New Insights into Progressive Pulmonary Fibrosis: Diagnostic and Therapeutic Advances

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Discovering New Biomarkers for Progressive Pulmonary Fibrosis: A Promising Path Forward

Interstitial lung diseases (ILDs) are a diverse group of disorders affecting the lung parenchyma, characterized by varying degrees of inflammation and fibrosis. Among these, idiopathic pulmonary fibrosis (IPF) stands out due to its typically progressive nature, often leading to severe lung function deterioration and early death. However, some patients with non-IPF ILDs also experience a similar decline, prompting the classification of these conditions as “progressive pulmonary fibrosis” (PPF). This article delves into the recent advancements in understanding PPF, particularly focusing on the identification of new biomarkers that could revolutionize early diagnosis and treatment strategies.

The classification of PPF emerged from the recognition that patients with various forms of ILDs could exhibit a progressive phenotype akin to IPF. This classification is critical as it underscores the need for timely intervention with antifibrotic therapies, which have been shown to slow disease progression. Nintedanib, a drug initially approved for IPF, has demonstrated efficacy in treating PPF, highlighting the importance of early diagnosis. However, current diagnostic methods rely on observing disease progression through functional decline, symptom worsening, and imaging studies, which means that PPF can only be diagnosed after significant damage has occurred. This delay emphasizes the urgent need for reliable biomarkers that can predict PPF before noticeable progression.

Recent technological advancements, particularly in next-generation sequencing and mass spectrometry (MS), have paved the way for the discovery of novel biomarkers through omics approaches. Peripheral blood is a prime candidate for biomarker discovery due to its accessibility and the reproducibility of measurements. Nonetheless, traditional proteomics faces significant challenges, primarily due to the dominance of a few abundant proteins that mask the detection of potential biomarker candidates present in lower quantities.

This is where extracellular vesicles (EVs) come into play. EVs are tiny vesicles secreted by various cell types, containing diverse biomolecules such as proteins, RNA, and lipids. These vesicles protect their cargo from degradation, making it easier to detect low-abundance proteins. EVs have shown great potential as sources of biomarkers in various diseases, including ILDs. However, their specific utility in identifying biomarkers for PPF has not been extensively studied until recently.

To identify specific biomarkers for PPF, a comprehensive proteomic analysis of serum EVs was conducted. The study aimed to evaluate the clinical relevance of candidate biomarkers through a multi-phase approach involving discovery, validation, and functional analysis using patient samples and a bleomycin-induced pulmonary fibrosis mouse model. The discovery phase employed a data-independent acquisition (DIA) method to analyze serum EVs, identifying over 2,000 proteins, surpassing the number reported in previous studies. This unbiased approach facilitated the identification of surfactant protein B (SFTPB) in serum EVs as a predictive biomarker for non-IPF ILD progression. Notably, SFTPB in serum EVs was found to be an independent prognostic factor, distinct from the ILD-GAP index.

The validation phase, involving additional cohorts, confirmed the clinical utility of SFTPB in serum EVs. This biomarker demonstrated potential for stratifying patients at risk for non-IPF ILD progression, enabling timely therapeutic interventions. Functional studies using a bleomycin-induced pulmonary fibrosis mouse model further highlighted the temporal dynamics of SFTPB during fibrosis development. Elevated pro-SFTPB levels in serum EVs correlated with early fibrotic changes, suggesting its role in the pathogenesis of pulmonary fibrosis.

The identification of SFTPB in serum EVs as a biomarker for PPF has significant clinical implications. It provides a non-invasive tool for early diagnosis and risk stratification, facilitating personalized treatment approaches. Unlike traditional serum biomarkers, the encapsulation of SFTPB within EVs may confer protection from proteolytic degradation, enhancing its stability and diagnostic accuracy.

Despite these promising findings, the study acknowledges certain limitations. The small sample size in the discovery cohort may have led to the omission of other potential biomarkers. Technical challenges associated with EV isolation and protein quantification currently limit the clinical application of these findings. However, advancements in technologies such as digital ELISA offer hope for overcoming these hurdles. Moreover, the association of SFTPB with ILD progression was primarily observed in patients with a lower ILD-GAP index, necessitating further validation in more severe cases. The impact of ILD therapeutics on SFTPB levels also warrants investigation to ensure the robustness of this biomarker across different treatment modalities.

