Deep learning has become an active research topic in the field of medical image analysis. In particular, for the automatic segmentation of stomatological images, great advances have been made in segmentation performance. In this paper, we systematically reviewed the recent literature on segmentation methods for stomatological images based on deep learning, and their clinical applications. We categorized them into different tasks and analyze their advantages and disadvantages. The main categories that we explored were the data sources, backbone network, and task formulation. We categorized data sources into panoramic radiography, dental X-rays, cone-beam computed tomography, multi-slice spiral computed tomography, and methods based on intraoral scan images. For the backbone network, we distinguished methods based on convolutional neural networks from those based on transformers. We divided task formulations into semantic segmentation tasks and instance segmentation tasks. Toward the end of the paper, we discussed the challenges and provide several directions for further research on the automatic segmentation of stomatological images. Imaging examinations, intraoral scanning, and other technologies are often required to assist diagnosis and treatment of diseases because of the complex structure of the oral and maxillofacial region and various types of diseases. Imaging examinations use dental X-rays, panoramic radiography, cone-beam computed tomography (CBCT), and multi-slice spiral computed tomography (MSCT). These are widely used in stomatology and produce large amounts of medical image data. Efficient and accurate processing of medical images is essential for the development of stomatology. The key task is image segmentation, which can realize the localization and the  analysis of lesions, help to design a treatment plan, and analyze the efficacy of the treatment. The traditional manual segmentation method is time-consuming and the segmentation effect depends on the experience of the doctor, leading to an unsatisfactory result. Therefore, the application of modern image segmentation technology to stomatology is very important.Deep learning (DL) is a branch of machine learning and is a promising method of achieving artificial intelligence. Owing to the availability of large-scale annotated data and powerful computing resources, DL-based medical image segmentation algorithms have achieved excellent performance. These methods have successfully assisted the accurate diagnosis and minimally invasive treatment of brain tumors , retinalCommon stomatological images can be categorized into five types: panoramic radiography, dental X-rays, CBCT, MSCT, and intraoral scanning (IOS). Each type is suitable for specific clinical applications, according to its unique imaging principles. Dental X-rays and panoramic radiography are mainly used for dental caries, alveolar bone resorption, and impacted teeth. CBCT is mainly used for the early diagnosis and comprehensive analysis of cracked teeth, diseases after root canal treatment, jaw lesions, and other diseases. CBCT can also assist the design of implant guides, orthodontic treatment, and maxillofacial disease treatment. MSCT is often conducted to assist the diagnosis, treatment, and postoperative efficacy analysis of soft and hard tissue lesions in the maxillofacial region. IOS is generally employed in chair-side digital restoration, digital orthodontics, and digital implant surgery. There is a structural overlap between dental X-rays and panoramic radiography because both produce 2D images. Without clinical experience in reading films, missed diagnoses and misdiagnoses may easily occur. Although CBCT and MSCT produce 3D images with clear layers, traditional empirical reading could also lead to missed diagnoses and misdiagnoses of early and minor lesions. Image segmentation aims to simplify or change the representation of images, making them easier to understand and analyze. Image segmentation can be divided into the semantic segmentation task and the instance segmentation task. The semantic segmentation task focuses on differences between categories, whereas the instance segmentation task focuses on differences between individuals . In the de facto standard in image segmentation tasks. Their excellent segmentation ability has been demonstrated experimentally and theoretically and can be further applied to medical images. In addition to the popularity of CNNs, the transformer structure   split anThe aim of the semantic segmentation task is to assign a unique category label to each pixel or voxel in the image. Semantic segmentation can both identify and mark the boundaries of different categories, such as the boundaries of teeth and jaws. Depending on the backbone network used, CNN-based and transformer-based approaches have been developed . CNN-basAs an iconic in image semantic segmentation, FCN  replacedThe DeepLab series focused on enlarging the receptive field and integrating multi-scale feature information. DeepLabV1  used dilUNet  was one SETR  used a pSwin-UNet  unified Depending on the backbone network used, instance segmentation methods can also be categorized into CNN-based and transformer-based methods. In addition, from the perspective of algorithms, instance segmentation methods can be divided into detection-based and detection-free methods. Detection-based methods can be regarded as extensions of object detection: they obtain bounding boxes by object detection methods and then perform segmentation within the bounding boxes. Moreover, the detection methods can be divided into single-stage and two-stage methods. Single-stage methods include You Only Look At Coefficient Ts (YOLCAT) , You OnlMost existing transformer-based instance segmentation algorithms are built on a detection method, DETR , so theyDetection-based instance segmentation methods follow the principle of detecting first and then segmenting. The performance of such methods is heavily dependent on the performance of the object detector, and so a better detector would improve the quality of instance segmentation. As discussed above, detection methods can be divided into single-stage and two-stage methods. A typical example of a single-stage method is YOLCAT , which fDetection-free instance segmentation methods learn the affinity relation by projecting each pixel onto embedding space, pushing pixels of different instances apart, and pulling pixels of the same instance closer in the embedding space; finally, a postprocessing step such as grouping can formulate the instance segmentation result. SOLO  was an eApplying the transformer structure to instance segmentation tasks is a relatively new research area. Cell-DETR  was one The characteristics of semantic segmentation algorithms are shown in The segmentation of teeth, jaws and their related diseases is usually considered as a preprocessing step to complete tooth matching –62, tootAutomatic segmentation of teeth in stomatological images can contribute to the location of supernumerary teeth and impacted teeth, as well as digital restoration, digital orthodontics, and digital implant surgery. Automatic segmentation of caries and other related lesions is helpful for the early diagnosis of caries, particularly those that are easily missed, such as hidden caries and adjacent caries. At present, the types of medical image data that are commonly used for the segmentation of teeth and related lesions include panoramic radiography, CBCT, dental X-rays, and IOS.Semantic segmentation is the most common type used for the DL-based automatic segmentation of teeth and their related diseases. This paper reviews 11 articles on semantic segmentation , findingFor 2D images, different models can be trained to segment different areas, such as all teeth –72 or adMost 3D images of teeth originate from CBCT data, and semantic segmentation of these 3D images requires a 3D semantic segmentation network, such as VNet , multi-tThe gingival tissue cannot be shown on the panoramic radiography or CBCT image, but it is very important for clarifying the relationship between the tooth and gingiva for digital restoration, implant, and orthodontics. For this reason, another imaging method has emerged in stomatology, namely, IOS, which can obtain real-time 3D data (which are point cloud data) of teeth and soft tissues. Zanjani et al.  proposedThe performance of the above methods is shown in Instance segmentation can mark both the boundaries between different categories in the image, such as the boundaries between teeth and jaws and the boundaries of different individuals in the same category, such as the boundaries between different teeth.Tooth instance segmentation from panoramic radiography is a common task in dentistry. Using the Mask R-CNN algorithm, Jader et al.  performeThe tooth structure from 3D data is clearer, which is an important clinical advantage in instance segmentation of teeth. Wu et al.  used a tTooth instance segmentation with IOS is also an important research direction. Zanjani et al.  proposedThe performance of the above methods is shown in There are many types of jaw diseases; moreover, the number of benign and malignant samples is unbalanced, which may easily cause missed diagnoses and misdiagnoses. Minimally invasive and precise treatment of these diseases generally requires precise location of lesions through preoperative planning and accurate intraoperative image guidance. Patients with craniomaxillofacial malformations require intelligent 3D symmetry analysis. The analysis of postoperative efficacy requires both subjective evaluations by doctors and patients, in addition to the quantitative and objective evaluation of the progression and outcome of lesions. Precise segmentation of the jaw or related diseases is important for clinical diagnosis and treatment. In the past, manual segmentation of the jaw and its lesions was time-consuming and laborious. Since the development of DL, researchers have used DL methods to learn the features of the jaw and its lesions, realizing automatic segmentation. The main sources of medical image data used for automatic segmentation are panoramic radiography, CBCT, and MSCT.Six relevant articles showed that current DL-based automatic segmentation methods for jaws and related diseases mainly focus on semantic segmentation . There aFor panoramic radiography, Kong et al.  adopted The performance of the above methods is shown in As a consequence of the need to protect patient privacy and the right to be informed, there are not always enough cases to establish a large-scale dataset dedicated to the segmentation of stomatological images. Moreover, the collected data are usually taken from diverse hospitals and machines, which further increases the difficulty of formulating universal benchmarks. Therefore, methods to effectively integrate, store, and safely share these data are of vital importance and are urgently required. The establishment of a shared dento-maxillofacial database can help to solve this problem, to some extent. Differences in the data acquisition settings and conditions (such as exposure time) used in each hospital lead to variation in the quality of image data , which affects the accuracy and robustness of image segmentation. Further study should focus on standardizing and normalizing image data and improving data quality.Currently, most data used for image segmentation in stomatology are produced by a single modality (single CBCT or MSCT). In the future, multi-modality data of the same case can be employed collaboratively, to fully exploit the correlative and complementary essence among these modalities; this may further boost the performance.The most common methods of image segmentation in stomatology are built on top of a CNN. However, the transformer structure has been gradually emerging in the field of computer vision because of its global modeling ability. It has been applied to mandible segmentation by researchers, outperforming the current CNN-based model. Transformer-based methods have the potential to obtain satisfactory results in medical image segmentation in the future. In addition, how to reduce the number of model parameters while ensuring