This article proceeds with a discussion of the causes and mechanisms of an elevation in cardiac troponins in pathological conditions not associated with acute myocardial infarction. The second part of the article discusses the causes and mechanisms of cardiac troponins elevation in diabetes mellitus, arterial hypertension, hereditary cardiomyopathies, cardiac arrhythmias , acute aortic dissection, and diseases of the central nervous system . The final chapter of this article discusses in detail the false-positive causes and mechanisms of elevated cardiac troponins. D< 0.001) . Another< 0.001) .A study conducted by Yiu K. and colleagues proved that asymptomatic myocardial injury detected by high-sensitive cardiac troponin I (hs-cTnI) is associated with increased arterial stiffness . The forAnother mechanism that may lead to an increase in the concentration of hs-cTnT and hs-cTnI in the blood serum in diabetes mellitus is the disturbed elimination of protein molecules of cardiac troponins from the blood serum. Kidney damage (nephropathy) is a frequent complication of diabetes mellitus and, without optimal treatment, further leads to the formation of chronic kidney disease (CKD) . CKD is Alongside the determination of highly sensitive troponins (hs-cTnT and hs-cTnI) in blood serum, it is possible to study them in other biological fluids; in particular, in the patients’ oral fluid ,28,29,30All the above allows distinguishing the following mechanisms for the elevation in cardiac troponins in diabetes mellitus: (1) myocardial ischemia caused by an imbalance between oxygen demand and delivery; (2) myocardial hypertrophy caused by an increase in the stiffness of the arterial wall; and (3) a decrease in the elimination of cardiac troponin molecules from the blood serum, due to a decrease in GFR in CKD. Since elevated serum and urine levels of cardiac troponins in diabetes mellitus are associated with the risk of adverse outcomes, they can be considered useful prognostic biomarkers to optimize the management of patients with diabetes mellitus.Arterial hypertension (AH) is a significant risk factor for the development of CVD, which has a tremendous impact on the quality of life and mortality of the population on our planet. Thus, according to a large study by Lawes et al., hypertension causes 47% of cases of ischemic heart disease/AMI and 54% of strokes annually . The prep < 0.001) [Several studies have noted that arterial hypertension is a significant cause of elevated cardiac troponins in patients without AMI ,40,41,42< 0.001) .Modern high-sensitive immunoassays allow the detection of asymptomatic myocardial damage at the first stages of hypertension and the identification of individuals at high risk of developing this pathology. Thus, in a recent large study, elevated serum hs-cTnT levels in healthy patients were associated with a higher risk of hypertension in the long term. In addition, elevated hs-cTnT concentrations (≥14 ng/L) in healthy patients without obvious signs of CVD were associated with the risk of developing left ventricular hypertrophy during the 6-year follow-up period  . Thus, hAccording to a study by Pervan et al. , urinaryThe mechanisms of the elevation in cardiac troponins in hypertension have not been finally defined and further research is required to clarify them. Some studies distinguish the following mechanisms of increasing cardiac troponins in hypertension:(1) Activation of the processes of apoptosis of cardiomyocytes, caused by an increase in the load on the myocardium and its stretching ,48, or a(2) Myocardial hypertrophy, conditioned by exposure to high blood pressure. The evidence for this mechanism is proved by studies that revealed the association of hypertrophy and elevated serum levels of cardiac troponins , as well(3) The effect of blood pressure on the processes of elimination of cardiac troponins from blood serum may play a role in the elevation of the urinary levels of cardiac troponins . So, witMolecules of cardiac troponins in cardiomyopathies have long been of considerable interest to many specialists. Thus, the widespread attention of genetic and pathophysiology scientists to the protein molecules of troponins is due to the mutations in the genes encoding these proteins that disrupt the functioning of troponins and the entire myocardium contractile apparatus, which manifests itself in the form of hereditary cardiomyopathies ,52,53,54p < 0.0001) increased, the shortening fraction (p < 0.0004) decreased, and the left atrial size dimension was enlarged (p < 0.0001). Heart failure developed in 18 patients with elevated levels of creatine kinase-MB and only in four patients with normal concentrations of creatine kinase-MB. In addition, among patients with elevated levels of creatine kinase-MB, mortality from heart failure was significantly higher among patients with elevated levels of creatine kinase-MB [Japanese researchers, guided by Hamada, observed 77 patients with hypertrophic cardiomyopathy (HCM) for 20 years. The concentrations of creatine kinase-MB, lactate dehydrogenase-1, troponin T, and myosin light chains were measured in all patients. An increase in the troponin T levels was noted in only three patients and creatine kinase-MB levels in 64% of patients. The concentrations of lactate dehydrogenase-1 and myosin light chains were not significantly elevated compared with the control group. During the observation period, it was noted that in patients with increased concentrations of creatine kinase-MB, the left ventricular end-diastolic dimension  in patients with HCM (n = 183). At the same time, increased levels of hs-cTnT were detected in 54% of patients . ComparaHładij et al. in their study found increased levels of hs-cTnT in 26 of 51 patients with HCM. Subsequently, the authors compared echocardiographic parameters used as risk factors for sudden cardiac death (SCD) among two groups of patients: (1) patients with elevated hs-cTnT levels (n = 26); and (2) patients with normal hs-cTnT levels (n = 25). Elevated hs-cTnT levels were found to be associated with all three echocardiographic parameters (risk factors for SCD) , left atrial diameter) recommended by the European Society of Cardiology for assessing the prognosis of HCM patients .Ho and colleagues studied the possibility of using laboratory biomarkers to identify individuals with overt HCM and those with asymptomatic HCM and sarcomere gene mutations preceding the development of HCM. Researchers measured cardiomarkers in patients with overt hypertrophic cardiomyopathy (n = 76), individuals with sarcomeric gene mutations  (n = 50), and a genotype-negative control group (n = 41) at rest and after challenge . Patients with overt hypertrophic cardiomyopathy had significantly higher levels of N-terminal natriuretic peptide and hs-TnI both at rest and in response to exercise. However, there was no significant difference in the concentrations of these biomarkers between patients with preclinical HCM and control patients, both at rest and challenge tests with maximum exercise .The mechanisms of elevation of cardiac troponins in HCM are not fully understood. The most likely is the input of the following mechanisms ,57,58,59Elevated levels of cardiac troponins are often detected in cardiac arrhythmias , which should be considered in differential diagnostics. Zellweger et al. described four clinical cases of elevated troponin I with supraventricular tachyarrhythmia (heart rate (HR) = 170–250) with no coronary artery disease indications. In addition, three out of four patients showed an increase in the levels of total creatine kinase and creatine kinase-MB, which additionally indicates non-AMI-related damage to cardiomyocytes. The relationship between heart rate, tachycardia duration, and troponin I levels was not observed in this study .p = 0.02) [In a larger study, Chow et al. analyzed the case histories of 78 patients with supraventricular tachycardia. The concentration of troponin I was above the 99th percentile (0.06 ng/mL) in 29 patients (37.2%), while the overall range of elevated values was 0.06–7.78 ng/mL. Elevated troponin I level in multivariate analysis were associated with an increased risk of adverse events   . Thus, tXue et al. described two clinical cases of increased cardiac troponins I in patients with paroxysmal supraventricular tachycardia. Both patients were admitted to the emergency room with chest pain complaints. The concentration of troponin I on admission was 0.09 ng/mL for the first and 0.16 ng/mL for the second patient . After a few hours, the troponin concentrations increased to 0.52 and 2.28, respectively, but the results of the electrocardiography and echocardiograms showed no significant abnormalities. However, an initially wrong ACS diagnosis was made. Within a week, both underwent coronary angiography, which showed absolutely intact coronary vessels. According to subsequent data, the patients were nevertheless given the correct diagnosis and passed radiofrequency ablation, after which both patients were safely discharged . The finp < 0.001). Multivariate Cox regression analysis showed that troponin elevations were an independent predictor of all-cause death  in addition to age and prior heart failure [In a recent study by Gonzalez-Del-Hoyo et al., troponin I was elevated in 73 (32.9%) of 222 patients. Patients with high troponin levels were older. When assessing the long-term prognosis, five-year mortality was higher in the group of patients with elevated troponin . Similarly, there was a significant correlation between the maximum heart rate during tachyarrhythmia and increased concentrations of troponin T  [The exact mechanisms of the release of cardiac troponins from cardiomyocytes in supraventricular tachycardia are undefined. As suggested by most authors, the reason for the release of troponins is associated with an imbalance between myocardial oxygen demand and the capability of oxygen delivery by the coronary arteries. As per the anatomical and physiological characteristics, the myocardium blood supply occurs in the relaxation phase (diastole). During systole, the opened three leaflets of the aortal valve occupy the three spaces of the Valsalva sinuses . In the area of two of them are the openings of the coronary vessels, which are thereby closed. In the