The findings from this comprehensive study represent a paradigm shift in the approach to diagnosing and managing progressive pulmonary fibrosis. The identification of SFTPB in serum EVs as a predictive biomarker not only enhances the understanding of disease mechanisms but also opens new avenues for early diagnosis and personalized treatment. As research progresses and technological advancements continue, the integration of these biomarkers into clinical practice holds the potential to significantly improve patient outcomes, offering hope to those affected by this debilitating condition.

The journey towards fully understanding and managing PPF is ongoing. The identification of SFTPB as a biomarker is a significant milestone, but it is just the beginning. Future research should focus on uncovering additional biomarkers, understanding their interactions, and elucidating the underlying biological mechanisms. This holistic approach will ultimately lead to more effective and personalized interventions, improving the quality of life for patients with ILDs.

The integration of multi-omics data, combined with advanced bioinformatics tools, holds the promise of unraveling the complex biological networks involved in PPF. Such integrative approaches can identify novel therapeutic targets and biomarkers, paving the way for personalized medicine. The development of predictive models incorporating clinical, omics, and imaging data can enhance the precision of risk stratification and treatment planning.

The advancement of technologies for EV isolation and protein quantification will be pivotal in translating these research findings into clinical applications. Innovations in microfluidics, nanoscale biosensors, and high-throughput screening platforms can enhance the sensitivity and specificity of biomarker detection. Additionally, the development of point-of-care diagnostic tools can facilitate the timely and accurate assessment of disease status in clinical settings.

Translational research bridging the gap between laboratory findings and clinical practice is essential for validating the clinical utility of identified biomarkers. Rigorous clinical trials assessing the efficacy of biomarkers like SFTPB in guiding treatment decisions and predicting outcomes are necessary. Collaboration between academic institutions, research organizations, and pharmaceutical companies can accelerate the development and validation of these biomarkers.

As with any new diagnostic and therapeutic approach, ethical and regulatory considerations must be addressed. Ensuring patient privacy, data security, and ethical use of biomarker information is paramount. Regulatory frameworks need to evolve to accommodate the rapid advancements in biomarker discovery and validation, ensuring the safe and effective implementation of new diagnostic tools.

The findings from this comprehensive study represent a significant step forward in understanding and managing progressive pulmonary fibrosis. The identification of SFTPB in serum EVs as a predictive biomarker enhances the understanding of disease mechanisms and opens new avenues for early diagnosis and personalized treatment. As research progresses and technological advancements continue, the integration of these biomarkers into clinical practice holds the potential to significantly improve patient outcomes, offering hope to those affected by this debilitating condition.

The journey towards fully understanding and managing PPF is ongoing. The identification of SFTPB as a biomarker is a significant milestone, but it is just the beginning. Future research should focus on uncovering additional biomarkers, understanding their interactions, and elucidating the underlying biological mechanisms. This holistic approach will ultimately lead to more effective and personalized interventions, improving the quality of life for patients with ILDs.

The integration of multi-omics data, combined with advanced bioinformatics tools, holds the promise of unraveling the complex biological networks involved in PPF. Such integrative approaches can identify novel therapeutic targets and biomarkers, paving the way for personalized medicine. The development of predictive models incorporating clinical, omics, and imaging data can enhance the precision of risk stratification and treatment planning.

The advancement of technologies for EV isolation and protein quantification will be pivotal in translating these research findings into clinical applications. Innovations in microfluidics, nanoscale biosensors, and high-throughput screening platforms can enhance the sensitivity and specificity of biomarker detection. Additionally, the development of point-of-care diagnostic tools can facilitate the timely and accurate assessment of disease status in clinical settings.

Translational research bridging the gap between laboratory findings and clinical practice is essential for validating the clinical utility of identified biomarkers. Rigorous clinical trials assessing the efficacy of biomarkers like SFTPB in guiding treatment decisions and predicting outcomes are necessary. Collaboration between academic institutions, research organizations, and pharmaceutical companies can accelerate the development and validation of these biomarkers.

As with any new diagnostic and therapeutic approach, ethical and regulatory considerations must be addressed. Ensuring patient privacy, data security, and ethical use of biomarker information is paramount. Regulatory frameworks need to evolve to accommodate the rapid advancements in biomarker discovery and validation, ensuring the safe and effective implementation of new diagnostic tools.

