Cardiovascular diseases, including myocardial infarction, are among the most common diseases worldwide. Markers associated with the diagnosis of myocardial infarction have been in the spotlight for many years. The most commonly used markers of myocardial infarction are cardiac troponins. However, insufficient understanding of the biology and metabolism of cardiac troponins does not allow us to fully unlock the full diagnostic potential of these cardiomarkers. In this article, I summarized and discussed in detail the features of the metabolism of cardiac troponins. I conducted a comprehensive review of current literary sources and presented my point of view. The format of the manuscript includes a consistent description of the biology and stages of the metabolism of cardiac troponins, starting from the release and circulation, and ending with the features of elimination of cardiac troponins. The possible influence of the biology of cardiac troponins on the diagnostic value of cardiac troponins is analyzed. Based on the analysis of the literature, I found a close relationship between the diagnostic value of cardiac troponins and their biology/metabolism. Further research is needed to increase the diagnostic value of cardiac troponins, and to fully unlock their diagnostic potential.Understanding of the biology of endo- and exogenous molecules, in particular their metabolism, is not only of great theoretical importance, but also of high practical significance, since many molecules serve as drug targets or markers for the laboratory diagnostics of many human diseases. Thus, cardiac troponin (cTns) molecules have long been used as key markers for the confirmation of diagnosis of myocardial infarction (MI), and with the introduction of contemporary (high sensitivity) test methods, many of our concepts related to the biology of these cardiac markers have changed significantly. In current clinical practice, there are opening new promising diagnostic capabilities of cTns, the understanding and justification of which is closely connected with the theoretical principles of the metabolism of these molecules. However, today, the biology and metabolism of cTns have not been properly investigated; in particular, we do not know the precise mechanisms of release of these molecules from the myocardial cells (MCs) of healthy people and the mechanisms of circulation, and the elimination of cTns from the bloodstream. The main purpose of this manuscript is to systematize information about the biology of cTns, with an emphasis on the metabolism of cTns. The format of this paper, starting with the release of cTns in the blood and concluding with the metabolism/filtration of troponins, provides a comprehensive yet logically easy way for the readers to approach our current knowledge in the framework of understanding the basic mechanisms by which cTns are produced and processed. Conclusions. Based on the analysis of the current literature, the important role of biology and all stages of metabolism  of cTns in laboratory diagnostics should be noted. It is necessary to continue studying the biology and metabolism of cTns, because this will improve the differential diagnosis of MI and i a new application of cTns immunoassays in current clinical practice. Troponins (troponin I (TnI), troponin T (TnT), troponin C (TnC)) are proteins that are parts of the troponin complex, which is bound to the protein tropomyosin (TPM). TPM, in its turn, together with actin, forms thin filaments of myocytes—the most important component of the contractile apparatus of striated muscle cells  ,2. All tThe molecules of troponins have different amino acid structures depending on their localization in muscles, on the basis of which troponin isoforms are distinguished. Thus, TnI has three isoforms: cardiac troponin I (cTnI), TnI of fast-twitch skeletal muscle fibers, and TnI of slow-twitch skeletal muscle fibers. TnT also has three main isoforms: cardiac troponin T (cTnT), the TnT of fast-twitch skeletal muscle fibers, and the TnT of slow-twitch skeletal muscle fibers. According to molecular genetic studies, the amino acid sequence of cTnI and cTnT differs from the amino acid sequences of the corresponding isoforms of skeletal Tns localized in skeletal muscle fibers by approximately 40–60% ,8. This Notwithstanding the solid achievements in the study of etiopathogenesis, diagnostics, and treatment of acute coronary syndrome (ACS), it still remains one of the leading reasons for disability and mortality in all the developed countries of the world. All patients with ACS have a higher risk of developing myocardial infarction (MI) and death ,16,17,18Although the regulatory documents concerning the diagnostics and treatment of different forms of ACS and MI contain clear recommendations on the time of troponin testing and decision-making levels, and the sensitivity and specificity of most immunoassays approximate 100%, there still remain a number of unsolved problems and issues relating to the application of these markers in clinical practice. Some of these problems are connected with the variety of troponin diagnostic agents, their unequal sensitivity and diagnostic accuracy, and different susceptibility to cross-reactive substances (molecules), i.e., with different analytical characteristics of test systems ,20. AnotDue to modern ultra-sensitive tests, medical practitioners have the opportunity to diagnose MI early (within the first two hours from the admission of the patient) through the evaluation of the dynamic changes of cTns. The changes (increases) in the concentration of cardiac troponin molecules within the first two hours are very small , and cannot be detected by moderately sensitive test systems. It should be noted that, due to a number of multicenter studies, algorithms of the early diagnostics  of non-ST-segment elevation MI (NSTEMI) have been validated for the ultra-sensitive test systems of various manufacturers  33]..33].According to the data of modern (ultra-sensitive) troponin test methods, the molecules of cTns are detected in blood and a number of other biological fluids in all healthy people ,40,41,42One of the significant problems of both moderately sensitive and modern highly sensitive immunoassays is the lack of their standardization ,63,64. TIt should be noted separately that the molecules of cTns can be affected by the very numerous proteolytic enzymes present in the blood, which thereby can indirectly affect the levels of cTns in the blood of patients. For example, due to an increase in the activity of proteases that cause the fragmentation of troponin molecules, the duration of the circulation  of cTns in the bloodstream will decrease, which can potentially lead to false-negative results when using those test systems that have diagnostic antibodies directed against the fragmented epitopes of troponin molecules ,66. A deA very interesting direction in studying the diagnostic value of cTns is the assessment of the possibility of using other biological fluids as biomaterials for the detection of troponin molecules. This direction is developing due to an increase in the sensitivity of immunoassays (the creation of highly sensitive and ultra-sensitive test systems), which can detect very low concentrations  of cTns that circulate in many biological fluids, including non-invasively obtained fluids  ,71,72,73The main biological fluids in which the molecules of cTns are detected and their diagnostic value are summarized in Conventionally, three main stages of the metabolic pathway of cTns can be distinguished : (1) theEach of these stages of metabolism can play a decisive role in the regulation of the concentrations of cTns in blood, i.e., their diagnostic value. In addition, there are a number of factors that can have a potential and hypothetical influence on these stages of the metabolic pathway of cTns. These factors can be physiological conditions; for example, gender, age, and circadian characteristics, which have a certain effect on the degree of release of troponin molecules from the myocardium of healthy people, or changes in the activity of the proteolytic enzymes that target cardiac troponin molecules. The activity of proteolytic enzymes can also change under pathological conditions and/or in the case of taking certain medications. Renal failure can be noted as an example of a significant factor affecting the removal of cTns from the bloodstream. It is important to emphasize that there may be an extremely large number of such factors, and some of them are probably still unknown.Furthermore, in the course of this manuscript, I will sequentially consider each of the stages of the metabolic pathway of cTns, and note the main known and assumed factors that may affect these mechanisms and the diagnostic value of cTns.The introduction of highly sensitive test systems into practice made it possible, with high accuracy , to detect very low concentrations of cTns, ranging from 0.001 to 0.01 ng/mL, and below the values corresponding to the 99th percentile (upper limit of the norm). As a result, cTns molecules were found in almost 100% of healthy people, and instead of a clear borderline level typical of MI, a smooth scale appeared, capable of reflecting the subclinical myocardial pathology associated with structural (non-ischemic) damage, stable coronary artery diseases, and other pathological conditions that negatively affect MCs ,88,89. CBelow, I will consider each of the above mechanisms of cTns release, sequentially and in more detail.14-labeled DNA molecules in MCs. A long-term observation of people with the inclusion of a radioactive isotope of carbon (C14) in the DNA of cardiomyocytes, which occurred as a result of nuclear weapons tests, was carried out. The authors calculated the rate of renewal of cardiomyocytes by studying the rate of DNA synthesis, which was calculated by investigating the rate of accumulation of C14 in MCs. A renewal of cardiomyocytes, the intensity of which decreased annually—from 1% per year at the age of 25 years to 0.45% per year at the age of 75 years—was found. In general, about 50% of cardiomyocytes underwent renewal throughout life [Evidence of the fact that MCs can regenerate/renew has been obtained by studying the metabolism of Cout life ,106. Theout life , howeverIn accordance with the data of other researchers, the average rate of cardiomyocyte renewal in mammals is 0.5–2.0% per year, and can vary depending on the influence of certain factors, such as physiological conditions , trauma, and concomitant diseases ,109,110.However, the assessment of the degree of regeneration and the rate of renewal of MCs can be significantly influenced by inflammatory processes, the proliferation of non-myocyte cells, and the formation of a connective tissue scar in the myocardium, which often complicates and/or distorts investigation results ,116. FurTo date, a large number of factors have been discovered that can trigger the processes of the apoptosis of cardiomyocytes ,118. TheAn experimental study led by Weil et al. has shown that the short-term ischemia activates apoptosis of MCs in experimental animals, and the apoptosis of cardiomyocytes is accompanied by an increase in the serum levels of cTns. Short-term myocardial ischemia was simulated by means of the balloon occlusion of a branch of the left coronary artery, and the fact of