diastolic phase, the aortal valve closes, and the lumen of the coronary arteries opens, into which blood rushes. Thus, conditioned by increased demand for oxygen and nutrients in tachycardia, due to the shortening of diastole, blood flow through the coronary arteries is reduced, which cannot fully meet the demand of the myocardium. Evidence for the involvement of this mechanism in increasing serum troponin levels is presented in a clinical study conducted by Ben Yedder et al. The researchers found increased troponin T levels in 24 of 73 subjects (32.9%) with supraventricular tachycardia. In this case, serious anomalies of the coronary arteries were excluded by coronary angiography and stress testing. It was found that in troponin-positive patients, the heart rate was significantly higher than in troponin-negative patients  ,68. Furt= 0.001) . Thus, i= 0.001) ,61,62,63= 0.001) ,65,66,67Thus, an increase in cardiac troponins in the blood serum in supraventricular tachycardia in some cases complicates the differential diagnosis of myocardial infarction and often leads to an erroneous diagnosis. On the other hand, the use of troponin tests has a high predictive value and can be used in clinical practice to manage patients with supraventricular tachycardia.There are few studies to measure the troponin levels in acute aortic dissection. The most comprehensive meta-analysis was conducted by Vrsalovic et al., reviewing four studies and 496 patients with acute aortic dissection. Elevated troponin was found in 26.8% and ranged from 23 to 33%. Elevated troponin levels were significantly associated with an increased risk of short-term death : 40.6% of patients with acute aortic dissection and elevated troponin levels died, compared with 20.9% of negative troponin patients .p = 0.024). In the group of the deceased, hs-TnT concentrations were significantly higher than in the group of survivors . Hs-TnT values ≥ 0.042 ng/mL predicted short-term mortality in hospital with a sensitivity of 70.8% and a specificity of 76.4% [Li et al. first identified highly sensitive troponin T (hs-TnT) in patients with acute aortic dissection. Elevated hs-TnT levels (≥0.014 ng/mL) were observed in more than half of the patients (61.2%) . Multivaof 76.4% .p = 0.46) and in the groups with and without coronary artery lesions according to coronary angiography (p = 0.54), which indicates a non-coronarogenic (not associated with ischemia) increase in troponins [Pourafkari et al. studied electrocardiographic and angiographic changes and the troponin T concentration in patients  with acute aortic dissection. Ischemic ECG changes were registered in 38% of cases, while elevated cardiac troponin was in 36.6%. Nevertheless, the prevalence of elevated troponin T did not significantly differ in the groups of patients with and without ischemic changes on the ECG  have long been considered significant causes of increased cardiac troponins. According to a systematic review of 15 studies and 2901 patients with acute stroke over the period 2000–2007, the prevalence of elevated troponin values averaged 18.1% (95% CI 13.6–22.6). The percentage of results with elevated troponin was strongly influenced by the baseline characteristics of the subjects: studies that excluded patients with heart disease had a lower prevalence of positive troponin than the studies that did not exclude prior heart disease (10.2% (95% CI 6.0–14.5) versus 21.7% (95% CI 15.4–28.0)). Patients with acute stroke and elevated troponin were more likely to have signs of myocardial ischemia on an ECG  and had an increased risk of death .The main causes and pathophysiological mechanisms conditioning the after-stroke increase in cardiac troponins are associated with impaired self-contained (autonomic) sympathetic and parasympathetic regulation of the myocardium. Excessive activation of the sympathoadrenal system is accompanied by an increased release of catecholamines  into the blood and the synaptic gap. Excessive concentration of catecholamines disrupts the course of metabolic reactions of the myocardium and also causes vasoconstriction, which also indicates the contribution of the ischemic mechanism to troponin elevation . CatechoAccording to a retrospective study by Cui et al., elevated troponin I levels were observed in 18.5% of patients with acute ischemic stroke. Patients with elevated troponins were more likely to have hypertension and were older, had elevated levels of D-dimer, inflammatory cytokines, and decreased renal function (decreased glomerular filtration rate), which is one of the pathomechanisms leading to increased troponins. In addition, troponin-positive patients had a poor short-term prognosis .Ahn et al. evaluated the long-term survival of troponin-positive patients with ischemic stroke, which the authors themselves report was the first time. An increase in troponins in patients with an acute stage of ischemic stroke (n = 1692) is associated with long-term death: up to 1 year after, patients more often died from stroke and oncology; after 1 year, death from heart failure prevailed over a 6-year period .p = 0.0001) [Atrial fibrillation is one of the leading causes of death from ischemic stroke. Beaulieu-Boire et al. reported that elevated troponin I in patients with strokes and transient ischemic attacks can predict the occurrence of atrial fibrillation detected by 24 hours Holter monitoring. In addition to the predictive role of elevated troponin I in atrial fibrillation, the authors noted its association with a higher risk of 3-month death compared to troponin-negative patients  .Persistently elevated concentrations of highly sensitive troponins (>99th percentile) indicate chronic myocardial damage. Ryden et al. found a relationship between elevated hs-cTnT concentrations and the risk of stroke in 19,460 patients, among which 1528 (7.9%) had chronic myocardial damage. During a mean follow-up period of 2.1 years, stroke occurred in 244 patients (1.2%). At the same time, the risk of stroke increased 4 times in patients with an hs-cTnT concentration > the 99th percentile, compared with patients whose hs-TnT level remained <5 ng/L .p = 0.007). The authors believe measuring hs-TnT may improve the prediction of stroke risk in patients admitted with atrial fibrillation compared to traditional risk stratification on the CHA2DS2-VASc scale based on clinical variables alone [Vafaie et al. evaluated the relationship of elevated hs-TnT concentrations in patients with atrial fibrillation to the possibility of stroke. The study group included 2898 patients who were admitted to the emergency cardiology department of the University Hospital Heidelberg (Germany) with atrial fibrillation. Multivariate Cox regression established an association of increased hs-TnT concentrations > the 99 the percentile (14 ng/mL) with the risk of stroke  medications that cause the death of cardiomyocytes and irreversible dysfunction of the myocardium; and (2) medications that cause temporary (reversible) dysfunction without further consequences after the completion of the course . The mecGuidelines from the European Society for Medical Oncology (ESMO) recommend the use of troponin assays for patients undergoing chemotherapy, especially anthracyclines .p = 0.015). On Day 12 after anthracycline treatment, the troponin T levels completely normalized, while hs-TnI remained elevated in 11 patients (10.9%) [Several studies have demonstrated the high diagnostic value of highly sensitive troponins and their advantages over the use of moderately sensitive methods for the determination of cardiac troponins ,91,92,93 (10.9%) . This stIn another work, Jones and colleagues compared the hs-cTnI concentrations in patients receiving anthracyclines (doxorubicin) (n = 38) with the control group (n = 46). The authors also examined the correlation between medication dose and the degree of increase in serum hs-cTnI levels. At the same time, the hs-cTnI concentrations in the anthracycline cohort were significantly higher than in the non-anthracycline cohort . The correlation between doxorubicin dose and hs-TnI concentration was very low (r < −0.22) .Hole described a case of cardiotoxic effect in a 41-year-old man using methylphenidate , while the clinical picture  and troponin I concentration  in dynamics corresponded to the diagnosis of myocardial infarction. The acute coronary syndrome was ruled out by coronary angiography. Considering the mechanism of action of this medication, the authors suggested the temporary occurrence of vasoconstriction of the coronary arteries against the background of tachycardia of increased myocardial oxygen demand .In a recent study, it was also found that the use of statins is accompanied by an increase in the concentration of hs-cTnI in the blood serum , which mThus, laboratory determinations of the concentrations of cardiac troponin molecules, performed by the highly sensitive methods, are capable of registering even minor (asymptomatic) myocardial damage. At the moment, the availability of pronounced cardiotoxic effects has been proven in many chemotherapeutic medications used to treat cancer. At the same time, the presence of cardiotoxic properties in some other medications applied is very likely, which makes their study essential to adjust for safe dosages. This is especially true for groups of patients with a reduced reserve capacity of the cardiovascular system and additional factors in the development of myocardial infarction.In addition to the above reasons for the increase in cardiac troponins due to the direct or indirect effects of factors damaging the myocardium, it should be kept in mind that the increase in the levels of cardiac troponins may be due to false-positive causes and mechanisms. In particular, some influencing pre-analytical (pre-laboratory) and analytical factors can falsely overestimate the results in the absence of asymptomatic myocardial damage. Combinations of several minor interfering factors, especially those that arise against the background of asymptomatic myocardial damage, can also lead to an excess of the diagnostic threshold and a misdiagnosis. The possibility of obtaining a false-positive result is reflected in the term “99-percentile”, according to which 1 person out of 100 (1%) will have an unreasonably overestimated result ,98. In rThe most common causes of falsely high troponin concentrations at pre-laboratory and laboratory stages are heterophilic antibodies and autoantibodies, in particular, rheumatoid factor, immune complexes, cross-reactions with skeletal muscle troponins, fibrin clots, microparticles, endogenous interference , as well as malfunction of the analyzer  ,105,106.Heterophilic antibodies  include two types: (1) “true” heterophilic antibodies are formed in response to poorly recognized antigens, as a rule, to foreign animal proteins, possess a weak avidity, but multi-specific  activity; and (2) human anti-mouse antibodies are generated against well-defined antigens , for example, against monoclonal mouse sera, and are characterized by strong avidity. Both, under certain conditions, can become a source of significant interference in immunochemical methods for the analysis of many parameters, including cardiac troponins T and I.Heterophilic antibodies are produced by B-lymphocytes of the human immune system in response to exposure to various antigens, such as blood transfusion, vaccines (vaccinations), contact with animal antigens , persistence of viral infections, therapeutic use of mouse monoclonal antibodies, or incompletely humanized (human) antibodies, etc. ,101,102.Lippi et al. described a clinical episode of false elevation in cardiac troponin I and conducted a systematic literature review for the period 1998–2012. During this time, the researchers found 16 original studies and clinical cases that noted the false-positive effect of heterophilic antibodies on the concentration of cardiac troponins. According to the literature data obtained, the frequency of false-positive results is 0.1–3.1% in the general population; however, it can be significantly increased, up to 50% in a specific category of patients. Heterophilic antibodies can affect both the troponin I and T of any test system. This type of interference is practically unpredictable; for example, it cannot be detected by visual inspection of the sample, unlike hemolysis or fibrin clots. A false-positive result due to heterophilic antibodies can only be suspected by clinicians since it is they who receive information about all diagnostic methods for a given patient. However, even in the case of a clear discrepancy between the result of troponin T or I, clinical and instrumental data, and/or the results of other cardiomarkers , the final confirmation requires time and expansion of extra resources [A study by Zaidi et al. reported a false-positive increase in troponin I in a 53-year-old woman. The patient was admitted three times during the year with chest pains; however, there were no ischemic changes on the ECG, and the angiography showed intact coronary vessels. However, the concentration of troponin I on admission was 0.37, which is 5 times higher than the reference (0–0.069). A blood sample from a patient sent to another laboratory to test for a different type of troponin (troponin T) showed normal results. Further investigation and treatment of this sample with heterophilic antibody blockers confirmed the presence of a false–positive increase in troponin I . In a stIn general, strategies for dealing with heterophilic antibodies include (1) testing the sample on a different analyzer and/or using another cardiomarker  if the results are equivocal; (2) serial dilution of the sample and assessing the linearity of the results; and (3) adding heterophilic blocking reagents or pooled animal sera into a sample ,107,108.Rheumatoid factor (RF) means autoantibodies of the IgM class directed against their own antibodies (immunoglobulins) of the IgG class. Produced in large quantities in autoimmune diseases , rheumatoid factor usually binds to IgG Fc fragments, forming immune complexes that, in addition to damaging the body, have an interfering effect on laboratory results, including the number of troponin tests.A multicenter study of the influence of the rheumatoid factor included 10 donors. Their blood serum samples were sent to 66 clinical laboratories, in which a total of 74 indicators  were examined. Of the 3445 results, approximately 8.7% were considered false positives, with many resulting in clinically significant overestimations. About half of the false positives would potentially be misleading in diagnosis and would not be corrected by the addition of a heterophilic antibody blocking reagent .Another study examined 12 serum samples with positive rheumatoid factor and no evidence of myocardial infarction. Serum samples from 7 of 12 patients containing rheumatoid factors had measurable troponin I concentrations, while 4 patients had a troponin I level above 2.0 ng/mL. At the same time, troponin T, measured by another method, did not reveal a single case of a false increase. After the addition of a polyclonal anti-rheumatoid factor antiserum, false-positive troponin I results were eliminated. Therefore, the results of elevated troponin concentrations in patients with elevated rheumatoid factor levels should be interpreted with caution . Howeverp < 0.02) [Al-Awadhi (2007) measured troponin I with the Beckman Access test system in patients with autoimmune diseases: seropositive rheumatoid arthritis (RA) (n = 50), seronegative RA (n = 50), systemic lupus erythematosus (n = 50), primary Sjogren’s syndrome (n = 20), and Graves’ disease (n = 15). Of the 50 patients with seropositive rheumatoid arthritis, 5 subjects had troponin I concentrations higher than the diagnostic value for myocardial infarction. At the same time, in no patient with seronegative RA and other autoimmune diseases, troponin I values went beyond the reference limits. The authors noted that in univariate regression analysis, troponin I and rheumatoid factor concentrations in patients with seropositive RA were positively associated  .Thus, the rheumatoid factors can have different effects on the troponin results, and the frequency of such cases is also highly variable depending on the equipment. It is also notable that several studies have had small patient populations, which may also play a role. Larger population studies are needed for each specific test system used to confidently say that there is no interference.Cross-reactions of the diagnostic antibodies of troponin immunoassays with skeletal muscle troponin isoforms arising in diseases and injuries of skeletal muscles  were considered frequent when using “outdated” immunoassays of the first and second generation ,118,119.The concentration of alkaline phosphatase can significantly increase in several pathologies . Alkaline phosphatase is commonly used to enhance the signal in some immunoassays. Some studies have demonstrated the effect of endogenous alkaline phosphatase on the results of cardiomarkers, including troponins. Butch et al. were among the first to describe the effect of alkaline phosphatase on the concentration of creatine kinase-MB-mass, determined on the Stratus immunochemical analyzer . DasguptMarinheiro et al. reported falsely elevated troponin I in an 18-year-old female patient who was hospitalized several times for three years for recurrent myopericarditis. The troponin I concentrations on admission were always positive . During the next hospitalization due to complaints of palpitations and mild chest pain, the troponin I value on admission was 1.31 ng/mL; however, on the following days of hospitalization, the troponin I levels were negative. Physical examination, ECG, echocardiography, and cardiac MRI showed no signs of active myocarditis. Based on this, the doctors had assumptions about the falsely high result. To exclude a false-positive cause of an increase in troponin I, two blood samples were taken from the patient simultaneously and sent to two different laboratories: (1) a laboratory using the Beckman Coulter Access AccuTnI + 3 test system ; and (2) a laboratory using the Abbott Architect STAT hs-TnI immunoassay . In the first laboratory, the troponin I result was significantly higher than normal (1.03 ng/mL), while in the second laboratory, the troponin levels were negative (hs-TnI = 0.00 ng/mL). Even though the activity of alkaline phosphatase was within the normal range , it was proved in the central laboratory of Beckman Coulter that falsely elevated troponin I is associated with the influence of this enzyme .Herman et al. also reported that alkaline phosphatase-based immunoassays lead to falsely elevated levels of not only troponin I but also other indicators, in particular, human chorionic gonadotropin. The authors recommend using alternative methods for the determination of troponins for those patients in whom the alkaline phosphatase activity and troponin concentration are significantly increased. Ultimately, it is recommended to switch to methods that do not use reagents with endogenous homologous compounds, as they are less prone to false results .Given the widespread use of quantitative troponin tests, false-positive results can harm the patient and/or lead to unnecessary costs  ,127,128.The reasons and mechanisms of pathological increase in cardiac troponins considered in this article , not associated with acute myocardial infarction, are of great practical importance. They should be considered by practicing physicians when making a differential diagnosis between acute myocardial infarction and other pathological conditions. Elevated levels of cardiac troponins, in particular highly sensitive cardiac troponins, in the pathologies discussed in this article have prognostic value and can be used in practical medicine. Hence, elevated levels of cardiac troponins in cardiac and non-cardiac diseases reported in this article , acute aortic dissection, diseases of the central nervous system ) can be used to identify patients with a poor prognosis, providing additional help to clinicians in choosing or modifying patient management tactics. Besides, the opportunity to study the urine cardiac troponins’ pathological conditions that cause damage to cardiomyocytes is a very interesting direction for future research. Obtaining this biomaterial has several advantages over blood serum  and the potential to replenish an array of existing diagnostic methods. The causes and mechanisms of false-positive increases in troponin levels deserve special attention from physicians and researchers.