The findings from this comprehensive study represent a significant step forward in understanding and managing progressive pulmonary fibrosis. The identification of SFTPB in serum EVs as a predictive biomarker enhances the understanding of disease mechanisms and opens new avenues for early diagnosis and personalized treatment. As research progresses and technological advancements continue, the integration of these biomarkers into clinical practice holds the potential to significantly improve patient outcomes, offering hope to those affected by this debilitating condition.

The journey towards fully understanding and managing PPF is ongoing. The identification of SFTPB as a biomarker is a significant milestone, but it is just the beginning. Future research should focus on uncovering additional biomarkers, understanding their interactions, and elucidating the underlying biological mechanisms. This holistic approach will ultimately lead to more effective and personalized interventions, improving the quality of life for patients with ILDs.

The integration of multi-omics data, combined with advanced bioinformatics tools, holds the promise of unraveling the complex biological networks involved in PPF. Such integrative approaches can identify novel therapeutic targets and biomarkers, paving the way for personalized medicine. The development of predictive models incorporating clinical, omics, and imaging data can enhance the precision of risk stratification and treatment planning.

The advancement of technologies for EV isolation and protein quantification will be pivotal in translating these research findings into clinical applications. Innovations in microfluidics, nanoscale biosensors, and high-throughput screening platforms can enhance the sensitivity and specificity of biomarker detection. Additionally, the development of point-of-care diagnostic tools can facilitate the timely and accurate assessment of disease status in clinical settings.

Translational research bridging the gap between laboratory findings and clinical practice is essential for validating the clinical utility of identified biomarkers. Rigorous clinical trials assessing the efficacy of biomarkers like SFTPB in guiding treatment decisions and predicting outcomes are necessary. Collaboration between academic institutions, research organizations, and pharmaceutical companies can accelerate the development and validation of these biomarkers.

As with any new diagnostic and therapeutic approach, ethical and regulatory considerations must be addressed. Ensuring patient privacy, data security, and ethical use of biomarker information is paramount. Regulatory frameworks need to evolve to accommodate the rapid advancements in biomarker discovery and validation, ensuring the safe and effective implementation of new diagnostic tools.

In conclusion, the proteomic analysis of serum EVs has unveiled SFTPB as a promising biomarker for predicting the progression of non-IPF ILDs. This study highlights the potential of serum EVs as a rich source of clinically relevant biomarkers, offering new avenues for early diagnosis and personalized treatment in progressive pulmonary fibrosis. Continued research and technological advancements are essential to translate these findings into routine clinical practice, ultimately improving outcomes for patients with ILDs.

Therapeutic Advances in Progressive Pulmonary Fibrosis: New Treatments and Hope for a Cure

Interstitial lung diseases (ILDs) comprise a broad range of lung disorders that are characterized by varying degrees of inflammation and fibrosis. Among these, idiopathic pulmonary fibrosis (IPF) is particularly notable for its progressive nature, often leading to severe lung function decline and early mortality. However, many patients with non-IPF ILDs also experience similar deterioration, which has led to the classification of these conditions under the umbrella term “progressive pulmonary fibrosis” (PPF). Recent advances in the understanding of PPF have paved the way for new therapeutic strategies, offering hope for more effective treatments and potential resolutions to this debilitating disease.

The classification of PPF acknowledges that patients with different types of ILDs can exhibit a progressive phenotype similar to IPF. This recognition has underscored the need for early and aggressive intervention with antifibrotic therapies. One such therapy is nintedanib, a tyrosine kinase inhibitor initially approved for the treatment of IPF. Nintedanib has shown efficacy in slowing disease progression in PPF, demonstrating its potential across a broader spectrum of fibrotic lung diseases.

Nintedanib works by inhibiting several tyrosine kinases involved in the pathways that lead to fibrosis. Specifically, it targets the receptors for vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). By blocking these pathways, nintedanib helps to reduce the proliferation and migration of fibroblasts, the cells responsible for the excessive deposition of extracellular matrix that characterizes fibrosis. Clinical trials have shown that nintedanib can significantly reduce the annual rate of decline in forced vital capacity (FVC), a measure of lung function, in patients with IPF and other progressive fibrotic ILDs.