occlusion was confirmed by coronary angiography. The duration of ischemia was 10 min, after which reperfusion was carried out by deflation of the balloon. To confirm the apoptosis of MCs, the TUNEL method was used, according to the results of which, the number of cardiomyocytes in the state of apoptosis was significantly increased . At the same time, no histological signs of myocardial necrosis were observed. This suggests that short-term  ischemia does not cause the ischemic necrosis of cardiomyocytes, but enhances apoptotic processes in the myocardium. However, the levels of cTns began to rise rapidly: 30 min after reperfusion, the cTnI concentration approached the upper limit of the norm (38 ng/L), and after 1 h, exceeded it (51 ± 17 ng/L). Two and three hours after reperfusion, the serum levels of cTnI were 148 ± 88 ng/L and 180 ± 117 ng/L, respectively, which indicated the continuing release of troponin molecules from the myocardium. Finally, 24 h after reperfusion, the cTnI concentration reached its peak and amounted to 1021 ± 574 ng/L . Thus, tThe literature also describes other situations when the apoptosis of cardiac myocytes is induced by other mechanisms that are not associated with the reversible (short-term) ischemia of cardiac muscle tissue. The authors identify the following mechanisms of apoptosis that can promote the release of cTns from MCs: the stretching of the myocardial walls, increased preload on the heart, and the increased activity of the sympathoadrenal system ,100,123.In another experimental study, Weil et al. concluded that an increase in preload on the heart triggers apoptosis, and causes an increase in the concentration of cTnI in the blood of experimental animals. To increase the preload on the heart, the experimental group of animals received an intravenous drug—phenylephrine (300 μg of the drug per minute)—for one hour. After the simulation, echocardiography was used to confirm myocardial overload, and to verify apoptosis and determine cardiac troponin levels, histological methods were used, including the TUNEL method and a moderately sensitive immunoassay, respectively. As a result of the histological examination of the myocardium of the experimental group of animals, a significant increase in the number of cardiomyocytes in the state of apoptosis was noted, as compared to the control group. At the same time, no histological signs of myocardial necrosis were recorded. Moreover, 24 h after the simulation, the number of cardiomyocytes in the state of apoptosis decreased to the level of the control group, which indicates the reversibility of apoptotic changes. The cTnI concentration exceeded the upper limit of the norm 30 min after the simulation, and then the cTnI levels continued to rise sharply, and reached a value of 856 ± 956 ng/L one hour after the simulation. The serum levels of cTnI remained elevated throughout the study period (24 h) and peaked at 1462 ± 1691 ng/L . Since sThe degree of release of cardiac troponin molecules from MCs as a result of apoptosis induced by myocardial overload depends on the strength and duration of exposure. For example, relatively small myocardial overload is observed on mild to moderate exertion, in hypertension and non-massive pulmonary embolism, so the increase in serum levels of cTns in these conditions is also relatively small. However, for example, on high-intensity exertion, or in massive pulmonary embolism, myocardial overload becomes much more significant, and therefore, these conditions are accompanied by relatively higher serum levels of cTns ,130,131.Another very interesting mechanism for the initiation of apoptosis is an increase in the activity of the sympathoadrenal system. A research group led by Singh et al. found that the stimulation of beta-adrenergic receptors (β-AR) regulates intracellular apoptotic signaling pathways in cardiomyocytes. Moreover, the stimulation of β1-AR enhances the apoptosis of MCs, while the stimulation of β2-AR has the opposite effect ,133. It Considering the above, the apoptosis of cardiomyocytes should be considered as a significant mechanism for the release of cardiac troponin molecules from MCs. This mechanism is not associated with the necrosis of cardiomyocytes, and contributes to a very significant increase in the serum levels of cTns. Thus, the apoptosis of MCs can be of great diagnostic value in conditions such as prolonged and intense physical activity, arterial hypertension, pulmonary embolism, heart failure, and, probably, in old age. Further research is needed to clarify the exact role of apoptosis in the release of cTns in physiological and pathological conditions.This mechanism of release of cTns from MCs was first described in an experimental study a relatively long time ago. A research group led by Schwartz reported that, on the plasma membrane of MCs, membrane vesicles (blebbing vesicles) are formed ,138. MorThe size and location of intracellular molecules are two key factors that affect the transport (release) of molecules across the cell membrane. Low molecular weight biomarkers are much more intensively released across the plasma membrane, which plays a role in the diagnostics of many diseases, including cardiovascular pathologies. So, for example, with the development of MI, the concentration of low molecular weight cardiac markers (myoglobin) in blood serum increases much earlier than the concentration of high molecular weight cardiac markers (lactate dehydrogenase-1) ,144,145.The most important factor that can affect the size of a molecule (biomarker) and, accordingly, the possibility of its release, is the degree of activity of enzymes that cause the proteolysis (fragmentation) of this molecule ,147. TheIn addition to the enzyme calpain, the cleavage of cTns molecules can be catalyzed by some types of matrix metalloproteinases (MMP 2 and MMP 14) ,149,150 Changes in acidity (pH) can also modulate the activity of intracellular proteolytic enzymes ,157. So,The membrane permeability of MCs is an important factor that plays a role in the release of cardiac marker molecules from MCs into the bloodstream. Based on the analysis of the results of existing experimental data, two main mechanisms can be distinguished that underlie the change (increase) in the membrane permeability of MCs: (1) an increase in the membrane permeability of MCs as a result of an increase in the load on the myocardium and stretching of its walls; (2) an increase in the membrane permeability of MCs as a result of myocardial ischemia, and the activation of proteolytic enzymes that can damage the cell membrane.The first mechanism for the release of cTns was studied by Hessel et al. . In theiThe second mechanism for increasing membrane permeability is associated with membrane damage during the ischemia of MCs. As already described above, myocardial ischemia initiates changes in the metabolism of cardiomyocytes and the acidification (acidosis) of the intracellular space of MCs, which, in turn, will lead to the activation of proteolytic and proapoptotic enzymes. These enzymes have many targets, and in addition to the specific action (fragmentation of cTns), they can obviously catalyze the proteolysis of proteins that make up cell organelles and membranes ,162,163.A possible mechanism underlying the release of cTns is small-scale necrotic processes, which can be caused by both ischemia and inflammatory-toxic processes, imbalances in the neurohumoral system.So, according to some researchers, regular heavy physical exertion, myocarditis, and stressful situations can cause subclinical damage to myocardial tissue (death of single cardiomyocytes), which can subsequently be associated with the formation of relatively small areas of fibrosis and an increased risk of sudden cardiac death . So, forSome studies registered extremely high levels of cardiac markers, including cTns in the blood serum of athletes, after serious and prolonged physical activity ,169,170,Although, during psycho-emotional stress, the level of troponin increase is relatively small (rarely exceeds the levels of the 99th percentile in the isolated effect of stress), it cannot be considered a safe process ,173. TheOne of the controversial but hypothetically possible mechanisms underlying the increase in serum levels of cTns is the release of these molecules from non-cardiac cells. Several experimental and clinical studies indicate the expression of cardiac troponin molecules in skeletal muscle cells ,176,177 A second potential non-cardiac source of cardiac troponin release is the walls of large veins (venae cavae and pulmonary veins). Some studies report only the presence of the expression of cTns in the walls of these veins, but do not describe the possible role of these troponins in diagnostics ,179. HypThus, due to the fact that data on extracardiac expression are either insufficient or contradictory, further research is needed to validate this mechanism.The mechanisms of cardiac troponin release described above, and their diagnostic values, are summarized in The second major stage of the metabolic pathway of cTns is circulation in the bloodstream. At this stage, the molecules of cTns are influenced by a number of factors , which can affect the serum levels of cTns and, therefore, their diagnostic value. The molecules of cTns released into the bloodstream are represented by a heterogeneous fraction (a significant variety of different forms of troponin molecules): free cTns; combined complexes consisting of several free forms of cTns , and small fragments of cTns ,186,187.Clear evidence that cardiac troponin molecules can pass (filter) through the glomerular filter has been presented in several recent clinical studies due to the use of highly sensitive troponin immunoassays ,71,73. AThe search for specific mechanisms of proteolytic cleavage of cTns in the bloodstream is of great practical importance, since it will optimize laboratory diagnostics: in particular, there is a possibility of developing antibodies directed against individual fragments of cTns, or introducing inhibitors of the main proteolytic enzymes that catalyze troponin proteolysis into diagnostic test systems to reduce interference and more thoroughly interpret the test results, taking into account comorbidities that affect the activity of enzymes breaking down cTns, etc. Unfortunately, the number of fundamental studies devoted to the investigation of the processes of proteolytic cleavage of cTns in the bloodstream is extremely small. To date, only one specific mechanism is known, described in the study by Katrukha et al. ,152. AccIn general, a number of research groups studying the processes of proteolytic cleavage in the bloodstream report the presence of a very large number of fragments  of cardiac troponin molecules, which have different sizes , stability, half-lives in the bloodstream , and conditions of formation  ,186,187.Very interesting data are presented by the researchers Zahran et al., who studied the degree of proteolytic degradation of cTnI in patients with varying degrees of ischemia and damage to cardiac muscle tissue . The res(1)Study of the fundamental specific mechanisms of proteolytic degradation of cTns in the bloodstream, both under normal conditions and under the conditions of simulated concomitant pathologies. This requires a targeted and thorough study of the potential effect of individual serum proteolytic enzymes .