Background: Astrocytes and microglia play an important role in the inflammatory process of multiple sclerosis (MS). We investigated the associations between the cerebrospinal fluid (CSF) levels of glial fibrillary acid protein (GFAP) and soluble triggering receptors expressed on myeloid cells-2 (sTREM-2), inflammatory molecules, and clinical characteristics in a group of patients with relapsing-remitting MS (RRMS). Methods: Fifty-one RRMS patients participated in the study. Clinical evaluation and CSF collection were performed at the time of diagnosis. The CSF levels of GFAP, sTREM-2, and of a large set of inflammatory and anti-inflammatory molecules were determined. MRI structural measures  were examined. Results: The CSF levels of GFAP and sTREM-2 showed significant correlations with inflammatory cytokines IL-8, G-CSF, and IL-5. Both GFAP and sTREM-2 CSF levels positively correlated with age at diagnosis. GFAP was also higher in male MS patients, and was associated with an increased risk of MS progression, as evidenced by higher BREMS at the onset. Finally, a negative association was found between GFAP CSF levels and cerebellar volume in RRMS at diagnosis. Conclusions: GFAP and sTREM-2 represent suitable biomarkers of central inflammation in MS. Our results suggest that enhanced CSF expression of GFAP may characterize patients with a higher risk of progression. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by neuroinflammation and neurodegeneration often coexisting from the earliest stages of the disease. The pathogenesis of relapsing-remitting (RR) MS is characterized by infiltration of autoreactive lymphocytes, activation of resident immune cells, and release of a number of inflammatory mediators leading to axonal damage and neurodegeneration .Microglia and astrocytes physiologically play important homeostatic functions such as supporting neuronal activity, development, and survival . HoweverA group of 51 RRMS patients admitted to the Neurology Clinic of Neuromed Hospital and diagnosed as RRMS was enrolled. The study was approved by the Ethics Committee of IRCCS Neuromed (protocol 06/2017). All patients gave written informed consent to the study.The diagnosis of RRMS was based on published criteria . All patCSF was collected by lumbar puncture, centrifuged at 1300 rpm for 10 min, and stored at −80 °C. At the time of CSF collection, all patients were treatment-naïve and none of them had previously been treated with steroids. All CSF samples were tested for oligoclonal bands (OCB) detection.CSF GFAP and sTREM-2 levels were measured by using Human ProcartaPlex multiplex immunoassay kits , according to the manufacturer’s instructions. Fluorescence intensity was measured with the Luminex 200 analyzer  and data were analyzed using the xPonent 3.1 software .Analysis of CSF proinflammatory and anti-inflammatory cytokines and chemokines was performed using a Bio-Plex multiplex cytokine assay , according to the manufacturer’s instructions. Samples were analyzed in triplicate. Concentrations were calculated according to a standard curve generated for the specific target and expressed in picograms per millilitre. The following CSF molecules were examined: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-1 receptor antagonist (ra), G-CSF, GM-CSF, IP-10, TNF, MIP1a, MCP1, IFN-γ.All patients underwent a standard acquisition protocol with 1.5 or 3 Tesla brain MRI scan with gadolinium (Gd) administration (0.2 mL/Kg IV) with the following images: dual-echo proton density, fluid-attenuated inversion recovery (FLAIR), T2-weighted spin-echo images, and pre-contrast and post-contrast T1-weighted spin-echo. A neuroradiologist, blinded to clinical data, evaluated the presence of Gd enhancing lesions.www.statistical-modelling.de/lst.html) for SPM12 (https://www.fl.ion.ucl.ac.uk/spm). Furthermore, we used the computational anatomy toolbox  to extract individual cortical thickness values from lesion-filled MR images. Finally, we used the volBrain pipeline [For the analysis of brain structural measures, in 22 MS patients, standard brain MRI acquisition protocol by using a 3T MR scanner , including the following MR series: a 3D Spoiled Gradient Recalled (SPGR) T1-weighted sequence  and a 3D FLAIR sequence . We first segmented white matter lesions from FLAIR and T1 images by using the lesion growth algorithm as implemented in version 2.0.15 of the lesion segmentation tool  procedure was used to decrease the false discovery rate and avoid Type I errors . Analyses were performed using IBM SPSS Statistics for Windows .The Kolmogorov–Smirnov test was used to assess the normality distribution of data. Categorical variables were presented as number (n) and frequency (%). Continuous data were shown as median . To test possible associations between nonparametric variables, Spearman’s non-parametric correlation was used. Partial Spearman’s correlations were used to test the correlation between two variables, while controlling for the effect of other confounding factors . The χThe clinical characteristics of MS patients are shown in Infiltrating immune cells release proinflammatory cytokines in MS brains, that could, in turn, activate astroglia and microglial cells. Thus, we explored the correlations between the CSF levels of GFAP and sTREM2 and inflammatory cytokines.p = 0.038), IL-8 , G-CSF , and IFNγ .Correlations between CSF inflammatory molecules and GFAP and sTREM2 are shown in the p = 0.045), IL-8 , G-CSF , IL-9 , and IL-13 .Significant correlations were found between the CSF levels of sTREM-2 and IL-5, IL-8, G-CSF, IL-13, and IL-9 B. These Finally, according to the idea that astroglia and microglial cells are activated in parallel and interact mutually, we also found a strong correlation between GFAP and sTREM-2 CSF levels C.p = 0.002, N = 51) and sTREM-2    A,B. Furt= 0.424) C,D.p = 0.304 and p = 0.748 respectively), radiological activity at LP (p = 0.789 and p = 0.878 respectively), and the presence of OCB (p = 0.184 and p = 0.102 respectively). In addition, no significant correlations were observed between the CSF levels of GFAP and sTREM-2 and EDSS at LP (p = 0.431 and p = 0.903 respectively).No significant associations emerged between the CSF levels of GFAP and sTREM-2 and disease duration . Conversely, no significant correlations emerged between BREMS at onset and CSF levels of sTREM-2 (p = 0.142)  E,F.p = 0.036), and cerebellar volume . Conversely no significant association emerged between GFAP and T2 lesion load (p = 0.414) (p = 0.072).In 22 RRMS patients the associations between CSF levels of GFAP and sTREM-2 with structural MRI measures were explored. A significant correlation emerged between GFAP and both cortical thickness  A. In add= 0.414) B, althoup = 0.046). Conversely, the correlation between GFAP and cortical thickness was not significant when controlling for the effect of age at diagnosis and sex .The correlation between GFAP and cerebellar volume was significant, also controlling for the effect of age at diagnosis and sex  and microglial  biomarkers. In addition, prospective studies are needed to assess the impact of the CSF levels of GFAP and sTREM-2 on the MS disease course, and particularly on the risk of secondary progression.In conclusion, the correlation between GFAP, sTREM-2, and CSF cytokines, may indicate an association between central inflammation and microglial and astroglial pathological reactivity, in the early MS stages. Our results suggest that GFAP and sTREM-2 represent suitable biomarkers of central inflammation in MS. Increased CSF expression of GFAP at the time MS diagnosis may characterize patients with a higher risk of progression.