Another antifibrotic agent, pirfenidone, has also shown promise in the treatment of PPF. Pirfenidone exerts its effects through multiple mechanisms, including the inhibition of transforming growth factor-beta (TGF-β), a key cytokine involved in the fibrotic process. By downregulating TGF-β and other pro-fibrotic cytokines, pirfenidone helps to mitigate the inflammation and fibrosis that contribute to disease progression. Clinical studies have demonstrated that pirfenidone can slow the decline in lung function and improve progression-free survival in patients with IPF.

The success of nintedanib and pirfenidone in treating IPF has spurred interest in their potential use for other types of fibrotic ILDs. Recent studies have extended these findings to patients with other forms of PPF, suggesting that these drugs may provide similar benefits across a range of conditions. This has led to a broader application of antifibrotic therapies in clinical practice, offering new hope for patients with progressive fibrotic ILDs.

Despite the efficacy of these antifibrotic agents, there remains a critical need for biomarkers that can predict disease progression and guide treatment decisions. The identification of such biomarkers would enable earlier intervention and more personalized treatment strategies. Recent advances in next-generation sequencing and mass spectrometry (MS) have facilitated the discovery of novel biomarkers through omics approaches. One promising avenue of research involves the study of extracellular vesicles (EVs), which are nanoscale vesicles secreted by cells that contain a variety of biomolecules.

EVs are of particular interest because they can protect their cargo from degradation, making it easier to detect low-abundance proteins that may serve as biomarkers. Recent studies have identified surfactant protein B (SFTPB) in serum EVs as a potential biomarker for PPF. SFTPB, a component of lung surfactant, has been shown to correlate with disease progression in non-IPF ILDs. By identifying patients at risk for rapid progression, SFTPB could help guide early and targeted therapeutic interventions, improving outcomes for patients with PPF.

Another area of active research is the development of combination therapies that target multiple pathways involved in fibrosis. Given the complex and multifactorial nature of fibrotic diseases, a single therapeutic target may not be sufficient to halt disease progression. Combining antifibrotic agents with other treatments that address different aspects of the disease process holds promise for more effective management of PPF.

For example, combining nintedanib or pirfenidone with immunomodulatory therapies could provide a synergistic effect, enhancing the overall antifibrotic response. Immunomodulatory agents such as mycophenolate mofetil and azathioprine have been used to treat ILDs associated with connective tissue diseases, and their potential role in combination with antifibrotic therapies is an area of ongoing investigation.

Furthermore, advancements in regenerative medicine offer exciting possibilities for the treatment of PPF. Stem cell therapy, which involves the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs), has shown promise in preclinical models of fibrosis. These cells have the potential to differentiate into various cell types, promote tissue repair, and modulate the immune response. Clinical trials are currently underway to evaluate the safety and efficacy of stem cell therapies in patients with fibrotic lung diseases.

Another promising approach is the use of gene editing technologies, such as CRISPR/Cas9, to correct genetic mutations associated with fibrotic diseases. This technology has the potential to target and modify specific genes involved in the fibrotic process, offering a more precise and personalized treatment strategy. While still in the early stages of development, gene editing holds significant promise for the future of fibrosis treatment.

In addition to these therapeutic advances, there is growing interest in the role of the microbiome in fibrotic lung diseases. The lung microbiome, composed of the diverse community of microorganisms residing in the respiratory tract, is thought to influence the immune response and disease progression in ILDs. Research is ongoing to understand the interactions between the microbiome and the host immune system, with the aim of developing microbiome-targeted therapies to modulate disease progression.

Moreover, advances in imaging techniques are enhancing the ability to diagnose and monitor fibrotic lung diseases. High-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) provide detailed images of lung tissue, allowing for the detection of subtle changes in lung structure and the assessment of disease progression. These imaging modalities, combined with quantitative analysis tools, are improving the accuracy and reliability of diagnosis and disease monitoring, facilitating more informed treatment decisions.

The integration of multi-omics data, including genomics, transcriptomics, proteomics, and metabolomics, is also playing a crucial role in advancing the understanding of PPF. By analyzing large datasets generated from these different omics platforms, researchers can identify key molecular pathways involved in disease progression and discover new therapeutic targets. This systems biology approach allows for a more comprehensive understanding of the complex biological networks underlying fibrotic diseases, paving the way for the development of targeted therapies.