(2)Search for specific fragments of cTns, which are released at the earliest possible time after the onset of myocardial ischemia and the creation of antibodies to them, which will increase the sensitivity and specificity of troponin immunoassays.(3)Search for specific fragments of cTns, which have a small molecular weight and are able to pass through the glomerular and blood-salivary barriers. The creation of antibodies to these fragments will make it possible to develop specific highly sensitive test systems for the analysis of non-invasive biological fluids  and for the introduction of new methods of non-invasive diagnostics and monitoring of cardiovascular pathologies, including MI, into routine clinical practice.(4)Study and identification of potentially possible specific mechanisms of proteolytic cleavage of cTns under the action of other (non-ischemic) factors. This will allow the development of specific troponin immunoassays to identify those fragments that, for example, will increase exclusively with the stretching of the myocardium or exclusively with an increase in the activity of the adrenergic nervous system and an increase in β-AR stimulation, etc. Thus, it will be possible to carry out a more specific diagnosis of non-ischemic myocardial damage in some physiological and pathological conditions not associated with ischemia of the cardiac muscle tissue.Summing up the role of the stage of cTns circulation, we should once again emphasize its potentially high diagnostic value in practical medicine. At the moment, this stage is a relatively poorly studied area of the biology of cTns. The main directions of further work in this area, in my opinion, should be as follows:The final stage of the metabolic pathway of cTns in the bloodstream is as important as the other two stages (release and circulation). Both of these stages are closely related to the terminal stage of the metabolic pathway of cTns. So, for example, when small fragments are released from cardiomyocytes (as a result of the intracellular proteolytic cleavage of cTns), they will obviously be almost immediately removed from the bloodstream by filtration through the glomerular and blood–salivary barriers. When larger fragments of cTns and/or binary and ternary complexes are released, the filtration of these molecules is unlikely due to their large size (molecular weight).The circulation of cTns is equally closely related to the removal of these molecules. So, for example, with a higher activity of serum proteolytic enzymes, the process of degradation of cardiac troponin molecules will be more active, which will lead to the more rapid formation of small troponin molecules and their filtration  from the bloodstream.In general, today, the mechanism of filtering cTns through the glomerular barrier is one of the main and definitively proven ways to remove cTns from the bloodstream. The inferential (indirect) evidence is that when the filtration rate decreases , cardiac troponin molecules accumulate in the bloodstream and their serum levels begin to rise sharply in those patients who do not have any signs of cardiovascular pathology and damage of MCs. The more the renal function is suppressed , the higher the concentration of cTns in the bloodstream rises ,197,198.Recent clinical studies by several research groups can be considered as valuable evidence of the existence of a mechanism for the elimination of cTns across the filtration barrier ,71. A keOne of the key and very labile factors affecting the glomerular filtration rate  is blood pressure. So, with a decrease in blood pressure, the filtration rate will slow down and the degree of removal of cTns from the bloodstream will decrease. This mechanism, in particular, can contribute to the fact that the molecules of cTns will increase much more and circulate in the bloodstream for longer in pathological conditions, accompanied by a sharp drop in blood pressure. This can be typical for large focal myocardial infarctions, which are often accompanied by a sharp decrease in blood pressure (cardiogenic shock), and the degree of increase/duration of circulation of cTns in the bloodstream can be considered as a prognostically unfavorable sign . With anAnother method of cTns removal is associated with the activity of the reticuloendothelial system, the cells of which capture the protein molecules of cardiac markers from the bloodstream, and cause their intracellular proteolytic cleavage ,202,203.As noted earlier, the proteolytic cleavage of cTn molecules in the bloodstream is an extremely understudied mechanism for the elimination of cTns. As a result of this mechanism, a large number of small fragments of cTns are formed, which can be immunoreactive (can interact with antibodies and be detected by immunoassays) and non-immunoreactive fragments (which will not interact with antibodies). From the point of view of laboratory diagnostics, non-immunoreactive fragments of cTns can be considered to be already removed from the bloodstream, since they will not bind to antibodies, and thus will not have an effect on the result of the laboratory diagnostics of MI or any other pathology. To elucidate the mechanism of cTns removal by proteases, well-controlled basic research is needed to thoroughly investigate the role of individual serum proteolytic enzymes in the degradation of cTn molecules in the bloodstream.Thus, three main mechanisms of elimination of cTns from the bloodstream can be distinguished: (1) the elimination (filtration) of cTns through the glomerular barrier, (2) the removal of cTns from the bloodstream by cells of the reticuloendothelial system, (3) the proteolytic cleavage of cTns molecules and/or their fragments in the bloodstream to non-immunoreactive forms. Taking into account the analysis of the literature, the main mechanism for the removal of cTns, in my opinion, is the elimination of cTns through a three-layer filtration (glomerular) barrier. This mechanism can have a significant impact on the diagnostics of cardiovascular diseases, including MI, since the impaired removal of cTns from the bloodstream is often accompanied by a significant increase in the serum levels of cTns. In addition, many patients have comorbid pathologies, among which kidney damage  is relatively common. Many other common diseases, for example, diabetes mellitus and sepsis, are also often complicated by renal failure. Thus, they may increase the serum levels of cTns in patients with no signs of cardiovascular diseases.The removal of cTns from the bloodstream by glomerular filtration may have an important impact on rapid algorithms for the diagnostics/exclusion of MI. Thus, the research group led by Kavsak reported that the currently established upper threshold levels of cTns (99th percentile) for the diagnostics/exclusion of MI can be used only for patients with an optimal glomerular filtration rate (≥90 mL/min) . In patiFinally, the filtration of troponin fragments through the blood–brain barrier into the cerebrospinal fluid and through the blood–salivary barrier into saliva can be considered as additional potential mechanisms for the removal of cTns. As evidence of the existence of these mechanisms, one can consider studies ,78,79,80The activity of many systems  of our body changes cyclically during the day (with the change of day and night), commonly called circadian or diurnal rhythms. Circadian rhythms are an evolutionarily developed mechanism necessary to maintain the optimal functioning of the body and adapt to changing environmental conditions .Due to the fact that the tissues and cells of our body change, there is a change in the concentration of a number of molecules , which are produced or metabolized by these tissues and cells. Many of these molecules are laboratory biomarkers, the concentration of which is used to diagnose diseases ,207. ThiRecent clinical studies have reported that the bloodstream levels of cTns are dependent on circadian rhythms. These studies used highly sensitive troponin immunoassays able to detect small fluctuations in the concentration of cTns in the bloodstream  ,209,210.The precise mechanisms of the formation of circadian rhythms of cTns are unknown, however, it can be assumed that they will be associated with changes in the functional activity of those organs, tissues, and cells that can somehow affect the metabolic pathway of cTns, in particular, the stages of their release into the bloodstream, the stage of circulation , or the elimination stage . Among the most probable mechanisms for the formation of circadian rhythms of cTns, in my opinion, there are circadian fluctuations in the activity of the cortex and medulla of the adrenal glands, of the thyroid gland, and the activity of enzymes of the hemostatic system ,217,218.A possible explanation of the reason for the fact that the circadian rhythms of cTnT are more significant than the circadian rhythms of cTnI is their biochemical features, in particular, the fact that the volume of the cytoplasmic fraction of cTnT is almost twice the volume of the cytoplasmic fraction of cTnI (approximately 7–8% versus 3–4%) ,58. ThusThe metabolic pathway of cTns includes three main stages , each of which can have a very significant effect on the serum levels of cTns, i.e., on their diagnostic value. The format of the review, starting with the release of troponin in blood, and concluding with the metabolism/filtration of troponins, provides a comprehensive yet logically easy way for the reader to approach our current knowledge in the framework of understanding the basic mechanisms by which troponins are produced and processed.Based on the analysis of the current literature, the important role of biology and all the stages of metabolism  of cTns in laboratory diagnostics should be noted. It is necessary to continue studying the biology and metabolism of cTns, because this will improve the differential diagnosis of MI, and create a new application of cTns immunoassays in current clinical practice.It should be noted that many new views on the biology, metabolism, and diagnostic value of cTns  were formed as a result of an increase in the sensitivity of troponin immunoassays.Unfortunately, today, many stages of the metabolic pathway of cTns and factors influencing the metabolic pathway of cTns are extremely poorly understood, and are hypothetical and/or contradictory. In particular, the specific mechanisms of the release of cTns from the myocardium into the bloodstream, as affected by physiological conditions and characteristics  and non-ischemic pathologies, which are often accompanied by an increase in the concentration of cTns in the bloodstream, are not very well known. Moreover, factors affecting the circulation of cTns molecules in the bloodstream, in particular, enzymes involved in the metabolism (fragmentation) of troponin molecules, remain unknown. The mechanisms of filtration (transport) of cardiac troponin molecules from the bloodstream to other biological fluids are not investigated, and, accordingly, these possibilities of non-invasive diagnostics have not been validated. Thus, the study of the biology and metabolism of cTns and potential factors influencing it is a relatively large and poorly studied area for further research, which is needed to optimize diagnostics and validate new diagnostic capabilities.