accuracy is an active research topic, which is particularly important for the deployment of the medical image segmentation model and the promotion of related technology in clinical settings.The existing DL-based algorithm relies heavily on large-scale data to learn discriminative features, but the process of labeling stomatological data is time-consuming and labor-intensive; therefore, how to learn effectively from an insufficient and imperfect dataset is an active research topic. There are several ways to solve such problems. First, to reduce the burden of the time-consuming and labor-intensive annotation process, for complete annotation data, weakly supervised and semi-supervised methods can be adopted. Second, to handle the existence of noise in manual labeling, algorithms that learn from noisy labels can be employed. Third, to solve the problem that existing methods cannot be generalized to new categories, techniques such as transfer learning, domain adaptation, and few-shot learning can be considered. In addition, unsupervised learning and self-supervised learning could also be used to explore the structural properties inside the dental image itself, providing a better prior for downstream tasks.Although existing DL methods have shown excellent performance in stomatology, they have not been widely promoted because of the limitations of DL. In addition to the high computing cost and the need for large-scale datasets, the “black box” characteristic of DL methods is the main factor that hinders their application. To gain the trust of doctors, regulators, and patients, a medical diagnostic system must be transparent, interpretable, and explicable. Ideally, it should explain the complete logic of how a decision is made. Therefore, research on interpretability is most urgently needed for the application of DL to clinical diagnosis and treatment.First, from the perspective of what to segment, current studies focus mainly on teeth and teeth-related diseases, whereas little attention is paid to jaw and jaw-related diseases, particularly for soft tissue and related diseases. However, studies on the latter aspects have more clinical significance, so more studies of this type are required. Second, the accuracy of image segmentation is the key to whether the DL methods can be applied clinically. Therefore, more studies are needed to enhance the accuracy and precision of image segmentation, to promote its use in the clinic. Finally, the first step of digital surgical technologies, such as guide templates, surgical navigation, and augmented reality technology, is to segment important structures or lesions, for which the traditional manual segmentation method is currently mainly used. In the future, DL-based automatic segmentation methods could be integrated with these technologies, to assist clinical practice more accurately and efficiently.This paper comprehensively reviews automatic segmentation algorithms based on DL and introduces their clinical applications. The review shows that DL has great potential to segment stomatological images accurately, and this can further promote the transformation of clinical practice from experientialism to digitization, precision, and individuation. In the future, more research is needed to further improve the accuracy of automatic image segmentation and realize intelligence.DL, WZ, JC, and WT contributed to the conception and design of the study. DL wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study was supported by Sichuan Province Regional Innovation Cooperation Project (2020YFQ0012).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The eight state-of-the-art reviews led by an outstanding panel of authors cover a wide range of topics, from current needs in preventive cardiology training and novel insights on the contextual factors that contribute to the development and prognosis of CVD to most recent updates on lipid-lowering therapy and aspirin, and from cardiovascular prevention in young adults and women in 2021 to the lessons learned during the ongoing Coronavirus Disease 2019 (COVID-19) pandemic and innovative approaches to enhance the management of individuals who have already had a CVD event.Given these trends, there is increasing recognition of the critical role of preventive cardiology, and this issue of the 8; however, fragmentation and lack of standardization are noted as significant issues. The authors also discuss novel notions including the need to expand the focus of cardiovascular prevention from ASCVD to also address other highly prevalent conditions, such as heart failure and atrial fibrillation, and the potential benefits of research networks involving preventive cardiology centers across the country. We applaud these propositions and believe the time has come to implement them.The need for a greater emphasis on the primordial and primary prevention of CVD is impeccably outlined in the first article of this issue, led by Drs. Tahir Mahmood and Michael Shapiro. The authors walk us through key milestones in cardiovascular epidemiology and preventive cardiology, from the landmark Framingham Heart Study to statin trials. They then discuss more recent developments, including advances in atherosclerotic CVD (ASCVD) risk assessment such as subclinical atherosclerosis imaging, novel therapeutics , and exciting research venues moving forward, such as novel genetic editing CRISPR-based techniques. Given a rapidly increasing therapeutic arsenal and the need for a multidisciplinary, highly specialized set of skills to ensure the highest quality preventive cardiology care, the authors make a compelling case about the need for a dedicated, officially recognized subspecialty in preventive cardiology. This is already being implemented in a number of programs across the country9 The authors discuss the protective effects of social support, social cohesion, lack of discrimination, and community engagement in cardiovascular health and outline the potential pathways involved. These mechanisms shape both our susceptibility/resilience to illness and our resources to deal with disease once developed, and the authors stress the need for greater awareness of their importance both at the population and individual-patient levels. Furthermore, the authors discuss policy recommendations aimed at enhancing social support and preventing discrimination, particularly against racial/ethnic minorities, and propose a number of research initiatives aimed at further expanding our understanding of this contextual factor. Beyond groundbreaking therapies and novel biomarkers, a greater attention to the context in which our patients live and care for their health will help further improve prevention and outcomes, especially among groups disproportionately affected by ASCVD.One of the skills that the modern preventive cardiologist will need to master is a good understanding of the complex social factors that shape the burden and prognosis of ASCVD in patients. There is increasing recognition of the importance of social determinants of health (SDOH) in cardiovascular medicine and specifically in preventive cardiology, and in the second article of this issue, Drs. Rahul Singh, Zulqarnain Javed, and colleagues shed light on the specific role of community and social context, an integral component of most SDOH frameworks.10 In their state-of-the-art review titled the “Past, Present, and Future of Familial Hypercholesterolemia Management,” Drs. Viviane Rocha and Raul Santos describe the genetics, epidemiology, pathophysiology, and management of FH, from statins (which in 2021 still represent the cornerstone of therapy in these patients) to more novel drugs—such as PCSK9 and angiopoietin-like protein 3 (ANGPTL3) inhibitors—that can yield dramatic reductions in LDL-C levels in patients in whom statins fall short. Recent studies have revealed that risk is far from homogeneous among individuals with FH,12 and in the context of costly novel LDL-C–lowering therapies and finite healthcare resources, the authors discuss the potential role that clinical scores, coronary imaging, and blood biomarkers may have for a more personalized and potentially cost-effective allocation of novel LDL-C-lowering drugs in these patients.In addition to social context, genetic factors are also important determinants of the risk of developing ASCVD. This is particularly true among individuals with familial hypercholesterolemia (FH), a monogenic condition that causes very high circulating levels of low-density lipoprotein cholesterol (LDL-C) from birth and is associated with a marked increase in the lifetime risk of ASCVD, including premature presentations.13 In their elegant, richly illustrated article, Drs. Ella Murphy, James Curneen, and John McEvoy discuss these trends and contrast them with recent analyses in the Multi-Ethnic Study of Atherosclerosis and Dallas Heart Study, which suggest that a careful selection of low-bleeding–risk candidates together with the prognostic information provided by coronary artery calcium (CAC) score can help implement the American College of Cardiology/American Heart Association (ACC/AHA) class IIb recommendation to consider low-dose aspirin among primary prevention individuals at highest risk of ASCVD events who are not at high risk of bleeding.16 In secondary prevention settings, the evidence is more robust and aspirin is a more established therapy. However, with recent developments in antithrombotic therapies such as P2Y12 inhibitors and declining rates of recurrent ASCVD events, the authors discuss how the recommendation for chronic therapy with aspirin after a first acute/chronic coronary syndrome may need to be re-evaluated in the near future.Besides lipid-lowering agents, aspirin has been another highly utilized pharmacological intervention in the primary and secondary prevention of ASCVD. Nevertheless, recent research, including three landmark trials published in 2018 , suggests that in the current era of widespread statin use, enhanced management of risk factors (such as hypertension and diabetes), anti-tobacco laws, and decreasing ASCVD event rates in most Western populations, aspirin’s relevance is shrinking in primary prevention.6 and clinical registries such as YOUNG-MI suggest that current risk estimation and management algorithms, such as the Pooled Cohort Equations and the associated ACC/AHA treatment thresholds, fail to consider many high-risk young adults as good candidates for preventive statin therapy before they have had a first MI.18 Consequently, there is increasing interest in characterizing the risk profile of men and women who develop MIs at early ages as well as in enhancing our societal ability to prevent premature events.19 To address this, Theresa Rizk and Dr. Ron Blankstein present us with an expert overview of this topic, which includes a systematic review of the latest literature in this field. As noted by the authors, a particularly relevant finding from a prevention standpoint is the finding, reported in multiple studies, of most patients with premature MIs having untreated traditional risk factors, especially tobacco use.21 This suggests that population-level interventions aimed at reducing first- and second-hand exposure to tobacco products, together with a timely, exhaustive screening and management of other traditional risk factors  in young adults can help dramatically curtail the rates of premature ASCVD. In addition, the authors discuss the potential role of the CAC score for further risk assessment in specific young adults, although available data in young individuals without a family history of ASCVD is mostly derived from clinical cohorts rather than from general population-based studies.Another increasingly important area of research and innovation in preventive cardiology in 2021 encompasses the prevention of ASCVD in younger adults. In the US, younger patients now comprise a growing proportion of those hospitalized with a first MI,16 and they should be screened systematically as part of a standard risk assessment visit for women. The authors provide suggestions for risk mitigation during pregnancy in women with cardiovascular risk factors as well as in nonpregnant patients with