In conclusion, significant progress has been made in the treatment of progressive pulmonary fibrosis, offering new hope for patients with this challenging condition. The development of antifibrotic therapies such as nintedanib and pirfenidone has provided a foundation for the management of PPF, while ongoing research into biomarkers, combination therapies, regenerative medicine, and gene editing holds promise for even more effective treatments in the future. The integration of advanced imaging techniques and multi-omics data is further enhancing the ability to diagnose and monitor disease progression, enabling more personalized and targeted therapeutic approaches.

As research continues to advance, the goal is to translate these findings into clinical practice, ultimately improving outcomes and quality of life for patients with progressive pulmonary fibrosis. The journey towards a cure is ongoing, but the strides made thus far represent a significant step forward in the fight against this debilitating disease.

The study in deep……

Interstitial lung diseases (ILDs) encompass a diverse range of parenchymal pulmonary disorders characterized by varying degrees of inflammation and fibrosis. Among these, idiopathic pulmonary fibrosis (IPF) represents a distinct entity known for its relentless progression. However, a subset of patients with non-IPF ILDs also experience significant deterioration in lung function and early mortality, akin to the clinical course of IPF. This subset of conditions has been recently recognized under the term “progressive pulmonary fibrosis” (PPF). The advent of nintedanib, a tyrosine kinase inhibitor, has shown promise in managing PPF, much like its established role in IPF.

Currently, PPF is diagnosed through retrospective observation of disease progression via functional decline, symptom exacerbation, and radiographic evidence. However, the inability to identify at-risk patients prior to progression remains a significant clinical challenge. This limitation underscores the necessity for early intervention with antifibrotic therapies, which is predicated on the early diagnosis of PPF. Despite this, no reliable biomarkers have been established to predict non-IPF ILD progression accurately.

Advances in Biomarker Discovery

The advent of next-generation sequencing and mass spectrometry (MS) has revolutionized biomarker discovery, enabling the identification of novel candidates through omics approaches. Peripheral blood, due to its accessibility and reproducibility, is a prime source for biomarker discovery. However, conventional proteomics faces challenges due to the overwhelming presence of a few abundant proteins, which mask less abundant biomarker candidates.

Extracellular vesicles (EVs), nanoscale vesicles secreted by various cell types, present a promising alternative. These vesicles encapsulate biomolecules, protecting them from degradation and facilitating the detection of low-abundance proteins. EVs have shown potential as sources of biomarkers in various diseases, including ILDs. However, their utility in identifying biomarkers specific to PPF remains underexplored.

Proteomic Analysis of Serum EVs

In an effort to identify specific biomarkers for PPF, a comprehensive proteomic analysis of serum EVs was undertaken. This study aimed to evaluate the clinical relevance of candidate biomarkers through a multi-phase approach involving discovery, validation, and functional analysis using patient samples and a bleomycin-induced pulmonary fibrosis mouse model.

The discovery phase utilized a data-independent acquisition (DIA) method to analyze serum EVs, identifying over 2,000 proteins, surpassing the number reported in previous studies. This unbiased approach facilitated the identification of surfactant protein B (SFTPB) in serum EVs as a predictive biomarker for non-IPF ILD progression. Notably, SFTPB in serum EVs was found to be an independent prognostic factor, distinct from the ILD-GAP index.

Clinical and Functional Validation

Subsequent validation using additional cohorts confirmed the clinical utility of SFTPB in serum EVs. This biomarker demonstrated potential for stratifying patients at risk for non-IPF ILD progression, enabling timely therapeutic interventions. Furthermore, functional studies involving a bleomycin-induced pulmonary fibrosis mouse model highlighted the temporal dynamics of SFTPB during fibrosis development. Elevated pro-SFTPB levels in serum EVs correlated with early fibrotic changes, suggesting its role in the pathogenesis of pulmonary fibrosis.

Implications for Clinical Practice

The identification of SFTPB in serum EVs as a biomarker for PPF offers significant clinical implications. It provides a non-invasive tool for early diagnosis and risk stratification, facilitating personalized treatment approaches. Unlike traditional serum biomarkers, the encapsulation of SFTPB within EVs may confer protection from proteolytic degradation, enhancing its stability and diagnostic accuracy.