Chronic non-communicable diseases (NCD) account for 72% of the causes of death in Brazil. In 2013, 54 million Brazilians reported having at least one NCD. The implementation of e-Health in the Unified Health System (SUS) could fill gaps in access to health in primary health care (PHC). Objective: to demonstrate telehealth strategies carried out within the scope of the Institutional Development Support Program of the Unified Health System (PROADI-SUS) and developed by Hospital Alemão Oswaldo Cruz, between 2018 and 2021, on evaluation, supply, and problem-solving capacity for patients with NCDs. Methodology: a prospective and descriptive study of three projects in the telehealth areas, using document analysis. The Brasil Redes project used availability, implementation, and cost-effectiveness analysis, TELEconsulta Diabetes is a randomized clinical trial, and Regula Mais Brasil is focused on the waiting list for regulation of specialties. All those strategies were developed within the scope of the SUS. Results: 161 patients were attended by endocrinology teleconsultation in one project and another two research projects, one evaluating Brazil’s Telehealth Network Program, and another evaluating effectiveness and safety of teleconsultation in patients with diabetes mellitus referred from primary care to specialized care in SUS. Despite the discrepancy in the provision of telehealth services in the country, there was an increase in access to specialized care on the three projects and especially on the Regula Mais Brasil Collaborative project; we observed a reduction on waiting time and favored distance education processes. Conclusion: the three projects offered subsidies for decision-making by the Ministry of Health in e-Health and two developed technologies that could be incorporated into SUS. With the change in the epidemiological and demographic profile of the population, in addition to the growing increase in chronic pathologies and people in vulnerable situations, the need for an integrated approach to the individual concerning health care emerges ,2,3. ChrDigital health, or e-Health, can be defined as “the safe and cost-effective use of information and communication technologies in support of health and health-related fields”, with the World Health Organization considering making e-Health a global priority for health systems development . The impWe Are Social in January 2020, identified 150.4 million internet users in Brazil [The distribution of income and access of the Brazilian population to technological resources is characterized by geographical and social inequality. Even so, the report “Digital 2020”, published by n Brazil , accountn Brazil . Considen Brazil . That wan Brazil ,15.This article aims to describe telehealth strategies carried out in the years 2018 to 2021 by the Hospital Alemão Oswaldo Cruz, in partnership with the Brazilian Ministry of Health through the Support Program for Institutional Development of the Unified Health System (PROADI-SUS) ,17.Between 2018 and 2021, Hospital Alemão Oswaldo Cruz, in partnership with the Ministry of Health, through PROADI-SUS, developed projects and actions in Telehealth aimed at improving management in various spheres of the SUS. Of these, we review three strategies aimed at reducing the impact of CNCD on health using different strategies in e-Health for this purpose. As these are three different projects, we will describe the methodology of each one separately.The Brasil Redes Project aimed to carry out a diagnostic evaluation of the National Telehealth Brazil Networks Program (PNTBR–in Portuguese), which completed 10 years of existence in 2017 . This prFive studies were carried out for this evaluation: evaluability study, implementation evaluation, and cost-effectiveness evaluation of two services offered in the list of activities foreseen by the program and program cost analysis . The evaRegula Mais Brasil Collaborative  is a proMotivated by the COVID-19 pandemic , the MinThis project’s main objective, until in recruitment phase, is to conduct clinical research to test the hypothesis that teleconsultation is non-inferior to the face-to-face care of patients with diabetes mellitus (DM) type II referred from primary health care (PHC) to specialized care in SUS .This is a randomized, pragmatic, phase-2, single-center, open, non-inferiority clinical trial, with central randomization, allocation confidentiality, and data analyst blinding, to assess the efficacy and safety of specialized care by teleconsultation compared to face-to-face care. A total of 250 participants of both sexes over 18 years old, with type 2 diabetes mellitus, will be included. This sample size will allow evaluating the non-inferiority of up to 0.5% between groups, assuming a standard deviation of 1.30.The outcomes that will be analyzed in this study are: the mean difference in the percentage of glycated hemoglobin (HbA1c) post- and pre-intervention in patients diagnosed with type 2 DM in 3 and 6 months, fasting blood glucose measurements and blood count, measurements of serum urea and creatinine, lipid profile measurements, systolic pressure measurements, in-office measurements, in-office diastolic pressure measurements, measurements of body weight and body mass index (BMI), the incidence of any adverse events, and quality measurements of patients’ lives using the diabetes quality of life measurement questionnaire (DQOL) .In the micro-costing analysis , this stThe main target audience of the Telessaúde Brasil Redes National Program is primary health care teams, and with that many of the actions offered by the centers were focused on caring for people with CNCD. In this sense, the project results highlighted opportunities for improvement of the telehealth program for CNCD at the federal level. In Brazil’s public health system, there is a necessity to homogenize the financing values considering the production potential of the centers, mainly for telediagnosis, and monitoring and evaluation methods of results. For the spheres of state centers aiming to value their actions, there is a need to reflect on challenges in the use of these services by health workers and on regional partnerships. The set of methods offered a broad vision of the program and articulated more detailed analyses of certain services offered by the telehealth centers. The purpose was to offer subsidies to the Ministry of Health in improving the telehealth program and using the expertise of certain centers as inspiring the formulation of procedures used to be offered by SUS.Since the creation of the Brazil Redes program in 2007, 33 telehealth centers have been identified in various regions of the country , with veIn this sense, the centers sought to articulate different fronts of activities to contemplate permanent education and the improvement of primary care professionals, whether through courses, virtual lectures, teleconsulting, production of training second opinions, and telediagnosis. Regarding the processes evaluated in the economic component, the two studies carried out with the Telehealth Center at Clinic’s Hospital from the Federal University of Minas Gerais clarify the cost and budget impact forecast for the implementation of telecardiology services in the public service network, which can greatly contribute to the improvement of care for people with CNCD.The Hospital Alemão Oswaldo Cruz carried out consolations in the Regula Mais Brasil Collaborative Project via teleconsultation of users, in the specialties of neurology, endocrinology, orthopedics, and mental health, totaling 1097 teleconsultations in this period. Specific actions for CNCDs are concentrated in the specialty of endocrinology, in which 161 teleconsultations were carried out, all with SUS users in the city of Recife, city located in the state of Pernambuco, in northeastern Brazil . The resDepending on the prevalence of endocrinological diseases, diabetes mellitus appears as the most prevalent reason for teleconsultations performed. Regarding the technology used for contact between the doctor and the patient, video calling (audio and video) was mostly used, since it represents the best possibility of remote interaction. The exclusive audio resource was only used when it was not possible to use video calling.The outcomes of the last teleconsultation were performed to allow an assessment of the resolvability potential of this assistive technology. The follow-up outcomes in PHC (40.3%) represent cases in which the specialist, based on the assessment in teleconsultation, considers that, based on the complexity of the case, the patient can be followed up in the PHC, close to their residence, avoiding unnecessary referral and displacement of the patient to the specialized center. In addition, he receives the first guidance and conduct by the specialist via teleconsultation. Likewise, the reassessment in teleconsultations (23.4%) also represents the cases in which digital technology allows for adequate follow-up with a specialist, without the need to travel. On the other hand, cases in which the outcomes indicate the need for a face-to-face consultation with the specialist, whether immediate or elective, represent the limitation of teleconsultation in the assessment or follow-up of cases. It is worth mentioning that all cases evaluated did not have a first face-to-face consultation which, in some cases, limits a better diagnosis.What corroborates the potential of teleconsultations is the result of the Net Promoter Score , which aRegarding the results of the teleconsultation diabetes research project, it was not yet possible to demonstrate aspects of the research results related to the results of complementary exams, questionnaires measuring the quality of life in diabetes (DQOL), and satisfaction assessment with telemedicine, due to the small number of participants included so far. Of the patients included in the study, the mean age was 59.4 years, with a predominance of 78% of white people, followed by black (12%) and mixed race (10%), and a slight predominance of males (54%) of the included participants.In addition, within the scope of the teleconsultation project, the time-driven activity-based costing (TDABC) micro-costing methodology, or costs based on time and activity, was adopted because it allows the identification of the unit cost of the service within the expected efficiency conditions, also acting as a comparison metric. In this scenario, the first hypothesis considered the duration of the teleconsultation and the face-to-face consultation to be identical, as well as the duration of the pre-consultation activities. This is a preliminary conclusion, considering that recruitment, until this period, was minimal and with low statistical power to detect differences in times. The second hypothesis considered that the costs with materials and structure of the UBS’s and the Polyclinic are also identical since the Health Department of Joinville is in the middle of the process of changing the methodology for this type of cost and must provide these data in a manner more accurate by mid-2021. In this hypothetical scenario, the cost of teleconsultation was 5% higher than that of a face-to-face consultation. As in both cases, the consultation is responsible for more than 90% of the total cost, the difference in duration between the two types of consultation will be the determining factor for the difference in costs between them. More details that relate the methodologic and statistic description are outlined in the design paper published before .Teleconsultation is a medical act and must abide by the Brazilian Medical Code of Ethics (MCE) ,28,29. ACritics of telemedicine approval warn that the possible overuse and careless use of telemedicine could turn doctors into “telemarketing operators”, which could lead to poor quality in appointments, medical errors, and unemployment by reducing the number of face-to-face doctors . AlthougThis whole context evidences the lack of alignment between the federal government, the Brazilian Medical Federal Council, health plan operators, medical associations, and medical professionals, especially concerning teleconsultations. The challenge is how to expand access to medical services mainly to specialists for populations in remote regions, reduce healthcare costs and the displacement of patients, and on the other hand, minimize the fear of damage to the medical profession . Other cThe Brazil Redes program showed the presence of decentralized and disseminated strategies throughout the national territory, with actions in telehealth, focused not only on CNCDs but also other health promotion strategies. The actions of teleophthalmology with identification of diabetic retinopathy based in Mato Grosso ,35 confiThe Regula Mais Brasil project, through the implementation of teleconsultation in the Unified Health System, demonstrated, in an unprecedented way, how strategies that allow the population’s access to different medical specialties can be feasible, in addition to allowing the capillarization of care, through the strategy to take the specialist wherever the patient is and not the other way around. Especially in the period of the SARS-CoV-2 pandemic, this project can maintain access to health care, especially for users with diabetes and sequelae after a stroke, ensuring the maintenance of care .Regarding the teleconsultation diabetes research project, if the efficacy and safety for patients assisted by teleconsultation are confirmed, once the normative issues are resolved by the Federal Council of Medicine (CFM), this will be able to effectively contribute to the promotion access of patients to the public health system, including specialist physicians. Likewise, there may be an increase in the resolvability of the population’s health needs, breaking the geographical barrier that a country with continental dimensions, such as Brazil, imposes on the provision and standardization of health, in addition to the potential savings for health systems, which may be used safely and with quality.This paper has several limitations: one of then is the fact we make a compilation of three different strategies implemented at SUS in a tentative way to delivery medical assistance to the general population. As the initial projects were not designed to analyze the impact on outcomes, for example, the incidence of myocardial infarct or stroke, the authors only could initiate a discussion, showing that e-Health strategies can be performed in a public health system.Although there is evidence in favor of the use of telehealth strategies to deal with CNCDs, in Brazil, due to difficulties in accessing technology in addition to important care gaps and legal impediments, we observe a lack of strategies in this area for health promotion within the scope of the SUS.Therefore, given the above, there is a need to generate reliable scientific evidence of the effectiveness and safety of applicability within the context of regulation and access to the SUS. In this article, the authors demonstrate how specific initiatives in telehealth, through partnerships between the Ministry of Health and Hospitals of Excellence, can foster the development of new research and assistance strategies within the scope of e-Health in Brazil.