Paliperidone was granted approval in the United States in 2006 to be used in the treatment of schizophrenia and in 2009 for schizoaffective disorder. Summary: Schizophrenia and schizoaffective disorder have a large impact on cognitive impairment, positive symptoms and negative symptoms. Patients with either of these mental illnesses suffer from impairments in everyday life. Paliperidone has been shown to reduce symptoms of schizophrenia and schizoaffective disorder.Purpose of Review: This is a comprehensive review of the literature regarding the use of paliperidone in the treatment of schizophrenia and schizoaffective disorder. It covers the background and presentation of schizophrenia and schizoaffective disorder, as well as the mechanism of action and drug information for paliperidone. It covers the existing evidence of the use of paliperidone for the treatment of schizophrenia and schizoaffective disorder. Recent Findings: Schizophrenia and schizoaffective disorder lead to significant cognitive impairment. It is thought that dopamine dysregulation is the culprit for the positive symptoms of schizophrenia and schizoaffective disorder. Similar to other second-generation antipsychotics, paliperidone has affinity for dopamine D Schizophrenia and schizoaffective disorder are two mental illnesses that have a deep impact on both their affected populations as well as our society as a whole. Multiple genetic and environmental factors contribute to the development of both disorders, leaving much of their etiology unknown . The triAlthough there is much undiscovered about the exact pathophysiology of these disorders, what is evident is the severe economic burden they bring to our society . The estTogether, these factors demonstrate a real need to find more effective treatments for these disorders. There are approximately 21 million people globally living with schizophrenia whose lives are hindered by the course of this illness . FindingSchizophrenia and schizoaffective disorder share a very similar epidemiology, pathophysiology and presenting symptoms. However, there are some differences between them. The point prevalence of both disorders is low with schizophrenia being estimated at 0.28% and schizoaffective disorder at 0.11% ,9. DiffeMultiple studies have implicated the role of genetic abnormalities being a contributing factor for the development of schizophrenia ranging from polymorphisms in single genetic loci to copy number variants (CNVs) ,2. HundrIn addition to genetic changes, other studies have demonstrated environmental relationships. Multiple groups have found that individuals being born during the winter/early spring months are at an increased risk for developing schizophrenia ,14. IndiAs previously mentioned, although there are several risk factors leading to increased susceptibility of developing schizophrenia and schizoaffective disorders, no one factor is solely responsible . These iDopamine dysregulation is one of the most widely accepted pathophysiological processes leading to the positive symptoms seen in schizophrenia . The basMultiple studies researching brain imaging identified that both schizophrenia and schizoaffective disorder patients had reduced grey matter volume ,5,23. AlSchizophrenia and schizoaffective disorder share many of the same presenting symptoms, but they differ in their severity leading to a considerably better prognosis in schizoaffective disorder . Both tyIn contrast, schizoaffective disorder is a much less stable diagnosis with much debate among clinicians and researchers . AccordiWhile dementia praecox, meaning premature dementia, was first described in 1887 by Emil Kraepelin , this wa2 receptors in the brain, affecting the positive symptoms  of schizophrenia. These typical antipsychotics do not selectively block the D2 dopamine receptors and can therefore have a wide range of side effects. Typical antipsychotics are further divided into high potency and low potency. The classification into high potency and low potency is based on “chlorpromazine equivalence,” where haloperidol and fluphenazine are categorized as high potency and thioridazine is low potency, making it comparable with chlorpromazine. High potency antipsychotics are more likely to cause extrapyramidal symptoms (EPS) than low potency antipsychotics [First-generation antipsychotics, also known as typical antipsychotics, work mainly by blocking the Dychotics . Second-generation antipsychotics, also known as atypical antipsychotics, are D2 and 5HT2A receptor antagonists. Studies have shown that 75–87% of patients presenting with first-episode psychosis respond to primary antipsychotic therapy within four weeks to one year ,31,32,332 receptors [2, D3 and 5-HT1A receptors, with an affinity 10 times higher for the D3 receptor than the D2 receptor. This affinity has made this drug especially useful for the treatment of schizophrenia with dominant negative symptoms, a classically difficult to treat subset of patients [Third generation antipsychotics are the newest group and have been individualized based on their mechanism of action at dopamine receptors. Unlike the first- and second-generation antagonists, the third generations act as partial agonists at the Deceptors . Cariprapatients .Side effects of antipsychotics include EPS , increased risk of neuroleptic malignant syndrome, weight gain, hyperprolactinemia and sedation . These sWhile treatment of schizophrenia and schizoaffective disorder remains anchored in pharmacologic therapy, non-pharmacological adjunctive treatments have proven to be effective. It has been shown that patients with less than six months duration of antipsychotic treatment who were enrolled in the model program NAVIGATE reported lower PANSS scores were more likely to remain in treatment, enjoy a better quality of life and participate more in work/school than usual care ,39. PatiSchizoaffective disorder can be more difficult to diagnose, making it harder to study and, therefore, leaving it with far fewer FDA approved drug treatments. Currently, only paliperidone extended-release (ER) and long-acting injectable (LAI) forms, along with risperidone, have been shown to be effective in the treatment of schizoaffective disorder . This isPaliperidone is an atypical antipsychotic that is a major active metabolite of risperidone (5-hydroxyrisperidone), approved for use in the US in 2006 as daily oral extended-release tablets and 1-month or 3-month LAI formulations ,49,50. P2 and serotonin 5-HT2A receptors [2A than D2 receptors and have varying effects on other receptors [2A and D2 antagonism, paliperidone has antagonistic effects at α1 and α2 adrenergic and H1 histaminergic receptors [1 cholinergic or β adrenergic receptors [2 receptors in striatal and temporal cortex with a median effective dose of 2.38 mg/day and 2.84 mg/day, respectively [2A/D2 antagonism, lower affinity for α1 and α2 receptors and higher affinity for H1 receptors [Paliperidone is in the benzisoxazole derivative class of atypical antipsychotics  and acts in accordance with others in the class . While teceptors . Unlike eceptors . In addieceptors . It has eceptors . Positroectively . Despiteeceptors . Palipereceptors . Additioeceptors . Palipereceptors . The moleceptors . max) in 24 h and increases in Cmax and the area under the drug concentration vs time curve (AUC) are observed after a high-fat or high-calorie meal [max in the recommended dose range [Paliperidone ER is designed with an osmotically controlled-release system which allows for continuous drug delivery after oral administration and no initial titration . Paliperrie meal ,51. Palise range ,51. The se range ,51.max in a median time of 13 days and 33 days, respectively, and both have higher Cmax when a deltoid injection is used rather than gluteal [The LAI paliperidone palmitate is deposited and slowly hydrolyzed to paliperidone over time. The 1-month and 3-month injectable forms reach C gluteal ,50,51. F gluteal ,50. max and AUC of oral paliperidone [Paliperidone is minimally metabolized by the cytochrome P450 2D6 and cytochrome P450 3A4 enzymes; however, these are suggested to play a clinically irrelevant role overall ,51. Paliperidone . Carbamaperidone . Renal iperidone . Mild toperidone . EffectsMany studies have explored the efficacy and safety of paliperidone in patients with schizophrenia and/or schizoaffective disorder. Common measures of drug efficacy used in these studies include the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Severity (CGI-S) Scale, the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale 21-item version (HDRS-21) and the Personal and Social Performance (PSP) Scale. Some studies also measured the time to relapse as a primary measure of clinical efficacy. In these studies, paliperidone was generally well tolerated; however, adverse effects were not uncommon and include headache, anxiety, insomnia, weight gain, suicidal ideation, nasopharyngitis, UTI and extrapyramidal symptoms. n = 206) and chronic illness  versus placebo [p ≤ 0.022). Relapse rates were higher in the placebo group compared to both PP1M subpopulations. In the recent onset subpopulation, the placebo group had a relapse rate of 30% and the PP1M participants had a relapse rate of 10.2% : 