women-specific risk factors, and we believe the readership of the Methodist DeBakey Cardiovascular Journal will find this guidance extremely useful. Finally, the authors identify the pregnancy and peripartum period as a window of opportunity in which women may be more receptive to lifestyle change and other cardiovascular health recommendations.Of note, Rizk and Blankstein describe important differences in the risk factor profile and outcomes of men and women who develop premature MIs. Building on this, in their comprehensive women’s health review, Drs. Lochan Shah, Garima Sharma, and colleagues present a thorough update on the current knowledge of cardiovascular risk factors specific to women. On one hand, the authors make a compelling case for the need to screen traditional risk factors before and during pregnancy because those are associated with a variety of adverse pregnancy outcomes including preeclampsia, gestational hypertension/other hypertensive diseases of pregnancy, gestational diabetes mellitus, preterm birth, small-for-gestational-age infant, placental abruption, ischemic stroke, and maternal and neonatal mortality, among other complications. On the other hand, maternal adverse pregnancy outcomes, polycystic ovarian syndrome, and premature menopause represent independent risk factors for CVD later in life,22 Drs. Eamon Duffy, Erin Michos, and colleagues discuss how this worldwide health crisis has also negatively disrupted preventive cardiology care, particularly during its initial months. Throughout lockdowns, many patients missed in-person visits, underwent fewer assessments of cardiovascular risk factors, reduced their levels of physical activity, increased their snacking and caloric intake, and felt isolated and stressed at home. Despite these challenges, the authors also describe important lessons learned and opportunities to enhance the prevention of ASCVD moving forward. Indeed, the pandemic has reshaped preventive cardiology, introducing almost overnight long-overdue improvements that can facilitate a more personalized and effective approach moving forward. Telemedicine has become a critical component of the “new normal,” and while it should not fully replace in-person interactions, it provides a powerful platform that can facilitate closer follow-up of higher-risk patients and earlier detection of poorly controlled risk factors and newly developed symptoms. For some, the pandemic was also an opportunity to quit tobacco and increase levels of physical activity at home using stationary bicycles and other devices, although more intensive public health efforts will be needed to expand these positive changes to larger populations and sustain them over time. The authors also discuss opportunities to leverage currently increased health awareness among the general population to enhance ASCVD prevention efforts, and stress the importance of COVID-19 vaccination as a critical step towards preventing morbidity and death — particularly among the elderly, minorities, and those with multiple cardiovascular risk factors and/or with established ASCVD.In August 2021, the COVID-19 pandemic continues to permeate all aspects of life and medicine and has a direct impact in the way we live, interact with each other, treat patients, and prevent disease.23 To ameliorate this, Drs. Mohamad Taha, Khurram Nasir, and colleagues present an innovative checklist-based approach aimed at facilitating a more systematic and complete implementation of evidence-based interventions. Checklists, which were initially developed in aviation, have been successfully implemented in other fields of medicine such as surgery and intensive care units. Several supporting materials are also proposed, including periodic quality and performance reports that can help identify specific implementation gaps and inform targeted timely improvements. Although formal research is needed to confirm the effectiveness of this strategy, in a context of typically busy preventive cardiology clinics, this approach can be a powerful aid for preventive cardiology professionals, potentially increasing the use of classic and novel interventions in secondary prevention, minimizing therapeutic inertia, and improving patient outcomes.Finally, what about developments for secondary ASCVD prevention among individuals who have already had a first event? A wealth of interventions is now available for these patients, and clinical practice guidelines from cardiovascular scientific societies are updated periodically to accommodate the most recent evidence. However, US and international registries reveal that the implementation of guideline recommendations among patients with established ASCVD remains far from optimal in most countries.Methodist DeBakey Cardiovascular Journal for their vision and support of preventive cardiology endeavors through this focused issue. We also thank the authors of the eight articles for their fabulous work and generous contributions to this issue, which we believe will provide our readers with a comprehensive overview of several landmark developments in this space. We hope this issue will help raise further awareness on critical topics such as SDOH, women’s cardiovascular health, the importance of COVID-19 vaccination, and the need for a more systematic implementation of existing guideline recommendations in primary and secondary prevention. Finally, we hope we were able to infect the readership with our enthusiasm moving forward. These are unprecedented times, but also very exciting ones in the field of preventive cardiology.We would like to thank the editors of the Cardiovascular Journal thank Drs. Khurram Nasir, Miguel Cainzos-Achirica, and Kershaw Patel for their enthusiasm and dedication in curating this issue on cardiovascular disease (CVD) prevention.The editors of the Methodist DeBakey KHURRAM NASIR, MD, MPH, MSC Khurram Nasir, MD, MPH, MSc, holds a broad range of leadership positions at Houston Methodist focusing on population health and preventive cardiology. He is the chief of the Division of Cardiovascular Prevention and Wellness in the Department of Cardiology, division chief of Health Equity and Disparities Research and co-director at the Center for Outcomes Research, and director of the Center for Cardiovascular Computation & Precision Health. He is also a professor of cardiology and Jerold B. Katz Investigator at the Houston Methodist Academic Institute. His research interests cover a range of topics including translation, population health, big data, and social aspects of cardiovascular prevention.Dr. Nasir earned his medical degree at Allama Iqbal Medical College in Pakistan followed by a Master of Public Health at Johns Hopkins University. He completed his internal medicine residency at Boston Medical Center and cardiology fellowship at Yale University. He then moved on to postdoctoral research training at Johns Hopkins Hospital and received a National Institutes of Health (NIH) T32 fellowship in cardiac imaging at Massachusetts General Hospital. In 2017, he continued his education with a Master of Science in health economics and policy management from the London School of Economics and Political Science.Circulation: Quality of Care and Outcomes; serves on the editorial boards of the Methodist DeBakey Cardiovascular Journal and Circulation; and is on the board of directors for the American Society of Preventative Cardiology. In recognition of his effort, he was recognized with the Johns Hopkins Distinguished Alumni Award in 2013, which honors alumni who have typified the Johns Hopkins tradition of excellence and brought credit to the University by their personal accomplishment, professional achievement, or humanitarian services. In 2020, he received the Arthur S. Agatston Cardiovascular Disease Prevention Award that recognizes individuals whose pioneering efforts have saved lives from the leading killer throughout the world, coronary artery disease.A prolific researcher, Dr. Nasir has published more than 730 peer-reviewed articles in leading cardiovascular journals and is an associate editor for MIGUEL CAINZOS-ACHIRICA, MD, MPH, PHD Miguel Cainzos-Achirica, MD, MPH, PhD, joined the Houston Methodist faculty in 2020 after completing his training in cardiology and cardiovascular epidemiology at leading academic institutions in the United States and Europe. He serves as associate director of Preventive Cardiology Research and Education at the Houston Methodist DeBakey Heart & Vascular Center and is an assistant professor of Preventive Cardiology at Cornell Weill and the Houston Methodist Center for Outcomes Research. He is also an adjunct assistant professor of medicine at Johns Hopkins University. With training in cardiology, epidemiology, biostatistics, cardiac imaging, and minority health, Dr. Cainzos-Achirica has research interests in CVD prevention, risk assessment, use of cardiac imaging modalities (particularly computed tomography) to enhance cardiovascular risk stratification, CVD prevention among vulnerable populations , and advanced epidemiological research methods.After earning his medical degree from the University of Santiago de Compostela in Spain, Dr. Cainzos-Achirica trained in cardiology in Barcelona, where he also completed a diploma in biostatistics and study design at the Autonomous University of Barcelona. He then moved to the United States, where he completed a Master of Public Health at the Johns Hopkins Bloomberg School of Public Health followed by 2 years of postdoctoral training in preventive cardiology research at the Johns Hopkins School of Medicine and Welch Center for Prevention. He also holds a Doctor of Philosophy in cardiovascular epidemiology from the Universitat de Barcelona and is a prospective student in the prestigious MSc in Clinical Trials program at the University of Oxford. Dr. Cainzos- Achirica has received multiple performance awards from public and private organizations and competitive training grants from the Spanish Society of Cardiology (2014), the Caixabank Foundation (2015), and the European Society of Cardiology (2021).Dr. Cainzos-Achirica has published more than 130 peer-reviewed articles, including original science, state-of-the-art review papers, invited commentaries, and research methods letters in the highest impact cardiovascular and medical peer-reviewed journals.KERSHAW PATEL, MD, MS Like Dr. Cainzos-Achirica, Kershaw Patel, MD, MS, joined the preventive cardiology team at Houston Methodist DeBakey Heart & Vascular Center in 2020. He is a cardiologist with Houston Methodist DeBakey Cardiology Associates in the hospital’s Division of Cardiovascular Prevention & Wellness, assistant professor of cardiology at The Houston Methodist Academic Institute, assistant professor of medicine at Weill Cornell Medical College, and an assistant clinical member of the Houston Methodist Research Institute. Dr. Patel’s clinical and research interests are in heart failure prevention in highrisk populations, including people with diabetes.Dr. Patel earned his medical degree at the University of Texas (UT) Medical Branch at Galveston and fulfilled his residency at the University of Chicago. He went on to complete a cardiovascular disease fellowship at UT Southwestern Medical Center in Dallas, where he also earned a Master of Science in clinical science.At Houston Methodist, Dr. Patel has been honored with the Academic Institute’s President’s Award for Excellence in Peer-Reviewed Publication and the Clinician Trialist Award. He was also a finalist in the American Heart Association’s (AHA) Lifestyle and Cardiometabolic Health Early Career Investigator Award Competition and won the AHA Get With the Guidelines Young Investigator Research Seed Grant Award.To date, Dr. Patel has published more than 30 manuscripts, many with original research on CVD and heart failure risk assessment, including focused work on cardiometabolic diseases such as type 2 diabetes and obesity.We are grateful to these three exceptional guest editors for their leadership and dedication and to the many authors who contributed their time and expertise to creating this comprehensive exploration of the present and future of cardiovascular disease prevention.