Premature ovarian insufficiency (POI) is defined as a decline in ovarian function before the age of 40 and is one of the leading causes of infertility in women. The etiology is complex, and the pathogenesis is not clear. The main treatment is hormone replacement therapy, but a growing body of data confirms that such treatment can increase the risk of endometrial disease and cardiovascular disease. Complementary and alternative medicine (CAM) has been widely used in patients with POI due to its limited adverse reactions and high efficiency. According to literature reports, CAM therapy for POI mainly includes traditional Chinese medicine, acupuncture, psychotherapy, dietary supplements, and exercise therapy. This article reviews the application of CAM in the treatment of POI and attempts to determine the therapeutic effects and the mechanisms behind these effects based on existing clinical and experimental studies in order to provide theoretical support for the treatment of POI. Compared with traditional acupuncture, it has the advantages of no trauma, less pain, and easy operation. TEAS can increase the number of antral follicles, improve basic endocrine indicators, and improve ovarian reserve function in POI patients, and it has a similar treatment effect as artificial cycle treatment . The mecPsychological stress is one of the main causative factors of POI , while, Pseudostellaria, and Rehmannia glutinosa, (2) Curculigo orchioides Gaertn, Epimedium brevicornu Maxim, ginger, and mutton, and (3) medlar, green beans, and Rana dybowskii. All three diets can tonify the liver and kidneys, improve ovarian function, and relieve the clinical symptoms of POI [A Chinese medicated diet is a rational combination of different Chinese drugs taken with food under the guidance of TCM theory and is devised using traditional and modern scientific processing technology. The theory of “medicine and food homology” has been known since ancient times in China, and the medicated diet embodies medicine in food, and it increases not only the efficiency of the medicine but also the nutritive value of food, and it can be used to prevent and cure diseases, build up health, and prolong life , 120. Chs of POI .κB signaling pathway to inhibit immune responses and reduce the risk of immune-induced POI [Vitamin D, a precursor of several lipid-soluble steroidal hormones, is involved in the regulation of the female reproductive system in addition to its well-known role in regulating the calcium-phosphorus balance of the blood and bone tissues. Its receptors are widely distributed in the reproductive tissues, including the ovary , 123. Stuced POI . It has uced POI . In addiuced POI .α-tocopherol as the major form, and it can effectively reverse the adverse effects of oxidative stress on the reproductive system [Vitamin E is a lipid-soluble antioxidant with e system . Increase system –129, ande system . Ma et ae system , and a re system .Vitamin C (ascorbic acid) is an essential nutrient with an antioxidant effect and can reduce the risk of chronic diseases, and it must be consumed regularly to prevent deficiency . An expeExercise is a type of physical activity that uses planned, structured, and repetitive limb activities to improve the function of the body as well as the mental health of women with POI. The application of exercise and psychotherapy in POI patients is of great value and can improve the level of sex hormones and clinical symptoms , 137. WoPOI refers to a decline in ovarian function before the age of 40 and is characterized by menstrual disturbances, infertility, and varying degrees of menopausal symptoms. CAM for POI mainly includes herbal products, acupuncture and moxibustion, psychotherapy, dietary supplements, and exercise therapy. Through these therapies, the levels of sex hormones in POI patients can be improved, menstrual cycles can be resumed, menopausal symptoms can be alleviated, pregnancy rates can be improved, and anxiety and depression can be relieved, thereby improving the quality of life of these patients. In conclusion, the active principle of CAM therapies has a strong scientific foundation, and researchers have shown increased interest in this area of medical treatment. Due to the small sample sizes of most studies, however, it is currently difficult to make clear recommendations for clinical guidance. Larger samples and RCTs are needed in the future to verify the efficacy and safety of CAM for the treatment of POI and to provide new strategies for treating POI.


Philip Ciunkiewicz was not included as an author in the published article. The corrected Author Contributions Statement appears below.KS and PC collected data, extracted features, deployed and evaluated machine learning algorithms, interpreted and visualized results, and drafted the manuscript. MR and PM conceptualized the project and participated in the study design, analysis and interpretation of results, and drafting of the manuscript. RB and SY provided expert guidance throughout the study and interpretation of results. All authors contributed to the article and approved the submitted version4Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada.In the published article, there was an error regarding the affiliation for Philip Ciunkiewicz. They should have The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated


In the original article, there was an error in affiliation 2 as published. Instead of University of the Chinese Academy of Sciences, Beijing, China, it should be University of Chinese Academy of Sciences, Beijing, China.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Policymakers, practitioners, and researchers need a balanced, thoughtful, and analytical resource to meet the challenge of global aging at a rate that’s historically unprecedented. The Journal of Aging & Social Policy (JASP), which was founded in 1989, serves this role by drawing contributions from an international panel of policy analysts and scholars who assume an interdisciplinary perspective in examining and analyzing critical phenomena that affect aging and the development and implementation of programs for elders from a global perspective. Study settings extend beyond the United States to include Europe, the Middle East, Australia, Latin America, Asia, and the Asia-Pacific rim. This presentation will document the scope, content, and focus of JASP, including the rise of international submissions, which now account for approximately half of articles published. Opportunities for publishing in JASP will be discussed; so too will strategies for navigating the peer-review process successfully.


Dear Editor,I began my school life in a white institution thanks to the good socio-economic status achieved by my parents after years of hard working. At the school, I was always the only black girl in the classroom. For this reason, at the age of 6-years, I became aware of the perverse racism presented in our society.However, in my multiethnic and multiracial family environment I was gifted with loving relationships and mutual commitment. For this reason, I developed mechanisms to sustains my ideal of healthy interethnic and interracial relationships.My dual ethnical background (white Christian and black Yoruba) and my dual nationality (Brazil-Nigeria) determined my personal, educational and professional paths. In addition, these were responsible for my entering in medical school at the age of 18, without ever questioning whether that was my place. As a black woman, I occupied and continue to occupy this space under questioning eyes related to my deservingness to be there, intellectual capacity, and under frequent microaggressions from colleagues, professors, and users of the health systems. Since the 1980s, new approaches in the historiography of slavery have made possible more accurate analyses of the Brazilian slave process, which was not enough, however, to overcome the reductionism of the history of blacks to the history of slavery.In the history of Brazil, serious misconceptions, which reduce a human condition to legal condition, were provoked by the synonym between “black” and “slave”. This misunderstanding was fed by researchers who rely on sources produced by foreigners incapable of discriminating between the conditions of enslaved and freed blacks. The latter, associated with tradictions, religion and geographical origin that make up the so-called “cultural racism”.The action of racism is perverse and shows how negatively stereotyped representations of Africans, African descendants, and their religions are related.The notion of race functions from two basic and complementary registers: the biological and the ethno-cultural.The psychosocial effects of racism shape behaviors, thoughts and feelings, on the basis of which discriminators and discriminated are differentiated. The victims, transformed into defendants, and solely responsibles for the suffering imposed on them, are conditioned to feel inferior or subhuman. The damage to psychological health includes anguish, panic, anxiety, insecurity, guilt, self-censorship, rigidity, loneliness, chemical dependencies, and syndromes. The promotion of equity, inclusion and recovery include factors related to socioeconomic and educational indices, and processes of reconstruction of subjectivities.Sistema Único de Saúde -SUS), defends equity in health for the black population, and has as the main guideline the “inclusion of the topics related to Racism and Health of the Black Population in the processes of training and permanent education of health workers and in the exercise of social control in health area.In Brazil, in the health field, the National Policy for Integral Health of the Black Population aims at fighting ethnic-racial discrimination in the Brazilian Public Health System ( Even more concerning are the invisibility of racism as a social determinant of health, the opportunity that is lost to prepare medical professionals for a humanized care that takes into consideration the biopsychosociocultural contexts in which patients are inserted, and the process on how these contexts affect the processes of health, disease, treatment, cure or death.Today, graduated for almost 10 years, I witness the intensification and spread of the Black Lives Matter Movement, which has expanded around the world, and also reached the Brazilian academic elite as a wave of collective awareness about racism. I had the opportunity to talk to medical students about this subject, which, although so necessary in our historical and social context, is still faces serious difficulties of consolidation in the curricula of training courses for health professionals, and seldom appear in the medical school curriculum.Clearly, the issue of racism will not be completely solved through medical education adequate to the Brazilian reality, but for the first time, I noticed a promising concern of young black and white future physicians engaged with racial/ethnic inequities in health area. I witness, for the first time in medicine, the impulse for the creation of strategies capable of reducing or even annullate ethno-racial inequalities in this country.Currently, more than ever, the time has come for higher education health institutions to act in a concrete and precise manner in the implementation of disciplines, courses, and undergraduate, and graduate programs of sufficient quality to deal effectively with the theme of Afro-descendant citizenship. are useful for the definition of strategies and tactics to achieve the desired goal.To achieve this goal, it is necessary to create, in the health field, a space for qualified debates on the African presence in the multicultural and multiracial composition of the Brazilian society. Some recommendations by Monteiro establishes five thematic axes to be considered in the continuing education of health professionals: racism, African and Afro-Brazilian history and culture, health of the black population, the body, and affirmative action practices. The articulation of themes and sub-themes around these axes results in a complex network of knowledge. Many of these knowledge come from ethnomedicine, an indispensable field for the dialogue between medicine and anthropology, between health and spirituality/religion, and between contemporary Western medicine and Afro-diasporic health care practices.Our first task is to identify the health needs and potentialities of the black population and, to accomplish this, it is necessary to articulate knowledge and methods from several areas of knowledge. For pedagogical purposes, MonteiroTotally aware of the history of humiliations experienced by black people, and due to my special condition as a black physician and of the commitments and responsibilities associated with my profession, I am trying to put my strength and my will at the service of justice and peace in human relations, and to the service of the health and well-being of the people with whom I share steps on my journey.