2.8; 95% confidence interval (CI): 1.11–7.12; p = 0.029). In the chronic illness subpopulation, the placebo group had a relapse rate of 35.5% and the PP1M participants had relapse rate of 18.1% : 2.8; 95% confidence interval (CI): 1.11–7.12; p = 0.029). Treatment-emergent adverse effects (TEAEs) occurred in over half of patients taking PP1M, with more noted in the chronic illness subpopulation (65.1%) compared to the recent onset (56.8%) subpopulation. The most common adverse effect was related to administration site conditions, such as pain. Other adverse effects reported were headache, insomnia, suicidal ideation, weight gain, akathisia, drug-induced parkinsonism, tremor and symptomatic prolactin related TEAEs, such as decreased libido and amenorrhea [Bossie et al. extrapolated data from a multiphase schizoaffective disorder study (NCT01193153) to examine the effect of paliperidone palmitate once-monthly injections (PP1M) in patients with recent-onset . The relapse risk was 3.38 times greater in the placebo group compared to PP1M monotherapy (p = 0.002) and 2.03 greater when compared to PP1M as adjunctive therapy (p = 0.021). The overall risk of relapse was 2.49 times greater for placebo , with an overall relapse rate of 33.5%. In contrast, the PP1M groups had relapse rates of 15.2%. Using the PSP scale, the researchers found that PP1M was superior to placebo in maintaining cognitive functioning. Common adverse effects found in this study were increased weight, insomnia, headache, nasopharyngitis and extrapyramidal symptoms [Fu et al. conducted a double-blind, randomized study evaluating the effects of paliperidone in 334 patients with schizoaffective disorder . Palipersymptoms . Management of elderly patients with schizophrenia can be challenging, as they often have reduced liver and kidney function required to metabolize certain antipsychotic medications. Paliperidone, the primary metabolite of risperidone, is thought to be less likely influenced by changes in metabolism, leading to better outcomes in elderly patients with schizophrenia, while reducing treatment-emergency adverse effects. This understanding prompted Suzuki et al. to study the efficacy and safety of switching patients from risperidone to a pump-administered extended-release paliperidone formulation . They enp < 0.0001) [n = 174) or risperidone long-acting medications (n = 57) to paliperidone once monthly had significant reductions in mean PANSS scores, as well as improvement in symptom severity measured by the CGI-S [Medication noncompliance is a major barrier for schizophrenia and schizoaffective disorder maintenance therapy. Like many patients with chronic medical conditions, patients with schizophrenia and schizoaffective disorder may not always comply with their antipsychotic medications because they have difficulty with daily oral therapy . Therefo 0.0001) . Another 0.0001) . A total 0.0001) . Furtherhe CGI-S . The aboPaliperidone injections can also be given once every three months. This formulation may be beneficial in preventing relapse of symptoms in schizophrenic and schizoaffective patients. Savitz et al. studied the efficacy and safety of paliperidone palmitate 3-month (PP3M) formulations for patients with schizophrenia in a randomized, multicenter, double-blind, noninferiority study . PP3M wap < 0.01) after 12 weeks of treatment, with no significant difference between the BDNF levels in the two treatment groups. N400 amplitudes also increased in both groups after treatment (p < 0.01). However, N400 latency periods were shorter with paliperidone therapy, compared to risperidone (p < 0.01), possibly indicating that paliperidone therapy leads to faster benefits in cognitive improvement. The researchers also used PANSS scores in their study, finding that it was significantly reduced in both groups (p < 0.01) after treatment [Recent advancements in psychiatric research has discovered that levels of brain-derived neurotrophic factor (BDNF) could correlate with neuroprotection in schizophrenia, with higher levels indicating better outcomes . A studyreatment . One draResearchers have also directly compared paliperidone to other treatment options in the management of schizophrenia and schizoaffective disorder. Alphs et al. compared once-monthly paliperidone palmitate to daily oral antipsychotic therapy in patients with schizophrenia using a randomized clinical trial . Time toLong-acting intramuscular versions of paliperidone have also been compared to long-acting haloperidol in the management of schizophrenia and schizoaffective disorder. McEvoy et al. found no significant difference between the efficacy of haloperidol and paliperidone . Stroup Aripiprazole is a third-generation antipsychotic that has demonstrated efficacy in treating schizophrenia and schizoaffective disorder. Its unique mechanism of action prompted Naber et al. to compare it to paliperidone. The researchers used the Heinrichs–Carpenter Quality-of-Life Scale (QLS) to compare once-monthly LAI formulations of aripiprazole to paliperidone in a 28-week randomized, noninferiority, rater-blinded, head-to-heady study. Aripiprazole was found to be superior to paliperidone in this regard . DespiteThese studies, as well as numerous others, demonstrate that paliperidone is an effective therapeutic option in treating patients with schizophrenia and schizoaffective disorder. It is generally well tolerated, with weight gain being a common side effect. A question physicians often want to know is the type of formulation to give. The above works support that long-acting formulations are associated with better outcomes in schizophrenic and schizoaffective patients. When deciding between extended release tablets and long-acting injectables, physicians must take into consideration a patient’s personal preference. However, research by Levitan et al. suggests that paliperidone once-monthly injections have shown greater benefits when compared to extended release tablets, especially early on in the disease process . This dr2 and 5-HT1A receptors. It has been shown to be effective and safe, compared to placebo, in the treatment of these disorders by various scoring measures in multiple studies. Paliperidone LAI is a favorable choice in patients who have failed oral antipsychotic regimens. Although some studies demonstrated slightly reduced efficacy compared to other antipsychotics, paliperidone has demonstrated reduced risk of treatment failure over time. Compared to its parent compound risperidone, paliperidone may be more favorable due to similar efficacy, increased safety and increased patient satisfaction. Paliperidone is not significantly affected by liver and renal function and is thus a good choice for consideration in patients with decreased hepatic or renal function. Further studies are required to evaluate combination long-term therapies and daily coadministration of other antipsychotics for schizophrenia or schizoaffective disorder.The use of atypical antipsychotics remains central in the long-term treatment of schizophrenia and schizoaffective disorder. Relatively new as a long-acting injectable antipsychotic, paliperidone is of particular interest in promoting treatment adherence and reducing symptoms over longer periods of time. The 3-month paliperidone palmitate is currently the longest-acting antipsychotic available for use in schizophrenia and schizoaffective disorder. Its mechanism of action is similar to most other atypical antipsychotics, antagonizing D


Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD.BSD donors  were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures.p = 0.09), systemic inflammation  and cardiac injury , requiring vasopressor support , with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic  and metabolic  parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures.Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation.The online version contains supplementary material available at 10.1186/s40635-021-00425-4. Heart transplantation (HTx) is the gold standard treatment for severe or end-stage cardiac disease patients, but is severely limited by the persistent global shortage of donor hearts . Hearts The global donor heart shortage has galvanised preclinical research around understanding BSD-mediated pathophysiology and resultant cardiac dysfunction. Clinical experience with donation after circulatory determination of death as an alternative source for donor hearts is expanding –8. FurthWe previously profiled the physiological and biological impact of BSD on donors over 24 h . To facin = 4), using previously published methods [n = 4, not exposed to neurological injury). Following confirmation of donor BSD (or sham), critical care management was provided for 24 h. The donor heart was then procured and preserved by CSS. Healthy recipient was then prepared, cardiopulmonary bypass (CPB) established, and the native heart removed. The preserved donor heart was implanted using the bicaval orthotopic HTx technique [Donor sheep were either exposed to 24 h brain death , and complied with the ARRIVE Guidelines [. Prior to group allocation, experimental sheep were matched for weight and blood compatibility [n = 4/group). Sheep within each pair were then randomly