Traumatic central nervous system (CNS) injury, which includes both traumatic brain injury (TBI) and spinal cord injury (SCI), is associated with irreversible loss of neurological function and high medical care costs. Currently, no effective treatment exists to improve the prognosis of patients. Astrocytes comprise the largest population of glial cells in the CNS and, with the advancements in the field of neurology, are increasingly recognized as having key functions in both the brain and the spinal cord. When stimulated by disease or injury, astrocytes become activated and undergo a series of changes, including alterations in gene expression, hypertrophy, the loss of inherent functions, and the acquisition of new ones. Studies have shown that astrocytes are highly heterogeneous with respect to their gene expression profiles, and this heterogeneity accounts for their observed context-dependent phenotypic diversity. In the inured CNS, activated astrocytes play a dual role both as regulators of neuroinflammation and in scar formation. Identifying the subpopulations of reactive astrocytes that exert beneficial or harmful effects will aid in deciphering the pathological mechanisms underlying CNS injuries and ultimately provide a theoretical basis for the development of effective strategies for the treatment of associated conditions. Following CNS injury, as the disease progresses, astrocyte phenotypes undergo continuous changes. Although current research methods do not allow a comprehensive and accurate classification of astrocyte subpopulations in complex pathological contexts, they can nonetheless aid in understanding the roles of astrocytes in disease. In this review, after a brief introduction to the pathology of CNS injury, we summarize current knowledge regarding astrocyte activation following CNS injury, including: (a) the regulatory factors involved in this process; (b) the functions of different astrocyte subgroups based on the existing classification of astrocytes; and (c) attempts at astrocyte-targeted therapy. After birth, astrocytes are primarily generated through the direct transformation of radial glial cells in the ventricular zone, the migration and development of postnatal progenitors in the subventricular zone, and the symmetrical division of differentiated astrocytes  and blood–spinal cord barrier (BSCB), signal transmission across synapses, the maintenance of neuronal function, and metabolic regulation -related genes, such as Xylt1, Csgalnact1, Chst11, Pcan, Acan, and Slit2. Nevertheless, RAs and SAs both display high expression levels of several proteins, including GFAP, nestin, β-catenin, N-cadherin, and SOX9. As the disease progresses, there is an overlap of RA subpopulations and RAs interact with Col1 and are converted into SAs via the integrin/N-cadherin pathway , RAs are also divided into different astrocyte subgroups. In 2012, Zamanian et al. undertook a genomic analysis using two mouse injury models  to profile RA phenotypes. The authors found that the RA phenotype was dependent on the type of inducing injury, and identified high Lcn2 and Serpina3n expression levels as strong markers of RA phenotype , seems unavoidable. Recently, Escartin et al.  and cationic conductance (via ion channels) contribute to this progress  and TLRs drove the complex inflammation network and astrocyte effector events R stimulation was shown to reduce the severity of brain edema and cytotoxic swelling  and excess glutamate derived from RAs after an injury can damage the BBB and the BSCB  and BQ788 (an ETB antagonist) effectively attenuated BBB disruption and cerebral edema in both patients and mice with TBI, whereas the ETA antagonists ambrisentan and FR139317 elicited no effect  while upregulating that of potentially beneficial neuroprotective phenotype-associated genes , thereby indirectly enhancing neuroprotection and neuroplasticity (Chan et al., via reducing mitochondria migration (Miyamoto et al., A drug-loaded nano-structured gel and ponesimod were shown to improve motor performance in the early stages after injury and protect neurons by suppressing the activation of the neurotoxic phenotype of RAs (Vismara et al., in vitro (Heins et al., in vivo (Torper et al., Astrocytes retain limited neural stem cell potential and can be reprogrammed into a stem cell-like state to replenish neurons lost after injury (Kriegstein and Alvarez-Buylla, Sodium houttuyfonate effectively inhibited the activation of microglia cells while promoting the activation of astrocytes and angiogenesis (Yao et al., Although attention has bright prospects, the difficulty in obtaining human CNS tissue and the substantial differences between rodents and human astrocytes (Zhang et al., The importance of astrocytes in CNS disease and injury is widely recognized; however, our understanding of astrocyte functions is still in its infancy. The continuous development and breakthrough of instruments and technologies provide conditions for accurate typing of astrocytes. The combination of single-cell and spatial transcriptome sequencing shows promise as a means of determining astrocyte heterogeneity after injury. Through the sequencing of several key times after injury, the time and space distribution of each astrocyte subpopulation can be determined. For example, astrocyte subpopulation D appears on the 7th day after SCI, mainly distributed in the core of injury. Further investigations to determine the temporal and spatial specificity of different astrocyte subpopulations with their specific genetic markers, thereby revealing their respective roles in injury, will provide a more precise indication to allow the targeting of specific astrocyte subpopulations for the treatment of CNS injuries. Such as the study of Hasel et al. , in the BN designed the research and revised the manuscript. YZ found some articles. GY wrote the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Recent years have documented a revolutionary change in research on parasitic organisms. The development of pioneering technologies has allowed answering fundamental questions of parasite biology, from the perspective of basic research but also with respect to applied aspects. Comprehensive molecular, cellular, and biochemical information is available today, which includes a wealth of information on genomes, transcriptomes, proteomes, and glycomes. This has not only revolutionized parasitology research but significantly advanced parasitological diagnostics. Flanked by improvements in parasite ex vivo culturing and maintenance, and promoted by groundbreaking methods for imaging and the functional analyses of genes of interest within their genomic settings, we have gained new and spectacular insights into parasite biology and host-parasite interactions. This unprecedented upswing has lifted parasitology to a new level, and it facilitates better understanding of parasites and the principles of parasitism. Thus, new strategies in fighting parasites may be achieved in the medium term. The latter is of utmost importance considering the lack of anti-parasitic vaccines, the alarmingly limited set of effective drugs available for humans and animals, and increasing reports on drug resistance.


Vasopressin (AVP) is a key neurohormone involved in the regulation of body functions. Due to its urine-concentrating effect in the kidneys, it is often referred to as antidiuretic hormone. Besides its antidiuretic renal effects, AVP is a potent neurohormone involved in the regulation of arterial blood pressure, sympathetic activity, baroreflex sensitivity, glucose homeostasis, release of glucocorticoids and catecholamines, stress response, anxiety, memory, and behavior. Vasopressin is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and released into the circulation from the posterior lobe of the pituitary gland together with a C-terminal fragment of pro-vasopressin, known as copeptin. Additionally, vasopressinergic neurons project from the hypothalamus to the brainstem nuclei. Increased release of AVP into the circulation and elevated levels of its surrogate marker copeptin are found in pulmonary diseases, arterial hypertension, heart failure, obstructive sleep apnoea, severe infections, COVID-19 due to SARS-CoV-2 infection, and brain injuries. All these conditions are usually accompanied by respiratory disturbances. The main stimuli that trigger AVP release include hyperosmolality, hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II (Ang II) and the same stimuli are known to affect pulmonary ventilation. In this light, we hypothesize that increased AVP release and changes in ventilation are not coincidental, but that the neurohormone contributes to the regulation of the respiratory system by fine-tuning of breathing in order to restore homeostasis. We discuss evidence in support of this presumption. Specifically, vasopressinergic neurons innervate the brainstem nuclei involved in the control of respiration. Moreover, vasopressin V1a receptors (V1aRs) are expressed on neurons in the respiratory centers of the brainstem, in the circumventricular organs (CVOs) that lack a blood-brain barrier, and on the chemosensitive type I cells in the carotid bodies. Finally, peripheral and central administrations of AVP or antagonists of V1aRs increase/decrease phrenic nerve activity and pulmonary ventilation in a site-specific manner. Altogether, the findings discussed in this review strongly argue for the hypothesis that vasopressin affects ventilation both as a blood-borne neurohormone and as a neurotransmitter within the central nervous system. Vasopressin (AVP), also known as antidiuretic hormone, is a neurohormone critically involved in maintaining body homeostasis. It is synthesized in discrete nuclei of the hypothalamus and transported to the posterior lobe of the pituitary gland, from where it is released into the circulation in response to increase of extracellular fluid osmolality. In the bloodstream, AVP is paramount for maintaining water balance thanks to its renal action resulting in water reabsorption and urine concentration. The other stimuli for AVP release include hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II Ang II; . The samIn addition to its effects in the kidney, AVP exerts numerous extra-renal effects, including circulatory, nervous, endocrine, metabolic, and