Urban rail transit is an important transportation infrastructure that mitigates the congestion of the central city and realizes compact city space development. However, the literature on the spatiotemporal coupling of urbanization and rail transit from the urban scale and its influencing factors is still uncommon. Taking Beijing as an example, based on the theory of coupling coordination, we have constructed a comprehensive indicator system for regional urbanization (hereafter RU)  and rail transit (hereafter RT). On this basis, we use the entropy method, coupling coordination degree model, and spatial autocorrelation analysis method to explore the spatiotemporal characteristics of the overall and pairwise coupling coordination between population, economy, spatial urbanization, and rail transit. Finally, we analyze the spatial correlation and standard deviational ellipse analysis of the coupling coordination degree between RU and RT. The results indicate the following: (1) In addition to population urbanization, the other urbanization indicators and the RT level all show a downward–rising–falling trend from 2006 to 2017, among which the level of economic urbanization is the highest. The degree of coupling coordination between RU and RT is unbalanced development and shows a trend of first rising and then falling. (2) The degree of coupling coordination between RU and RT presents an imbalanced distribution in various regions, and the coupling coordination degree in the central urban areas is significantly higher than that in the outer suburbs. (3) From 2006 to 2017, the spatial correlation of the coupling coordination degree between the various systems has a similar changing trend. Moreover, the distribution of the spatial agglomeration points of the coupling coordination degree between RU and the RT is similar, showing a decreasing trend from the central urban area to the surrounding urban area. Therefore, relevant departments can rationally plan the construction of urban rail transit according to the coordination relationship between RU and RT and the spatial aggregation degree to realize the benign and sustainable development between urban especially suburbanization and rail transit. In recent years, with the rapid development of the economy, urbanization and motorization have further accelerated, the urban population continues to increase, and the scope of urban scale is expanding. As of the end of 2020, China’s urbanization level exceeded 60%. However, with the speed of urbanization, it is a series of urban issues, such as road traffic congestion, unreasonable urban spatial structure, and waste of resources. The traffic problems of the city have always existed, but urban traffic contradictions are becoming more serious, and the unreasonable structural defects in the large urban spatial layout are more fully sufficient. For example, according to data statistics, Beijing’s annual traffic congestion is direct; indirect economic losses reaches tens of thousands of RMB, which probably accounts for 5% of Beijing’s GDP. The problems caused by air quality and friction disputes have also affected the quality of life of thousands of people, which has become a social problem that cannot be ignored. To support urban development and construction as well as the convenient travel of residents, many cities have begun to plan rail transit networks. As an important part of the urban public transportation system, urban rail transit is an important part of its shipping, speed, convenience, and punctuality, which solves one of the important tools of the city mayor. At the same time, the economic role of rail transit is also very significant, with the rail transit-oriented urban development model being an important trend in many world cities. Vigorously developing fast, environmentally friendly, economical urban rail transit has become the key to accelerating urbanization processes and resolving traffic contradictions in major cities. According to the data released by the Ministry of Transport, as of 31 December 2020, there were 44 cities in China to operate urban rail transit, which accounts for 6.29% of China’s total cities. This also depends to some extent on China’s urban rail transit systems still needing further rapid development. Among them, the planning and construction of the comprehensive transportation hub are strengthened, and the urban rail transit is axial, thereby achieving a comprehensive improvement of urban traffic congestion, improving working efficiency and the quality of urban life.On 19 January 2021, the National Development and Reform Commission of China held a press conference, indicating that China will focus on “two new” and shortboard weaknesses. It stated that China should speed up the construction of rail transit, gradually improve the urban rail transit network, and strive to establish a modern urban comprehensive transportation system with public transportation network as the main body and rapid rail transit as the backbone, which is in line with the process of urban development. Within the city, there is also a significant uncoordinated issue between rail transit and regional urbanization. For example, the urban rail construction in the central city is perfect, while in the outer suburbs, it is relatively deficient. In 2000, only Beijing, Tianjin, Shanghai, and Guangzhou had urban rail transit lines. The urban rail lines are mainly distributed in the city center, and there are relatively few in the outer suburbs. For example, the urban rail lines in Beijing only cover 11 administrative regions, and there are at least six urban rail lines in the central city, while in the outer suburbs such as Huairou, there are fewer than two. Therefore, in the process of urban construction, the coordinated development of urbanization and urban rail in different regions is important.The coordination and sustainability of urbanization have always been the focus of scholars. In the process of urbanization development, rail transit construction and urbanization development are mutually promoting, so the coordinated development between them is important. The existing research can be divided into two categories: qualitative research and quantitative research. For the former, scholars mainly take the perspective of whether the rail line optimization, rail station optimization, and comprehensive hub transfer mode are coordinated with urbanization. In addition, quantitative analysis mainly uses the quadrant graph, coupling degree model, Theil coefficient model, and spatial analysis method to analyze the coordination between rail transit and urbanization-related factors.Rail transit planning has gradually become an important part of urban construction, and rail transit construction has a significant promoting effect on urban economic growth . FirstlyPrevious studies mainly focused on the influence of rail transit construction planning on urbanization development, but they did not analyze and study from the direction of coordination between the two. Urbanization development is a complex process that we need to analyze from different angles. This paper studies the coordination between rail transit and urbanization and the related influencing factors from three perspectives of economic urbanization, population urbanization, and spatial urbanization, so as to provide some theoretical support for the healthy development of urban track and urbanization.Firstly, scholars have carried out multi-dimensional studies on the relationship between rail transit and urbanization development. For example, Hou has analyzed the coordination relationship between rail transit and land use based on multivariate data through data envelopment analysis (DEA) and the clustering method, finding that the relationship between rail transit capacity and land use of rail transit stations with high population density is unbalanced . Liu hasSecondly, scholars also have studied the factors influencing urbanization from the aspects of urban functional mixing degree, population, land, and so on. Based on information entropy and coupling coordination degree, the coordination relationship between urban function mixing state and urbanization development level and its influencing factors are analyzed from the perspective of urban spatial structure development . Cao hasMost of the existing studies focus on one aspect of the system elements in the process of urbanization from a certain perspective, and all of them are from the perspective of the city as a whole. Few studies have quantified and measured the coordinated development relationship between urban orbit and urbanization from the perspectives of economic urbanization, population urbanization, and spatial urbanization by taking different regions of a city as research units. The specific synchronization research comparison can be shown in To sum up, previous studies on the relationship between rail transit and urbanization mainly focus on the degree of mutual influence and promoting effect, and the coupling relationship between rail transit and urban population, space, and industrial structure. However, most of the previous studies have studied the causes of the imbalance between rail transit and urbanization development in different cities from the perspective of the city as a whole, and studies on the factors of the imbalance between rail transit and urbanization development from the perspective of urban internal regions remain rare. Compared with similar previous studies, our innovation is mainly reflected in the following two aspects. First, based on the coupling coordination model, we measure the coordination relationship among the economic, spatial, and population urbanization and rail transit as a whole, as well as pairwise. Second, we explore the internal reasons that affect the unbalanced development of urban regions by looking at the coordination relationship between rail transit and the urbanization level. Based on the data of rail transit and urbanization development level from 2006 to 2017, we construct a comprehensive indicator system of regional urbanization  and rail transit, and we calculate the coupling coordination degree between the urbanization and rail transit of each region in Beijing. Finally, based on the spatial autocorrelation model, the associated characteristics of the coupling coordination in space are analyzed. According to the research results, relevant departments can make corresponding decisions on urban rail line planning, reasonably plan the urban space layout, and provide theoretical support for urban optimization management and sustainable development.Beijing has a certain representation as China’s political, economic, technology, and transportation center. Taking Beijing as an example, we analyze the coordination relationship between regional urbanization and rail transit. With the rapid development of rail transit in China, the subway is not only the main form of urban rail transit but also the focus of urban rail transit construction in the future. As of January 2017, Beijing has a total of 19 subway lines covering 11 municipal districts, mainly including Dongcheng, Xicheng, Haidian, Chaoyang, Fengtai, Shijingshan, Changping, Fangshan, Tongzhou, Shunyi, and Daxing. Based on the actual operation of the Beijing subway, the research area of this paper is shown in Referring to the indicators of urbanization and rail transit at home and abroad, the indicator system of this paper mainly includes two aspects: regional urbanization and rail transit. According to the relevant regulations and description of urbanization by the Institute of Urban Environment, Chinese Academy of Sciences, urbanization is a multidimensional concept, including population urbanization, economic urbanization, and spatial urbanization. Since