allocated as an experimental donor or recipient.Sixteen female merino crossbred sheep , body weight 46.9 ± 5.8 kg, were approved for use by the facility veterinarian after a comprehensive health check. Animals were housed in flocks on large institutional paddocks with grass, and free access to shade and ad libitum water. One week prior to experimentation, sheep were transferred to the animal facility to acclimate, with ad libitum food and water. Animal studies were undertaken at the Queensland University of Technology (QUT) Medical Engineering Research Facility in Brisbane (March 2017–December 2018). Animal ethics was approved by the QUT Animal Ethics Committee (AEC) 16000001109) and ratified by the University of Queensland AEC (QUT/393/17/QUT). All experiments were performed in accordance with the National Health and Medical Research Council (NHMRC) 0000011092) and end-tidal carbon dioxide (ETCO2) were continuously monitored. The animal was connected to a mechanical ventilator  set as follows: tidal volume 8 ml/Kg, positive end expiratory pressure (PEEP) 5 cmH2O, respiratory rate (RR) adjusted to maintain arterial partial pressure of carbon dioxide (PaCO2) at 40 ± 4 mmHg, and inspiratory fraction of oxygen (FiO2) adjusted to maintain arterial partial pressure of oxygen (PaO2) > 60 mmHg. Anaesthesia and analgesia were maintained with continuous infusions of fentanyl (10–30 μg/kg/h), midazolam (1–3 mg/kg/h) and ketamine (4–12.5 mg/kg/h). All animals received an initial intravenous (i.v.) bolus of 0.25–1 L Hartmann’s solution , followed by a continuous infusion (1 mL/kg/h). Gastric and oropharyngeal secretions were continuously suctioned. Potassium chloride (10–30 mmol/L per h) was continuously infused to maintain serum potassium at 4.0–4.5 mmol/L. The femoral artery was cannulated for continuous arterial blood pressure monitoring and blood sampling. A 7.5 Fr pulmonary artery catheter was inserted for continuous cardiac output monitoring. A urinary catheter was then inserted for urine output monitoring and sampling. Throughout the course of the experiment (both donors and recipients), intravascular crystalloid and vasoactive support were provided to maintain hemodynamic stability, aiming for a mean arterial pressure (MAP) of ≥ 65 mmHg, heart rate (HR) 60–110 bpm, and urinary output of ≥ 0.5 mL/kg/h. Specific additional consumable details for the methodology presented are provided in Additional file All sheep were fasted overnight, and in the morning brought into the surgical theatre. Five mL of lidocaine 2% was administered into the neck skin, the external jugular veins were cannulated, and a baseline venous blood sample collected. The animal was then induced with midazolam (0.5 mg/kg) and propofol (2.5–3 mg/kg), and antibiotics were administered (gentamycin 80 mg and cefazolin 2 g). The animal was then intubated, and placed on the operating table in right lateral (donors) or supine position (recipients). Electrocardiography (ECG), oxygen saturation  was administered, and a mini left thoracotomy was performed through the upper border of the 5th rib .The skull was then prepared as previously described . BrieflyThen, in BSD donors, brain injury was developed by intra-cerebral Foley catheter inflation with 10 mL sterile water every 5 min (to a maximum of 60 mL) over 30 min . In case2 at 40 ± 4 mmHg and PaO2 > 60 mmHg ; desmopressin (i.v. 4 μg bolus) was administered if urine output consistently exceeded 200 mL in the two proceeding hours. Two hours after BSD confirmation, donors received i.v. methylprednisolone 15 mg/kg, triiodothyronine 4 μg bolus and 3 μg/h thereafter, and vasopressin 1.2 IU/h. The Foley catheter balloon was additionally inflated  after methylprednisolone administration to ensure absence of hemodynamic response and residual neurological function (BSD donors only). Sham donors received the same doses of methylprednisolone and triiodothyronine, without vasopressin. Anaesthesia and analgesia were maintained with continuous infusions of fentanyl (10–30 μg/kg/h), midazolam (1–3 mg/kg/h) and ketamine (4–12.5 mg/kg/h). However, in BSD donors, those infusion rates were reduced to trivial levels following BSD confirmation. Donors received continuous infusions of Hartmann’s (1 mL/kg/h) throughout the experiment and fluid boluses as necessary, guided by static parameters of fluid responsiveness, echocardiography and lactate levels.Donor critical care management: Noradrenaline (0.01–0.4 µg/kg/min), dopamine (1–20 µg/kg/min) and/or crystalloid challenges were administered to maintain MAP ≥ 65 mmHg; arterial blood gases and electrolytes were measured hourly  and potassium and calcium supplemented accordingly to maintain potassium 4.0–4.5 mmol/L and calcium > 1.1 mmol/L; ventilatory settings were adjusted to maintain PaCOFollowing 24 h monitoring, donors were placed supine and a median sternotomy was performed. A purse-string suture was placed in the ascending aorta for the cardioplegic needle . Recipients were then rested for 1 h (end of 1 h rest = stabilisation time point) to achieve vital signs stability (as outlined above for donors). Standard experimental settings for monitoring both donor and recipient  and methylprednisolone (250 mg) were administered intravenously, and a 7.5 Fr pulmonary artery catheter was inserted for continuous cardiac output monitoring (prior to completion of aortic anastomoses). Fluid infusions recommenced once the animal was rewarmed to 37.0 °C. Following completion of all anastomoses, de-airing was performed with a needle vent in the ascending aorta and the aortic cross-clamp removed. If ventricular fibrillation occurred, internal defibrillation was performed (10–20 Joules), and additional amiodarone (150–300 mg) and lignocaine (50–100 mg) were administered as needed. Cold ischemic time was defined as the time from donor heart placement into an ice cooler until it was removed ; total ischemic time was the total time between aortic cross-clamping in the donor, up to removal of the aortic cross-clamp in the recipient . The cardiac allograft was then perfused for 30 min, before attempting to wean from CPB.Once CPB was established and the recipient heart removed, standard orthotopic HTx was performed. Anastomoses were performed in the following order: left atrium, inferior vena cava, superior vena cava, pulmonary artery, ascending aorta. After completion of the pulmonary artery anastomosis, amiodarone (150 mg), lignocaine (50 mg), MgSOp = 1.00). Successful separation from CPB was defined as Time 0 in the recipient. Following CPB separation, the CPB cannulae were removed and cannulation sites closed. Residual blood in the extracorporeal circuit reservoir and venous tubing was prepared for transfusion back to the recipient through the central line as required. Anticoagulation was reversed with 25 mg of protamine. Recipient animals were followed up for 6 additional hours following successful separation from CPB. Investigators applied critical care management principles reported in earlier paragraphs ; adequate ventricle filling as observed using epicardial echocardiography. Total bypass time was defined as time that the recipient was placed on bypass to successful weaning from bypass . Continuous cardiac output, mixed venous oxygen saturation (SvO2), stroke volume, and systemic vascular resistance index were monitored using Vigilance II Monitor . The Hamilton-G5 ventilator was used to record ventilatory parameters at 100 Hz using custom software. Body surface area (BSA) was calculated using the following equation, BSA = 0.094 × (body weight in kg)0.67 [Hemodynamic parameters were captured at 1 kHz on a 16-channel PowerLab data acquisition system (model ML880) recorded with Labchart 7 . Central venous pressure, MAP, pulmonary artery pressure, ICP, ECG, HR and SpO kg)0.67 . As a me kg)0.67 , to dete2), end-systolic area , fractional area change , and global radial strain . FAC was defined as the EDA minus the ESA divided by the EDA. GRS was defined as the strain derived from the whole thickness of the myocardium in the radial direction.Epicardial echocardiography was performed through an X5-1 transducer with a spacer connected to an IE-33 ultrasound scanner . In donors, echocardiography was performed at stabilisation, T0 (upon BSD/sham corroboration), 1, 3, 6, 12, 18 and 24 h thereafter. In recipients, echocardiography was performed at baseline, T0 (successful weaning from CPB), and 1, 3 and 6 h thereafter. Three-beat ECG-gated loops in the conventional parasternal short axis (PSAX) view were obtained. Conventional apical views could not be obtained, due to anatomic constraints in accessing the apex related to the short thoracotomy or sternotomy. All images were transferred to a separate workstation and analysed offline by an experienced echocardiographer using TomTec-Arena . Automated Functional Imaging (AFI) was applied to appropriate echo-loops in the PSAX view. Speckle tracking was visually assessed for tracking accuracy and the end-diastolic timing marker manually adjusted if required. Data collected were end-diastolic area  to obtain platelet poor plasma, and stored at − 80 °C. Whole blood (EDTA) and plasma samples were externally assessed by a veterinary diagnostics laboratory  to determine full