behavioral ones, which are discussed in detail in recent reviews . TogetheVasopressin is synthesized in the form of pre-pro-AVP, which is processed into AVP, neurophysin II and C-terminal fragment of pre-pro-AVP known as copeptin. The neurohormone is produced predominantly in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in two histologically and functionally distinct pools of neurons – magnocellular cells projecting to the posterior pituitary and parvocellular cells projecting to the median eminence and extrahypothalamic brain structures, especially to the limbic system  and the via three subtypes of receptors, which belong to the G-protein coupled receptors: V1aR, V1bR, and V2R. Vasopressin released into the circulation exerts its cardiovascular effects mainly through V1aRs, which mediate vasoconstriction and increase in vascular resistance in most of the vascular beds  include the organum vasculosum laminae terminalis (OVLT) and the SFO that are located close to the third cerebral ventricle, and the area postrema (AP), which is situated in the dorsal surface of the medulla oblongata. They express numerous receptors, lack the blood-brain barrier and are accessible for hormones and mediators circulating in the bloodstream . All CVOIn rats, V1aRs are expressed on the sympathetic neurons of the rostral ventrolateral medulla (RVLM) and the respiratory neurons located in the rostral ventral respiratory column rVRC;  and pre-Circulating AVP may affect the neural control of the respiratory system either by binding to its receptors in the CVOs or receptors located in other peripheral tissues, especially the arterial chemoreceptors . OverallIntravenous infusions of AVP transiently decrease pulmonary ventilation and phrenic nerve activity in conscious dogs , anestheThe inhibitory effects of AVP on the respiratory activity depend on V1aRs, as blockade of these receptors with selective antagonists completely prevents changes in pulmonary ventilation induced by systemic administration of AVP in anesthetized rats . FurtherOne of the plausible explanations of the inhibitory action of systemic administration of AVP on ventilation is a baroreflex-mediated inhibition of the medullary respiratory neurons  due to tvia interaction with the CVOs. Thus, one of such mechanisms may involve stimulation of the V1aRs in the CVOs, specifically in the AP. In addition to the AP neurons responding to both AVP and the rise in blood pressure, indicating their pressure-sensitivity, there are at least two pools of neurons in the AP that respond to circulating AVP independently from the changes in arterial blood pressure, indicating their AVP-sensitivity. One pool increases and another one decreases the firing rate in response to intravenous AVP  caudal from the RVLM determined as a pressor region of the VLM in urethane anesthetized and vagotomized rats that were paralyzed and mechanically ventilated. In these experiments, microinjections of AVP applied into the VLM and the rostral ventral respiratory group (rVRG) caudal from the RVLM resulted in apnoea with subsequent inhibition of the phrenic nerve discharges , 2005. AThese two series of reports provide apparently conflicting results that may be caused by the several differences in the experimental paradigms, including use of neuromuscular blockade and atropine. In addition, mechanical ventilation with continuous positive end-expiratory pressure potently increases plasma concentration of AVP  and thisThe carotid body-evoked hyperglycemic response has been recognized as a contributing factor in the pathophysiology of metabolic syndrome  and blocThe role of endogenous AVP and vasopressinergic neurons in the regulation of the respiratory system is also indirectly supported by spectral analysis of the blood pressure variability, the heart rate variability, and selective pharmacological inhibition of AVP receptors in the central nervous system in awake rats, which suggests that vasopressin and V1aR/V1bRs are involved in enhancing ventilation and respiratory-induced blood pressure oscillations . FurtherEvidence pointing to the involvement of AVP in the regulation of respiration mainly emerges from experimental studies in anesthetized animals, in which either local or systemic injections of the neuropeptide or its selective antagonists were performed. Given the complexity of AVP-induced responses including water-electrolyte, cardiovascular, metabolic and behavioral ones, novel approaches are needed to decipher the integrative role of AVP in the regulation of breathing in conscious and intact animals under physiological conditions and in disturbed homeostasis.Targeted control and modification of the vasopressinergic neurons with optogenetics and chemogenetics have been proposed for determining the role of AVP in the regulation of physiological functions and behavior . These nvia the circumventricular organs, especially the AP, and the arterial chemoreceptors, specifically those located in the carotid bodies. In the area postrema, AVP inhibits the phrenic nerve activity, whereas in the carotid bodies it appears to promote ventilation. Acting as a neurotransmitter in the brainstem, AVP exerts both stimulatory and inhibitory effects on the phrenic nerve activity in a site-specific manner; however, this awaits further investigations in conscious animals. The respiratory effects of AVP appear to be predominantly mediated by the vasopressin V1a receptors. Strong evidence indicates that vasopressin may be an important neuropeptide involved in maintaining respiratory homeostasis.Vasopressin is one of the key hormones involved in maintaining body homeostasis and plays critical role in adjusting various body systems to changing internal and external environments. A great attention has been dedicated the role of AVP in maintaining renal water-electrolyte balance and regulation of the circulatory system. Recently, the central effects of AVP related to cognition, mood, memory, and pain have been recognized. Available evidence indicates that AVP also plays a complex role in the regulation of the respiratory system. As a neurohormone present in the circulation, AVP influences the respiratory activity MP designed the study, prepared the figure, and drafted the initial version of the manuscript. JP designed the study and revised the manuscript. AC-J and ES-S revised the manuscript. TŻ conceived the idea of the review, designed the study, prepared the figure, and revised and edited the final version of the manuscript. All authors contributed to the article and approved the submitted version.The study was funded by Diamond Grant from the Polish Ministry of Education and Science, grant number DI2018 020648, awarded to MP. The study was carried out with the use of CePT infrastructure financed by the European Union – the European Regional Development Fund within the Operational Programme “Innovative economy” for 2007–2013.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Those over the age of 50 represent the majority of people living with HIV (PWH), most of the HIV research, prevention and service retention work is targeted at ‘at-risk’ communities under age 50. Given this diverse and growing population, intersections of age with HIV need to be prioritized. This focus would actively increase quality of care and life experience for older PWH and the growing numbers transitioning into old age. Using local, national, and international data, this symposium will highlight the unmet social needs of older PWH. Presentations will provide evidence of unmet need, decreased self-esteem, enhanced health burden, and the damaging nature of stigma. Given the impact of COVID-19 globally, the data will further demonstrate the need to support immunocompromised older PWH. Older PWH are a marginalized community and the effects of COVID-19 have been disproportionately severe. With the adverse health outcomes experienced because of COVID-19 and intersectional stigma, it is important to understand the support structures that are and are not in place for older PWH. Advance care directives make up an integral part of future planning, especially for those living with chronic health concerns, yet little research has previously evidenced the steps taken by OPWH. Finally, using data from sub-Saharan Africa, emotional and instrumental social support sufficiency will be described to highlight the unmet needs of these older PWH. Our discussion will focus on the need for policies and programs to support this growing segment of the HIV population with increasingly diverse and unmet needs.


To the editor,With the current pandemic of coronavirus disease 2019 (COVID-19) raging, there has been a frantic search for treatment options. Out of the several treatment options that have been tried with varying degrees of success, systemic glucocorticoids have been shown to improve survival in COVID-19. Unfortunately, the widespread use of glucocorticoids has also led to an increase in the side effects of these drugs especially an increase in secondary bacterial or fungal infections. COVID-19-associated pulmonary aspergillosis (CAPA) complicating the course of COVID-19 has widely been reported; there are only a few reports on mucormycosis [Mucormycosis is an acute or subacute rapidly progressing infections caused by the angioinvasive fungi in the order of Mucorales . It mostMany challenges have also emerged in the management of mucormycosis during this pandemic. Early detection, control of hyperglycemia, liposomal amphotericin B, and surgical debridement are the cornerstones in the successful management of mucormycosis. However, in the current scenario, it is difficult to control the hyperglycemia due to the extensive use of steroids, most operation theaters remain shut due to diversion of manpower and other resources to other departments; therefore, delaying surgical debridement and the presence of coexisting multi-organ dysfunction in these patients makes it difficult to shift them for imaging studies.In this scenario, it is imperative that clinicians should be sensitized to the increased risk of development of this fatal infection, especially while treating diabetic coronavirus-affected patients with systemic steroids. In addition, judicious use of glucocorticoids must be advocated in all patients.