urbanization is a complex process, demography defines urbanization as the process of rural population transforming into urban population, economics defines urbanization from the perspective of economic model and mode of production, and geography defines urbanization as the process of rural areas or natural areas transforming into urban areas. Therefore, we select the corresponding indicator data from three aspects of population urbanization, economic urbanization, and spatial urbanization to measure the RU. Firstly, we construct the indicator system of regional urbanization from the three criteria layers of population urbanization, economic urbanization, and spatial urbanization . SecondlThe coupling degree refers to the phenomenon of two (or more) systems that affect each other by various interactions, including the promotion system from disordered ordered processes, which describes the interaction between systems or elements. The coupling coordination refers to the high and low level of the interaction between the two systems or the multi-system, as well as the uniformity of the benign association between the various elements within the system, indicating the tendency between the system from disordered to order. To study the coordination relationship between regional urbanization and urban orbit, we selected four systems with population urbanization, economic urbanization, spatial urbanization, and rail transit. Then, based on the coupling coordination model, we measure the coupling degree and coupling coordination between the four systems, and the specific calculation steps are as follows:Step 1: Measure the levels of each system. We integrate various types of evaluation methods, considering the lack of objective basis in the determination of the weight in the subjective empowerment evaluation method. In some cases, the subjective judgment may have a certain deviation. As an objective evaluation method, the entropy method can not only avoid the subjective judgment of the researcher but also solve the information overlap problems between multiple indicators ,46. Ther(1) Standardized processing. This type of processing is used to eliminate the inconsistency of the measurement units of each indicator, the size of the measurement units, and the direction of the positive and negative direction. Therefore, the data are standardized before calculating the comprehensive indicator, we homogenized the indicators of different qualities, and their value ranges are . Standardization of the forward indicators and negative indicators is shown in Equations (1) and (2), respectively.Positive indicator:Negative indicator:(2) Measure the level of each system. Firstly, we calculate the information entropy Here, Here, Step 2: Calculate the coupling degree between urbanization and urban orbit in region To further explore the coupling relationship between population urbanization, economic urbanization, spatial urbanization, and rail transit in region To judge the coupling degree of the three systems or two systems, the coupling degree is divided into four levels based on previous research results, as shown in Step 3: Calculate the coupling coordination degree between RU and RT in the region terature ,45, eachSimilarly, there are pairwise coupling coordination relationships among population urbanization, economic urbanization, spatial urbanization, and rail transit. The calculation formula is shown in Equation (8):Here, terature ,45, the The classification is based on the degree of coupling coordination, and the specific classification criteria are shown in The relation , and furFor If By calculating the At the same time, there are corresponding standardized statistics θ, the standard deviation of the long axis, the standard deviation of the short axis, and the center point. Among them, the long axis represents the direction of the data distribution, the short axis represents the range and dispersion of the data distribution, and the center point represents the center of gravity of the space element layout. The standard deviational ellipse method can identify the direction and distribution trend of data. We analyze the spatial evolution of the coupling coordination between RU and RT, which can understand the evolution of coordination between urbanization and rail transit. The calculation steps of the standard deviational ellipse method are as follows.The standard deviational ellipse method proposed by Professor Lefever in 1926 is one of the classical methods to analyze the directional characteristics of spatial distribution. This model takes the mean of x and y coordinates of all elements to calculate the mean center, which is taken as the starting point. Then, it calculates the standard deviation of x and y coordinates to define the axis of the ellipse containing the distribution of all elements . The calStep 1. Determine the ellipse center :Step 3. Determine the length of the elliptic length axis We use the standard deviational ellipse tool provided by ArcGIS  to conduct standard deviational ellipse analysis on the coupling coordination degree between RU and RT and the spatial aggregation degree of the coupling coordination degree. The output size was selected as “one standard deviation ellipse surface” (covering the point element set containing 68%) . The staUrban rail transit is the key to promoting urban economic development, optimizing the urban spatial structure, and realizing sustainable urban development. At the same time, with the continuous acceleration of urbanization, the construction of urban rail transit is also constantly improving. According to Equation (4), we have obtained the levels of population urbanization (PU), economic urbanization (EU), spatial urbanization (SU), and rail transit (RT), as shown in On the whole, from 2006 to 2017, except for PU, the changing trend of other urbanization indicators and the level of RT is consistent, which shows a downward trend from 2006 to 2008, a relatively stable rise from 2008 to 2015, and a downward trend from 2015 to 2017. In contrast, the level of PU has the highest value in 2010 but presents continuous decreasing trends from 2010 to 2017. The reasons mainly include the following three points: First, China was affected by the global financial crisis in 2008, and the economic development of Beijing showed a downward trend from 2006 to 2008. However, the 2008 Beijing Olympic Games promoted the city’s urban construction and economic development, resulting in a rising trend of urbanization indicators in Beijing from 2008 to 2015. Second, before 2008, Beijing’s urban rail construction was not perfect. In 2008, the mileage of Beijing’s rail transit reached 200 km, and 26 fast links between the new urban area and the city center, and between the city center and the suburbs were built. Therefore, urban rail transit has been on the rise since 2008. However, there has been no further development of the urban track since 2015. Third, with the removal of non-capital functions from Beijing and the construction of an “advanced and sophisticated” economic structure, employment in some traditional labor-intensive industries has decreased. According to the Blue Book of Beijing Population, Beijing’s permanent population is on the decline. For example, the number of permanent migrant residents in 2016 and 2017 dropped by 1.84 percent and 1.63 percent, respectively, compared with the previous year.It can also be seen from According to Equations (7) and (8), we can obtain the distribution of coupling coordination degree between RU and RT, as shown in According to Equations (5) and (6), the coupling relationship between each system is obtained, and the results are shown in As can be seen from From According to the spatial evolution pattern of the standard deviational ellipse of the coupling coordination degree between RU and RT in According to Equation (8), we obtain the pairwise coupling coordination degree of PT, ET, and ST and make spatial visualization with ArcGIS. The results are shown in On the whole, the pairwise coupling coordination relationships have a significant regional imbalance, which is mainly reflected by the continuous decrease from the central city to the outer suburbs. In addition, from 2006 to 2017, the coupling coordination degree of each region shows a trend of increasing first and then decreasing. The standard ellipse of the coupling coordination degree has no obvious change, which is mainly concentrated in the central urban area, Changping, and Shunyi. This indicates to some extent that the central urban area, Changping, and Shunyi are the main areas of coordinated development between urbanization and rail transit, and there are obvious differences in the coordination relations among different regions.From the perspective of each region, except ET, the pairwise coupling coordination relationship of PT and ST in each region is basically in a state of disorder, and the coordination relationship in the outer suburbs is almost in a state of extreme disorder or serious disorder. Firstly, the urban rail in the outer suburbs is built late, and the improvement is not as good as that in the central urban. According to data, the coverage rate of 750 m rail transit stations in the central urban reaches more than 90%, while that in Huairou and the other outer suburbs is not. Secondly, the permanent population of the central urban area has always been much higher than that of the outer suburbs. Thirdly, the construction of spatial facilities in Beijing has always been in a state of regional imbalance. For example, the spatial urbanization level of the central urban area is about 1.44 times that of the outer urban area. As can be seen from The distribution of spatial elements is mainly divided into three modes: agglomeration, dispersion, and enrichment. To further study the spatial distribution pattern and evolution law of On the whole, from 2006 to 2017, the spatial correlation of the coupling coordination degree among all systems shows a similar trend, which decreased first and then increased. In addition, we can find that except for ST, the From To further understand the spatial aggregation between the pairwise coupling coordination degrees, we use ArcGIS to carry out regional visualization, as shown in From the perspective of each region, Dongcheng, Xicheng, Haidian, and Shijingshan are high-value dispersion areas and high-value clustering areas, which belong to the region with a high coupling coordination degree and agglomeration of urbanization and rail transit. However, the coupling coordination degree of Chaoyang, Fengtai, Daxing, and Tongzhou are within the general area; Changping, Shunyi, and Fangshan are the low-value dispersion areas and low-value clustering areas of coupling coordination degree. This regional imbalance between urbanization and rail transit is mainly because the center urban development speed is higher than that in the outer suburbs. For example, the number of subway lines and subway stations in the central urban area is about 3.23 times that in the outer urban area, and the GDP of the central urban area is about 3.32 times that in the outer urban.According to Equations (11) and (12), we can get the spatiotemporal distribution of high–low value clustering points with different pairwise coupling coordination degrees, as shown in Overall, from 2006 to 2017, the high-value dispersion and clustering areas of PT and ST are increased from four to six, and the high-value dispersion and clustering areas of ET are four and five, which means that the coupling coordination degree of rail transit and urbanization has a significant regional imbalance.In various regions, Haidian, Dongcheng, Xicheng, and Shijingshan are high-value clustering and dispersion areas, which are the areas with a high degree of