MASLD patients based on the AR genetic variant. Lastly, AR-targeted interventions, the translational potential, safety profile, and risk of off-target effects of nuclear receptor signaling modulators, such as in the case of AR-targeted agents, require careful evaluation, as they are considered challenging due to their potential systemic hormonal impacts in humans.

 

Comment 11: “Multiple references appear to be duplicate, thoroughly check all references, especially 63, and 67 also.”
Response:
We have thoroughly reviewed the reference list and removed any duplicate entries.

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am happy with the substantial changes in the manuscript, and I would strongly recommend the acceptance of the manuscript in its current form. 

Reviewer 3 Report

Comments and Suggestions for Authors

The authors successfully addressed all my comments.