It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases, while in recent years, accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular disease and so on. Numerous microorganisms dwell in the gastrointestinal tract, which is a key interface for energy acquisition and can metabolize dietary nutrients into many bioactive substances, thus acting as a link between the gut microbiome and its host. The gut microbiome is shaped by host genetics, immune responses and dietary factors. The metabolic and immune potential of the gut microbiome determines its significance in host health and diseases. Therefore, targeting the gut microbiome and relevant metabolic pathways would be effective therapeutic treatments for many metabolic diseases in the near future. This review will summarize information about the role of the gut microbiome in organism metabolism and the relationship between gut microbiome-derived metabolites and the pathogenesis of many metabolic diseases. Furthermore, recent advances in improving metabolic diseases by regulating the gut microbiome will be discussed. The worldwide prevalence of metabolic diseases, including obesity, nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes mellitus (T2DM), atherosclerosis (AS) and polycystic ovary syndrome (PCOS), has grown dramatically  in the gut microbiome  in the gut, thereby suppressing intestinal FXR signaling. The antihyperglycemic effect of metformin occurs mainly through a B. fragilis-GUDCA-intestinal FXR axis  and TUDCA. GDCA induced intestinal group 3 innate lymphoid cell IL-22 secretion through TGR5, GATA binding protein 3, and IL-22, in turn improving the PCOS phenotype. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian function, insulin resistance, altered bile acid metabolism, and reduced interleukin-22 secretion and infertility  production. Treatment with the bile acid sequestrant colesevelam increases GLP-1 secretion and improves glycemia in It is well established that the gut microbiome is crucial for maintaining the physiological state and metabolic homeostasis of the host. The gut microbiome of patients with metabolic diseases is maladjusted, and the interaction between the gut microbiome and host is disordered. Therefore, regulation of the host gut microbiome may be a prospective method for the treatment of metabolic diseases. Gut microbiome colonization is thought to begin primarily at birth when the infant is exposed to the maternal microbiota during delivery , thus increasing glucose sensitivity  and other probiotics, including Lactobacillus and Akkermansia. SCFAs play important roles in inflammation suppression, thus promoting the integrity of the intestinal epithelium  and succinate. For the microbiome colonized in the distal colon, fermentable carbohydrates are depleted, and microorganisms turn to protein fermentation, mainly producing detrimental metabolites such as ammonia, phenols and branched-chain fatty acids  , thereby inducing IL-22 production. IL-22 upregulates the expression of AMP, which provide colonization resistance to pathogens such as the fungus Candida albicans (Zelante et al., + T cell activity, leading to impaired host lipid metabolism by reducing the expression of lipid transporters in the small intestine (Mao et al., Immunity also plays an important role in metabolic diseases. The gut microbiome has a highly coevolutionary relationship with the host immune system, and many of these microbes are essential to host physiology. Emerging evidence suggests that the mammalian immune system plays a crucial role in maintaining the homeostasis of the resident microbiome (Bain and Cerovic, We are living with an enormous number of microorganisms in our guts, ranging from bacteria, viruses, fungi, and archaea to phages and protozoa. The gut microbiome can modulate nutrient metabolism upon dietary intake and produce many metabolites to interact with the host in a variety of ways, including regulating glucose and lipid metabolism pathways, influencing the differentiation and function of immune cells, affecting insulin sensitivity and so on. An overwhelming amount of human and animal data provides strong evidence of a crucial role of the gut microbiome and its metabolites in the occurrence and development of many metabolic diseases.Based on the results of recent research and experiments, we have found many ways to improve metabolic diseases by regulating the gut microbiome, including dietary intervention, administration of probiotics, gene editing technology and drug use. Apart from the abovementioned application, we can also predict a person’s susceptibility to disease or response to drugs by detecting his or her microbiome features. Based on many clinical follow-up studies from different countries, most individuals (perhaps up to 70% (Shaw et al., There is no doubt that we have progressed considerably in the analysis of the composition and key metabolites of the gut microbiome. However, we must acknowledge that we still need to perform more work in addition to finding simple associations. The complex mechanisms underlying the interactions between the gut microbiome and host need to be further studied. In addition, new technologies should be applied to investigate and manipulate the microbiome to precisely intervene in a specific microbiome.


Acute kidney injury (AKI) occurs in ~20, 30, and 40–60% of pediatric patients in pediatric, neonatal and cardiac intensive care units, respectively , 2. TwenThe goals of this collection of 9 manuscripts are to provide an update on best practices for detection, management, and follow-up of pediatric AKI, and perspectives on the deleterious short- and long-term systemic sequelae of AKI in the context of evolving clinical, epidemiologic and fundamental AKI research.Leghrouz and Kaddourah provide an overview of the recent shifts in AKI definition, now centering on the KDIGO defined criteria using either a rise in serum creatinine, and/or a reduction in urine output. The authors highlight the importance of measuring urine output in order to recognize oliguric AKI for improved diagnostic precision. The review also provides a summary of the impact of AKI following hematopoietic stem cell transplant and emerging data on children with multisystem inflammatory syndrome as a result of the SARS-CoV-2 pandemic.In Impact of Acute Kidney Injury on Critically Ill Children and Neonates, authors Hessey et al. reviewed the last 5 years of peer-reviewed literature exploring the long-term outcomes of pediatric AKI. The summary provides an overview of the advancements and remaining challenges in investigating long-term outcomes after critical illness in hospitalized children. It also highlights the importance of implementing standardized follow-up of kidney health and outcomes after an episode of severe AKI. This aligns with recent recommendations in the neonatal and pediatric response to the Acute Disease Quality Initiative (ADQI) 22 guidance document  and identifies catheter size <8 French and lack of citrate regional anticoagulation as predictors of early discontinuation of treatment. With a mean follow-up time of 3.5 years, only 42% of the patients who survived did not have any long-term kidney sequelae, including CKD or proteinuria.In Continuous Renal Replacement Therapy in Critically Ill Children in the Pediatric Intensive Care Unit: A Retrospective Analysis of Real-Life Prescriptions, Complications, and Outcomes, Alge et al. provide a thorough review of the basic science and clinical data surrounding the development of AKI-mediated lung injury and the role that lung injury plays in affecting kidney function. The review highlights the complexity of identifying the bidirectional effects of hemodynamic alterations in critical illness, resulting from acute lung disease as well as from AKI.In Two to Tango: Kidney-Lung Interaction in Acute Kidney Injury and Acute Respiratory Distress Syndrome, Ulrich et al. summarize the opportunities and limitations of leveraging “big data” in administrative health repositories to investigate pediatric AKI outcomes. While big data research offers unique and unprecendented opportunities to evaluate pediatric AKI with large sample sizes, there is a need to validate these data for defining pediatric kidney outcomes and limiting associated biases.In A review on the application and limitations of administrative health care data for the study of acute kidney injury epidemiology and outcomes in children, Nguyen and Menon review best practices for AKI alerts, and how they can be implemented to hasten the diagnosis and optimize management in pediatric AKI. These AKI alerts and tools tie in with broader efforts within the nephrology community to utilize artificial intelligence and machine learning to improve outcomes in patients with AKI. The review provides examples of early applications of alert tools in pediatric AKI, including a nephrotoxic-mediated AKI stewardship program, which has been shown to reduce the rate, severity and duration of nephrotoxic AKI (In For Whom the Bell Tolls: Acute Kidney Injury and Electronic Alerts for the Pediatric Nephrologist, authors oxic AKI , 8.Piani et al. describe the pathophyisiology of AKI and its relation to diabetic kidney disease in children with types I and II diabetes mellitus. Children with diabetes are at an increased risk for developing AKI, and after an episode of AKI, they are at higher risk of developing diabetic kidney disease and CKD. The review also summarizes the increased risk of severe COVID-19 disease in patients with diabetes mellitus.In Acute kidney injury in pediatric diabetic kidney disease, Hegde et al. review the current literature on fracture risk after AKI, the mechanisms of dysregulation in bone metabolism in AKI, and suggest areas for future research, particularly with regard to skeletal growth in pediatric patients after AKI.In Acute Kidney Injury and Pediatric Bone Health, authors As the overall survival of critically ill pediatric patients improves, there are increasing survivors of childhood AKI. With these perspectives in mind, future research is required to explore the long-term impact of pediatric AKI on population health, health care costs, and how pediatric providers within varying healthcare contexts, can potentially improve care delivery with a goal to optimize their patients' outcomes later in life.DS, AD, KG, and MZ contributed to the editorial writing and revision process. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The concept of the antibiotic resistome was introduced just over a decade ago, and since then, active resistome studies have been conducted. In the present study, we describe the previously established concept of the resistome, which encompasses all types of antibiotic resistance genes (ARGs), and the important findings from each One-Health sector considering this concept, thereby emphasizing the significance of the One-Health approach in understanding ARG transmission. Cutting-edge research methodologies are essential for deciphering the complex resistome structure in the microbiomes of humans, animals, and the environment. Based on the recent achievements of resistome studies in multiple One-Health sectors, future directions for resistome research have been suggested to improve the understanding and control of ARG transmission: (1) ranking the critical ARGs and their hosts; (2) understanding ARG transmission at the interfaces of One-Health sectors; (3) identifying selective pressures affecting the emergence, transmission, and evolution of ARGs; and (4) elucidating the mechanisms that allow an organism to overcome taxonomic barriers in ARG transmission. A deeper understanding of the interplay between the human microbiome and micro-organisms present in animals and the environment will be critical for controlling antimicrobial resistance. Researchers have long known that naturally occurring antibiotic resistance genes (ARGs) can transfer between microbial species, disrupting clinical or veterinary antibiotic use. A review by Chang-Jun Cha at Chung-Ang University, Anseong, and Dae-Wi Kim, Jeonbuk National University, Jeonju, South Korea, highlights the importance of a holistic approach known as the ‘One Health’ model to ARG research. The authors explore known sources of ARGs, including soil- and water-dwelling microorganisms, and the pathogens and commensal species found in livestock, wild animals, and humans.The detailed