coupling coordination of RU and RT. Daxing, Chaoyang, Fengtai, and Tongzhou are general areas of coupling coordination degree, Shunyi, Changping, and Fangshan are low-value dispersion and clustering areas of coupling coordination degree. This regional imbalance results from the following: First, the urban rail construction in the central urban area is perfect, while the rail construction in the outer suburbs is relatively backward. By 2018, a total of 22 subway lines had been opened in Beijing, while there were only two subway lines to Fangshan. Second, the urbanization development level of the central urban area is significantly higher than that of the outer suburbs. For example, the GDP and per-capita disposable income of the central urban area is about 1.62 times and 1.12 times that of the outer suburbs.As the standard ellipse spatial evolution distribution of the coupling coordination between RT and RU  shows a consistent trend of change, we take the ellipse spatial evolution distribution of the overall coupling coordination as an example for analysis and use ArcGIS for visualization, as shown in According to the standard deviation ellipse spatial evolution distribution of coordination degree between RT and RU, the coordination degree of RT and RU generally presents a northwest to southeast evolution pattern from 2006 to 2017, and the distribution area is mainly in the six districts . It can be seen that the outer suburbs of Beijing will become the main body of improving the coordination between RT and RU.From From 2006 to 2017, the ellipse center shows a trend of developing from northwest to southeast, and the distribution area is mainly concentrated in the central urban area. Specifically, the ellipse coverage area is also shrinking, and the distribution center and coverage area of the coordinated degree of RT and RU are gradually spreading to the southeast. In terms of spatial distribution, Dongcheng, Xicheng, Haidian, Chaoyang, Shijingshan, and Fengtai have the highest coordination degree between RT and RU. This is because from 2006 to 2017, the coordination degree of RT and RU in this region is the highest, and the spatial pattern evolution characteristics also show a relatively unstable trend, which is manifested as northwest to southeast. Meanwhile, from 2006 to 2017, Changping, Shunyi, Fangshan, Tongzhou, and Daxing are the low-value distribution areas of the coordination degree between RT and RU, so they are always outside the coverage range of the standard deviation ellipse. This is because these regions are an exurb urban area, the urban rail opening is late, and the rail line is relatively imperfect, so the coordination degree of RT and RU in these regions is low, so the coverage of the standard deviation ellipse is relatively small.Compared with previous studies, our innovations mainly include the following three aspects. Firstly, based on the coupling coordination degree model and spatial autocorrelation model, we study and analyze the coordination relationship between rail transit and urbanization . Previous studies mainly focused on the relationship between urban spatial structure and rail transit, or the influence of population, land, and other factors on urbanization, but there were few studies on the relationship between rail transit and population, economy, and spatial urbanization. From the perspectives of population urbanization, economic urbanization, and spatial urbanization, we study the coordination relationship between them and rail transit respectively, and we analyze the causes of imbalance among different regions. Finally, based on the spatial autocorrelation model and standard deviation ellipse model, we study and analyze the spatial correlation and spatial evolution characteristic of coupling coordination degree among rail transit, population urbanization, economy urbanization, and spatial urbanization, thus further understanding the imbalance of rail transit and urbanization in different regions.Secondly, based on the urbanization and rail transit data of 11 administrative regions of Beijing from 2006 to 2017, we measure the coupling coordination degree and spatial correlation between rail transit and urbanization in different regions. Most of the previous studies on urbanization have studied the causes of imbalanced urbanization development among different cities from the perspective of the city as a whole. Few studies have analyzed the factors affecting the imbalance of urbanization and the coordination relationship between rail transit and urbanization from the perspective of the urban inner region. The results show that the coupling coordination degree between urbanization and rail transit presents an imbalanced distribution in various regions, and the coupling coordination degree in the central city is significantly higher than that in the outer suburbs. By studying the coupling coordination between rail transit and urbanization in different regions, we find the relationship between rail transit and urbanization. For example, the coupling coordination degree of suburbs is low, so it provides theoretical guidance for the suburbanization of rail transit, the development of commuter rail, and the development of suburban railway.Thirdly, we explore the internal causes of the imbalance of urban regional development from the coordination between rail transit and urbanization. From the perspective of time, different urbanization indicators and rail transit are in different trends. For example, from 2006 to 2017, the level of economic urbanization, spatial urbanization, and rail transit all showed a downward–upward–down trend, and the level of economic urbanization is the highest. From the perspective of space, the coupling coordination degree between rail transit and urbanization in different areas of the city is in an unbalanced state, but the spatial correlation of coupling coordination degree between each system has a similar trend. The coupling coordination degree of the central urban area is significantly higher than that of the outer suburbs, and the clustering points of high and low values are decreasing from the central urban area to the surrounding urban area. Therefore, it is necessary to strengthen the construction of suburban rail transit, develop the subcenter of the city, build a new suburbanization development model of urban space structure, and guide the orderly and compact expansion of urban space to achieve sustainable development of the city.The coordination relationship between rail transit and urbanization development level is related to the sustainable development of the whole city, among which the imbalanced development of urban regions has gradually attracted attention. Taking Beijing as an example, we use the data of rail transit and urbanization from 2006 to 2017 to build a coupling coordination degree model. Finally, based on the spatial autocorrelation model, we analyze the spatial aggregation of coupling coordination degree. The specific conclusions are as follows:Firstly, except for population urbanization, economic urbanization, spatial urbanization, and the rail transit system level have the same trend, and economic urbanization is at the highest level. On the whole, the coupling coordination degree between RU and RT is in a state of disorder, and the coupling coordination degree between various systems presents a consistent trend of change. The coupling coordination degree between EU and RT is at the highest level, while the coupling coordination degree between SU and RT is at the lowest level.Secondly, the coupling coordination degree between RU and RT is imbalanced in each region, and the coupling coordination degree in the central urban area is significantly higher than that in the outer suburbs. On the whole, from 2006 to 2014, there is no significant change in the overall coupling coordination degree in the central urban area, but the coupling coordination degree in the outer suburbs  shows an obvious upward trend. In addition, the degree of coupling coordination in all regions significantly decreases in 2017. In addition, from the perspective of the spatial evolution pattern of the standard deviational ellipse, the distribution of the overall coupling coordination degree between 2006 and 2017 is consistent, mainly in the central urban area, Changping, and Shunyi.Finally, on the whole, from 2006 to 2017, the coupling coordination degree between RU and RT has a similar trend in spatial correlation, and the Moran’s I values show a trend of decreasing first and then increasing. The high-value and low-value aggregation points of coupling coordination degree among the population, economy, and spatial urbanization and rail transit are similar, which shows a decreasing trend from the central urban to suburban areas.In summary, it is found that the coordination relationship between urbanization and rail transit has an obvious regional imbalance. Relevant departments can formulate corresponding urban development planning strategies and urban transportation policies according to the urbanization development level of different regions and the coupling coordination degree and spatial aggregation degree between RU and RT to realize the healthy, green, and sustainable development of urban transportation.Our research has some limitations at present. Firstly, the selection of evaluation indicators for RT and RU mainly relies on the previous literature indicator system and the existing statistical data of Beijing. Therefore, our selection of the indicators of RU and RT is not comprehensive; we need more open source data to support the selection of other indicators: for example, rail transit lines in different areas of the range, a single line of rail passenger flow data and residents’ commuting times, the total number of passengers, the train service quantity and train departure frequency, and so on. Secondly, limited by the availability of data, the multi-source data used in this paper are not perfect, such as the number of passengers in each rail line. Moreover, some social factors, such as local policies and data openness, make it difficult to obtain and quantify some data. As the city is a complex system, the data of the urban development level are formed by the interaction of complex data of multiple dimensions, which has the characteristics of multiple heterogeneity. Therefore, this paper only studies the coordination relationship between RT and RU from 2006 to 2017, and it does not expand the research period, which is not conducive to a more accurate and comprehensive grasp of the interaction between urbanization and urban rail and its change law. In the future, we can try to make innovations in the research factors, use multi-source data to supplement the research on the relationship between urbanization development level and rail transit, and analyze the factors affecting urbanization development and urban transportation from multiple dimensions and dividing scales. In addition, the influence of different public transport systems on urbanization is also worth further exploration.


The Donald P. Kent Award lecture will feature an address by the 2020 Kent Award recipient, David Ekerdt, PhD, FGSA, of the University of Kansas. The Kent Award is given annually to a member of The Gerontological Society of America who best exemplifies the highest standards of professional leadership in gerontology through teaching, service, and interpretation of gerontology to the larger society. The Robert W. Kleemeier Award lecture will feature an address by the 2020 Kleemeier Award recipient, Matt Kaeberlein, PhD, FGSA, of the University of Washington. The Kleemeier Award is given annually to a member of The Gerontological Society of America in recognition for outstanding research in the field of gerontology.