Challenges and Future Directions

Despite these promising findings, the study acknowledges certain limitations. The small sample size in the discovery cohort may have led to the omission of other potential biomarkers. Technical challenges associated with EV isolation and protein quantification currently limit the clinical application of these findings. However, advancements in technologies such as digital ELISA offer hope for overcoming these hurdles.

Moreover, the association of SFTPB with ILD progression was primarily observed in patients with a lower ILD-GAP index, necessitating further validation in more severe cases. The impact of ILD therapeutics on SFTPB levels also warrants investigation to ensure the robustness of this biomarker across different treatment modalities.

In conclusion, the proteomic analysis of serum EVs has unveiled SFTPB as a promising biomarker for predicting the progression of non-IPF ILDs. This study highlights the potential of serum EVs as a rich source of clinically relevant biomarkers, offering new avenues for early diagnosis and personalized treatment in progressive pulmonary fibrosis. Continued research and technological advancements are essential to translate these findings into routine clinical practice, ultimately improving outcomes for patients with ILDs.

Expanding the Research Framework

To further expand the understanding and application of these findings, it is crucial to delve deeper into the mechanisms underlying the role of SFTPB and other identified biomarkers in the pathogenesis of pulmonary fibrosis. Comprehensive studies involving larger and more diverse patient cohorts, longitudinal analyses, and integration with other omics data such as genomics and metabolomics could provide a more holistic view of disease progression and therapeutic response.

Integrative Approaches and Personalized Medicine

The integration of multi-omics data, combined with advanced bioinformatics tools, holds the promise of unraveling the complex biological networks involved in PPF. Such integrative approaches can identify novel therapeutic targets and biomarkers, paving the way for personalized medicine. The development of predictive models incorporating clinical, omics, and imaging data can enhance the precision of risk stratification and treatment planning.

Technological Innovations

The advancement of technologies for EV isolation and protein quantification will be pivotal in translating these research findings into clinical applications. Innovations in microfluidics, nanoscale biosensors, and high-throughput screening platforms can enhance the sensitivity and specificity of biomarker detection. Additionally, the development of point-of-care diagnostic tools can facilitate the timely and accurate assessment of disease status in clinical settings.

Translational Research and Clinical Trials

Translational research bridging the gap between laboratory findings and clinical practice is essential for validating the clinical utility of identified biomarkers. Rigorous clinical trials assessing the efficacy of biomarkers like SFTPB in guiding treatment decisions and predicting outcomes are necessary. Collaboration between academic institutions, research organizations, and pharmaceutical companies can accelerate the development and validation of these biomarkers.

Ethical and Regulatory Considerations

As with any new diagnostic and therapeutic approach, ethical and regulatory considerations must be addressed. Ensuring patient privacy, data security, and ethical use of biomarker information is paramount. Regulatory frameworks need to evolve to accommodate the rapid advancements in biomarker discovery and validation, ensuring the safe and effective implementation of new diagnostic tools.

Future Perspectives

The journey towards fully understanding and managing PPF is ongoing. The identification of SFTPB as a biomarker is a significant milestone, but it is just the beginning. Future research should focus on uncovering additional biomarkers, understanding their interactions, and elucidating the underlying biological mechanisms. This holistic approach will ultimately lead to more effective and personalized interventions, improving the quality of life for patients with ILDs.

Conclusion: A Paradigm Shift in Pulmonary Fibrosis Management

The findings from this comprehensive study represent a paradigm shift in the approach to diagnosing and managing progressive pulmonary fibrosis. The identification of SFTPB in serum EVs as a predictive biomarker not only enhances the understanding of disease mechanisms but also opens new avenues for early diagnosis and personalized treatment. As research progresses and technological advancements continue, the integration of these biomarkers into clinical practice holds the potential to significantly improve patient outcomes, offering hope to those affected by this debilitating condition.

The journey towards conquering PPF is complex and multifaceted, requiring sustained efforts in research, innovation, and collaboration. However, the strides made in this study provide a solid foundation upon which future advancements can build, ultimately transforming the landscape of pulmonary fibrosis care.


resource: https://insight.jci.org/articles/view/177937#SEC3


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