mechanisms of ARG transmission are not fully understood, and the authors stress the need for cutting-edge genome sequencing techniques and other tools to increase understanding. Since the use of early-date antibiotics, such as penicillin and salvarsan, emergence and dissemination of resistance have been observed after introducing antibiotics into clinical settings5; this resistance is considered to be mainly mediated by antibiotic resistance genes (ARGs). In 1973, environmental ARGs were characterized to be genetically similar to clinical ARGs, suggesting that these clinical genes originated from antibiotic-producing actinomycetes6. Consequently, after this discovery, ARGs were intensively studied in only clinical pathogens for >30 years until the resistome concept was proposed7; this concept has provided exceptional insights into the origin and dissemination of ARGs. This review aims to describe the concept of the antibiotic resistome; summarize the information from the last decade regarding approaches under the concept; and provide a comprehensive understanding of the origin, emergence, dissemination, and evolution of ARGs. In particular, resistome studies from the One-Health  perspective will be essential for deciphering the complex resistome structure and determining prioritized factors to aid in the mitigation of ARG transmission to the clinic.Since the discovery of the first antibiotic penicillin7. Later, the resistome was defined as “a collection of all the ARGs and their precursors in pathogenic and nonpathogenic bacteria”8. Its constituents were precisely described as “all ARGs, including those circulating in pathogenic bacteria, antibiotic producers, and benign nonpathogenic bacteria”9. Considering the origin of ARGs, the resistome has been suggested to include protoresistance genes as a deep reservoir of ARG precursors, as well as clinical, environmental, and intrinsic resistance genes10. After a large number of studies on the resistome were published, the definition was further refined by designating types of resistance, such as acquired resistance , intrinsic resistance , silent/cryptic resistance , and protoresistance 11. In summary, the antibiotic resistome encompasses all types of ARGs (acquired and intrinsic resistance genes), their precursors, and some potential resistance mechanisms within microbial communities that require evolution or alterations in the expression context to confer resistance  the antibiotic resistome is complex and diverse16; (iii) the environmental resistome is the origin and a reservoir of ARGs17; (iv) the resistome is generally determined by the microbial community structure in the natural environment18; (v) anthropogenic activities shape the environmental resistome19; (vi) mobile genetic elements are responsible for ARG transmission20; and (vii) ARGs flow among humans, animals, and the environment21. These discoveries have provided the base for recent approaches aimed at improving the understanding of AMR in the human, animal, and environmental sectors, namely, the “One-Health” approach.Since 2006, critical information about antimicrobial resistance (AMR) has been revealed based on the resistome concept. Old speculations were confirmed, and critical new findings were suggested as follows: (i) AMR is ancient and ubiquitous in various microbiomes23. Initially, zoonoses were recognized as major issues in both humans and animals. In 2008, the importance of “ecosystems” was particularly emphasized in the One-Health concept; this was documented by consultation from several organizations including the Food and Agriculture Organization (FAO), World Organization for Animal Health (OIE), and World Health Organization (WHO) (http://www.fao.org/3/aj137e/aj137e00.htm). In general, infectious diseases, including zoonoses, are the main concerns and targets of the One-Health approach. AMR, which is directly related to such diseases, was considered one of the three One-Health priorities during the tripartite (FAO-OIE-WHO) meeting in 201124. Considering ARG flow among the One-Health sectors, it has been recognized as one of the main issues in the One-Health approach26. The One-Health concept has focused on interconnections and interdependencies among sectors at local sites; however, recently, considering global health, the comprehension of communication among local ecosystems and the identification of factors that stimulate the global AMR crisis has also gained immense attention27. In the present study, we review the achievements in each sector and evaluate the factors that need to be prioritized to mitigate ARG transmission to the clinic.As mentioned above, ARGs circulate among the microbiomes of humans, animals, and the environment, which form the different sectors of the One-Health concept. One-Health is defined as the “collaborative effort of multiple disciplines–working locally, nationally, and globally–to attain optimal health for people, animals, and the environment through policy, research, education, and practice”7. ARGs, as ancient and ubiquitous components of bacteria, exist in all ecological niches that harbor various microbial communities28. From the viewpoint of microbial ecology, the environment can be classified into natural and built environments, and the former can be divided into aquatic and terrestrial environments. The aquatic environment includes marine ecosystems (oceans and estuaries) and freshwater ecosystems . The terrestrial environment includes all kinds of terrestrial ecosystems in various climate zones such as forests, deserts, grasslands, and tundra. Built environments include wastewater treatment plants (WWTPs), agricultural sites, aquaculture operations, and hospital environments. In this review, we focus on the environmental resistomes in soil, rivers, WWTPs, and agriculture and aquaculture operation sites.Since the resistome concept originated in the soil environment, the environmental resistome has been extensively deciphered29. Many novel ARGs have been characterized from the soil environmental isolates or metagenomic sequences32. The presence of complex resistomes in permafrost and an isolated cave indicates that the environment is indeed the origin of ARGs14. The natural soil environment is regarded as a major reservoir of the antibiotic resistome, including intrinsic resistance and acquired resistances genes33; however, only some of these ARGs can acquire mobility and subsequently emerge in clinical settings, considering that mobile genetic elements (MGEs) syntenic with ARGs are rare in soil compared with pathogens18.Numerous studies have demonstrated that the natural soil environment is the origin of ARGs34. Several studies have clearly depicted a larger increase in ARGs in human-impacted river sites than in the pristine river sites, indicating the effects of anthropogenic activities on the river resistome37. The river resistome is important for the potential reintroduction of AMR in humans because rivers are a major source of drinking water and irrigation water for agriculture39. Furthermore, in riverine ecosystems, the presence of novel ARG contexts, implying the evolution and adaptation of ARGs for transmission, can cause significant challenges when they are reintroduced into human populations41. The plausible factors influencing the river resistome have been analyzed in the contexts of the effects of pollution sources and the statistical evaluation of critical factors among various anthropogenic activities. Regarding pollution sources, the effects of WWTPs on the river resistome have been surveyed in various river systems because WWTPs are considered major pollution sources in rivers in urban regions42. In general, assessments of resistomes in upstream and downstream regions of particular river sites, to which WWTP effluents are exposed, revealed that effluents certainly affect the diversity and abundance of the river resistome45. For statistical elucidation, correlations between the river resistome and various factors were evaluated. Antibiotic residues, microbial community structures, environmental parameters, and socioeconomic factors related to anthropogenic activities were found to be associated with ARG increases and alterations in the diversity of the river resistome47. Moreover, fecal pollution has been identified as one of the major contributors to changes in the river resistome by tracking the genetic markers of human fecal contamination, such as crAssphage or fecal specific bacterial taxa49. However, a recent study reported that fecal contamination could not fully explain the dramatic ARG increase downstream of a heavily urbanized river, thereby indicating the proliferation of ARGs in the river environment via MGEs37. Unlike the natural soil resistome, the river resistome subjected to anthropogenic activity is not determined by the whole microbial community, indicating the prevalence of horizontal gene transfer (HGT) of ARGs among certain bacterial hosts50. Recent studies have also revealed a correlation between genetic traits and resistome changes, such as MGEs for HGT and metal resistance genes (MRGs) co-selected with ARGs, and the environmental hosts in which ARGs proliferate52. Among the MGEs, class 1 integrons have been demonstrated to be important molecular markers for resistome proliferation and anthropogenic pollution54. Some ARGs have been suggested as core resistome or critical ARGs responsible for altering the river resistome37. To prioritize critical factors affecting the river resistome, generalized approaches at the global scale and consolidation of the present river resistome data are required55.Freshwater environments, including rivers, are considered reservoirs and dissemination routes for AMR56. They are among the major interfaces between humans and the environment56 and are also recognized as hotspots for HGT of ARGs, resulting in the dissemination of AMR57. The presence of antibiotics, metals, and disinfectants in wastewater and WWTPs could act as selection pressures for ARG transfer and co-selection of ARGs with MRGs and disinfectant resistance genes, even though their concentrations are remarkably lower than therapeutic concentrations58. Recently, the mobile resistome in WWTPs comprised a major proportion of the WWTP resistome, resulting in the identification of critical ARGs in such environments59. The role of wastewater as a reservoir of ARGs is gaining substantial attention, considering the continuous reports on novel ARGs 60; moreover, antibiotic-resistant pathogens and ARGs have recently emerged in the clinical setting61. The resistome in WWTPs according to the treatment steps has been intensively studied, and the persistence of ARGs throughout the treatment stages was elucidated64. A long-term investigation of WWTPs revealed remarkable changes in the resistome every 2–3 years, indicating successive selection of the resistome in activated sludge61. These efforts have focused on risk assessments of WWTPs; however, the consolidation of WWTP data from various regions and the establishment of standardized methodologies are required to derive the environmental framework for wastewater and WWTP resistomes57.Wastewater and WWTPs are considered hotspots for the proliferation of antibiotic-resistant bacteria (ARB) and ARGs33. Organic manure and reclaimed wastewater have been identified as critical human and animal waste products that can induce alterations in the diversity and prevalence of ARGs and ARB in soil environments65. Agricultural sites (plant production environments) in which manure and wastewater are frequently used for soil amendment have been recognized as important routes for ARG transmission from humans and animals to the environment66. Moreover, introduced ARGs could be reintroduced into humans via agricultural products67. The FAO, WHO, and OIE emphasize the significance of the agricultural environment in ARG transmission . Furthermore, recent studies have emphasized overall surveillance of ARGs in the agricultural environment and agricultural products to understand and control ARG transmission to humans68.Previous studies have reported the importance of soil biota under the influence of anthropogenic activities in planetary health systems69. Diverse microbiota, highly populated aquacultured animals, and the overuse of antibiotics designate aquaculture a “genetic hotspot” for gene exchange70. Several studies have reported an increase in ARGs in aquaculture systems72. The use of a specific antibiotic could promote ARGs against other classes of antibiotics, thereby indicating co-selection of ARGs mediated by MGEs72. Furthermore, the selected ARB and enriched ARGs in aquaculture could affect the microbiota and resistomes of adjacent environments73. The incidence of AMR in aquaculture can cause negative economic and social repercussions in these industries69. Enriched ARGs could be reintroduced into humans via adjacent environments and aquacultured animal products, suggesting an urgent need for surveillance of AMR.Abundant use of antibiotics as prophylactic and therapeutic agents in aquaculture can induce selection, evolution, and HGT of ARB and ARGs in the environment74, antibiotics are used in livestock animals for three purposes: therapeutic veterinary medicine, disease prevention (prophylaxis and metaphylaxis), and growth promotion. The latter two are strongly associated with the overuse of antibiotics in animals maintained under crowded conditions. For growth promotion, sublethal concentrations of antibiotics are widely used, although the mechanisms associated with weight gain remain unclear. Recent studies have reported that even low antibiotic concentrations affect resistome expansion in animals75. The use of antibiotics in livestock animals could trigger the selection of ARB and ARGs, which could subsequently be transferred to humans21.According to the WHO76. A recent study on the resistomes of slaughtered pigs and broilers across nine European countries revealed that the abundance and diversity of the fecal resistomes depended on antibiotic use across the nation78. In a subsequent and cross-sectional  study, surveys of the resistomes of farm and slaughterhouse workers exposed to animals suggested that the human resistome was influenced by the animal resistome, thus, emphasizing the importance of surveillance for AMR in livestock animals80. Considering the complexity of the animal resistome and the presence of various external factors at livestock sites, systematic approaches should be implemented for further analysis.The resistomes of various livestock animals have been investigated, and some regional studies have revealed a positive correlation between antibiotic use and resistome profiles as well as MGE dependency82, thereby indicating that wild animals contribute to ARG transmission between humans and animals. Among wild animals, migratory birds were found to be responsible for ARG dissemination to the environment83. Moreover, the presence of pathogens carrying emerging ARGs in companion animals, such as dogs and cats, suggests that these animals act as ARB and ARG reservoirs84; however, resistome-level studies on these animals are scarce. Considering the proximity of companion animals to humans in daily life, the resistomes of these animals should be surveyed and assessed from the perspectives of the resistome and the One-Health to control ARG transmission to humans.In addition to livestock animals, wild animals are also known to be a source of ARG dissemination. The resistome of human-contacted wild animals revealed more-diverse ARGs than that of noncontacted animals85. The resistome of the commensal bacterial community in the human microbiome is regarded as an important reservoir and dissemination route for clinical ARGs86. Several studies have elucidated the role of the human gut resistome by deciphering it and comparing its similarity with those of pathogens88. Although the transmission of ARGs from commensal bacteria to pathogens seems to be scarce89, the presence of almost identical ARGs and similar genetic contexts between the human gut and pathogenic bacteria indicate the importance of the human gut microbiome in the emergence of clinical ARGs. Correlations between the human gut resistome and the animal gut and environmental resistomes have been characterized91. Worldwide cohort studies revealed a nation-level resistome structure93, and antibiotic administration played a pivotal role in resistome and mobilome  structures95. Among the complex human gut resistomes, the importance of the mobile resistome, in which ARGs are associated with MGE in a genetic context, has been emphasized to understand ARG transmission from animals and the environment to pathogens98. Continuous identification of novel ARGs in the human gut proved the role of the human gut as an ARG reservoir and transmission route99. Furthermore, the establishment of the human gut resistome in infants, vertical transmission of the resistome and mobilome from mother to infant, and the correlations between the resistome and diseases have been studied to characterize the dynamics of the human gut resistome102.Metagenomics based on next-generation sequencing technology has been applied to the human microbiomes of the gut, skin, and respiratory tract to assess their resistomes. Understanding the dynamics of the human resistome and its relatedness to the other One-Health sectors is essential to control ARG flow from the other sectors to the human sector, particularly ARG transmission to disease-causing bacteria103. In particular, resistance in the microbiome of the respiratory tract in patients with cystic fibrosis and chronic respiratory disease is of great concern due to frequent polymicrobial infection in these patients103. Moreover, respiratory tract infection in intensive care unit patients is a critical factor determining patient survival; however, current studies on the resistome of the respiratory tract are scarce, and further systematic approaches are required to characterize the resistome and provide guidance for proper antibiotic administration against such infections. The resistome of human skin of uncontacted Amerindian infants in a neonatal intensive care unit and hands exposed to the public metro system were characterized106, indicating a potential role of the skin microbiome in ARG transmission.The resistome of the human respiratory tract was assessed to understand the etiological cause and diagnosis of the AMR profile of infectionOver the last decade, the paradigm of AMR research has changed, as the origin, transmission, and evolution of AMR have been discovered; however, as ARG transmission to humans from other One-Health sectors is only partially understood, it is expected that in the future, the following research approaches will be conducted based on the foundation of scientific achievements over the last decade. These attempts will improve our understanding of ARG transmission and guide strategies to mitigate AMR dissemination Fig. .Fig. 2Fu11, thereby indicating the importance of cutting-edge technologies to elucidate its dynamics and to explore its diversity in depth. Newly developed next-generation sequencing methods and bioinformatics tools have accelerated the applications of such sequence-based methods for resistome studies in all One-Health sectors107. Metagenomics is an essential sequence-based approach to comprehend the complex resistome within the microbiome. Three different approaches, including functional metagenomics, shotgun metagenomics, and targeted gene sequencing (amplicon sequencing), have been applied in several studies, considering the trajectory of the studies over the last decade. Metagenomics has been widely used to identify novel ARGs 108 and ARG variants or genetic contexts of ARGs (targeted gene sequencing)110, and to analyze ARGs at the resistome level (shotgun metagenomics)113. According to specific research purposes, appropriate sequencing platforms, ARG databases, and analysis pipelines should be employed to understand AMR at the resistome level. A high-throughput quantitative polymerase chain reaction array, also termed the SmartChip system (Takara), has been widely used for resistome studies in various environmental microbiomes115. This system is advantageous, as a high number of ARGs can be analyzed simultaneously within a short time, and this system is more sensitive than the metagenomics approach for detecting ARGs; however, the limitation is that only previously characterized ARGs and MGEs can be detected, and information on the hosts carrying these genetic elements cannot be obtained. In the original primer version76, the primers were found to be redundant, and primers for newly discovered ARGs were absent. Recently, Primer set 2.0 was released to solve these issues116. Considering the cost, time, and sensitivity, this method can be widely used for resistome-level analysis if the continued development of primer sets is updated. For resistome analysis at the bacterial isolate level, whole-genome sequencing (WGS) for antibiotic susceptibility testing (AST) is gaining importance as a powerful approach to predict antibiotic susceptibility profiles at the genome level; this approach can be aided by machine learning and statistical models, although the inconsistency between the WGS method and culture-based AST needs to be improved117. In conclusion, these cutting-edge technologies will be essential for understanding ARG transmission between microbiomes or bacterial strains and will provide important information about the antibiotic resistome in the context of the One-Health approach.The antibiotic resistome has been recognized as dynamic and ever expanding119. Through these approaches, mobile ARGs in the microbiome have been recently reported119. Moreover, information about hosts of these mobile ARGs is essential to understand ARG carriers and their roles in transmission to humans113.Since a complex resistome exists in all microbiomes, recent studies have attempted to classify particular ARGs that pose great threats to humans and other organisms. Their classification was revealed by understanding the core resistome, which is relatively stable in the microbiome, and the mobile resistome, which is genetically associated with MGEs120. Thus, appropriate configuration of the associated testbeds and their interfaces is essential. If both culture-dependent and culture-independent methods are simultaneously employed in an appropriate manner to understand the resistome at the interfaces, then snapshots of transmission among the One-Health sectors can be obtained. Valuable information integrated into and accumulated through these approaches will reveal the actual dynamics of ARG transmission.It is important to understand ARG flow between the One-Health sectors by monitoring the interfaces among these sectors93; however, limited information about the specific factors that induce changes in the resistomes of One-Health sectors is available. To reveal the selective pressures causing such changes, it is necessary to collect relevant data in a more granular manner, and to compare the data with the resistome data in a reliable statistical way. Furthermore, monitoring changes in the resistome in response to individual selective pressure in microcosm or mesocosm studies are required to obtain experimental evidence. A systematic understanding of the correlation between selective pressure and resistome changes resulting from mitigation will be an essential prerequisite for mitigating ARG transmission to humans.Recent studies have reported that anthropogenic activities shape the environmental resistome121; however, at some point, after crossing over into pathogens or related strains through evolutionary events that crossed taxonomic barriers, ARGs became mobile and emerged in the clinical setting121. No clear mechanism has been clearly identified yet, although a case study suggested a “carry-back” mechanism for ARG transfer from antibiotic producers to pathogens122. Considering the substantial number of environmental ARGs that are not yet mobile, the mechanisms of taxonomic barrier crossing in ARG transmission need to be better understood.AMR has long been present in antibiotic-producing bacteria, typically nonpathogenic environmental bacteriaThe concept of the antibiotic resistome and a One-Health approach is crucial to understand and mitigate ARG transmission between the One-Health sectors. Although important findings of AMR in these sectors have been recently unveiled, various factors need to be explored to understand the origin, emergence, dissemination, and evolution of ARGs. Based on cutting-edge technologies, several research topics suggested in the present study need to be further explored in the near future. Such endeavors will facilitate our hopes to overcome the arms race between antibiotics and AMR.