blood counts, biochemistry and plasma free catecholamines (metanephrine and normetanephrine). Stored plasma samples were assessed in-house to determine levels of inflammatory cytokines and cardiac injury markers (details below).In donors, at baseline, stabilisation, upon confirmation of BSD/sham (T0), and 1, 3, 6, 9, 12, 18 and 24 h thereafter, arterial blood was collected. In recipients, arterial blood was collected at baseline, stabilisation, and 0.5, 1, 2, 3, 4 and 6 h after weaning from CPB (T0). Blood samples were centrifuged twice -6, IL-8, IL-10, and IL-1β were quantified using in-house developed ELISAs according to previously published methods . Tumour F values according to the sphericity of the data. Top F and p values on each graph represent effect of time, and bottom F and p values represent differences between BSD vs. sham over time (interaction). Continuous variables were compared with Mann–Whitney U test, and categorical variables using Pearson Chi-square test. All hypothesis testing was two-tailed and p-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 27 for Windows .Data in figures and tables is represented as mean ± standard error of the mean (SEM). Repeated measurements between the two different groups were assessed by ANOVA for repeated measures and reported as No significant differences were observed between donors and recipients in age, weight, body surface area (BSA) or body temperature Table .Table 1BDuring BSD development, ICP rose significantly in comparison to sham  were observed between groups  , the cliBrain death occurs following significant and persistent elevations in ICP, leading to exaggerated hemodynamic perturbations, commonly requiring vasoactive support. Despite donor management and optimisation strategies, cardiac dysfunction occurs in BSD due to systemic catecholamine response and impaired cardiac contraction , 30, whiDonor heart preservation methods are unchanged for over 40 years . In thisAfter weaning from CPB, recipient hemodynamic function was stable, but required increasing vasoactive support and was associated with increasing blood lactate. Our observations of increasing vasoactive requirements with concomitant elevations in blood lactate in the early post-operative period mimic clinical HTx observations –62. PostInterestingly, despite the profound hemodynamic and inflammatory perturbations in BSD donors, no major differences were evident in post-HTx hemodynamic, inflammatory or cardiac function parameters between groups. Our ability to successfully wean recipients from CPB following 24 h BSD is likely associated with reduced systemic inflammation at time of heart retrieval. During preliminary BSD-HTx studies, hearts exposed to 6 h BSD could not be weaned from CPB. During these studies, the cold ischemic time was comparable to the current study, and only differed in the length of or complete exposure to donor BSD. Other HTx animal studies incorporate BSD exposure up to 6 h , which iDeveloping large animal models that accurately represent clinical scenarios is complex, resource-intensive, expensive and often requires similar hospital technology and facilities. Development of this model was a complex and labour-intensive process, but was strengthened by the comprehensive research and clinical team with extensive experience in clinical and animal experimentation in critical care medicine and HTx. We used advanced ICU monitoring systems and protocols to increase the potential for clinically translatable outcomes. Nevertheless, the current study has several limitations. Despite all care taken to assess animal health prior to experimentation, and use of prophylactic broad-spectrum antibiotics throughout the study, there is potential, though unlikely, that concomitant undiagnosed infections could have contributed to the catecholamine storm in donors. This study has a small sample size, and thus meaningful statistical analysis is challenging. However, we have comprehensively assessed all donors and recipients over the entire time course of the experimental procedure. A longer post-HTx monitoring period would have been beneficial, but better suited to a smaller interventional study, where assessment of long-term outcomes is critical to efficacy of a desired intervention for patient survival.Cardiac transplantation is a complex field, where recipient outcomes are dependent upon an extended timeline that begins with donor injury. Any model hoping to advance the HTx field must incorporate the explosive brain insult, ICU care and hormone resuscitation, donor heart preservation, reimplantation and weaning from CPB. This model represents the first ovine model of bicaval HTx incorporating donor BSD for 24 h. Donor BSD induced significant hemodynamic and inflammatory perturbations requiring vasoactive management, yet was comparable to sham donors after 24 h. Following CSS and HTx, all animals were successfully weaned from CPB and monitored for up to 6 h (except one), with no significant differences in post-HTx hemodynamic, inflammatory or cardiac function between groups. This ovine model of BSD-HTx may have a promising role in evaluating novel peri-transplant techniques and therapies, with the aim of ultimately improving both the quality and quantity of donor hearts.Additional file 1.Table S1. Consumable details relevant to the methodology. Table S2. Hemodynamic and ventilatory parameters, blood results and vasoactive use during the course of the study at stabilisation , T0 (confirmation of BSD/Sham), T12 and T24 in donor animals. All values are mean (SD). NA – not available; FiO2 – inspiratory fraction of oxygen; PEEP – positive end-expiratory pressure; EtCO2 – end-tidal carbon dioxide; PaO2 – arterial partial pressure of oxygen; PaCO2 – arterial partial pressure of carbon dioxide; HCO3 – concentration ofbicarbonate in arterial blood. Table S3. Hemodynamic and ventilatory parameters, blood results and vasoactive use during the course of the study at stabilisation , T0 (successful weaning from CPB), T1, T3 and T6 in recipient animals. All values are mean (SD). NA – not available; FiO2 – inspiratory fraction of oxygen; PEEP – positive end-expiratory pressure; EtCO2 – end-tidal carbon dioxide; PaO2 – arterial partial pressure of oxygen; PaCO2 – arterial partial pressure of carbon dioxide; HCO3 – concentration of bicarbonate in arterial blood. Table S4. P values from multiple comparisons test for parameter estimates among Sham and BSD donors at each time point for donor heart rate (HR), plasma metanephrines (Met.), mean arterial pressure (MAP), vasopressor dependency index (VDI), blood lactate, minute volume and fluid balance. B – baseline, ST – stabilisation, T0 – confirmation of BSD, T1-T24 – 1-24 hours post-BSD confirmation.


Cerebrospinal fluid (CSF) leaks associated with endoscopic sinus surgery (ESS) are a rare complication affecting approximately 0.09% of patients. Although meningitis is a well-known complication of CSF leaks, the case we present is a rare and cautionary case of CSF leakage associated with ESS leading to aspiration pneumonia. A 43-year-old man with CSF leaks after ESS was referred to our hospital. After the operation, sometimes, he reported having a serous nasal discharge from the right side when he bent over, and he woke up choking on something every day. He also experienced headache, fever, fatigue, and cough. Interestingly, chest computed tomography (CT) showed a consolidation and ground-glass opacity in the posterior segments of the right upper lobes and superior segments of the bilateral lower lobes. These CT imaging findings were similar to those of aspiration pneumonia in bedridden patients who are always in a supine position. These findings suggest that CSF caused aspiration pneumonia. To the best of our knowledge, no case of aspiration pneumonia caused by CSF during endoscopic sinus surgery has been reported until now. If a patient with CSF leakage after ESS experiences fever, cough, or fatigue, physicians should consider aspiration pneumonia in addition to meningitis. Cerebrospinal fluid (CSF) leak associated with endoscopic sinus surgery (ESS) is a rare complication affecting approximately 0.09% of patients . If the A 43-year-old man with CSF leaks after ESS was referred to the Department of Otolaryngology at Juntendo University Hospital by a surgical clinic. His medical history was unremarkable. He underwent right-side ESS 9 days before and left-side ESS 6 days before presenting to our hospital. His right-side nasal packing was removed at the time of the left-side operation. After the operation on the left, sometimes, he reported having a serous nasal discharge from the right side when he bent over, and he woke up choking on something every day. He also experienced headache, fever, fatigue, and cough. He returned to the surgical clinic and was diagnosed with CSF leakage from his right skull base. At that time, nasal packings were inserted in the right side, and the CSF leakage was stopped temporarily.2 was 98% on room air, and his body temperature was 37.4°C. He reported having a headache, but neck stiffness was not observed. His bilateral nasal cavities were packed with gauzes. Postnasal discharge was not detected at his retropharyngeal wall. Blood test results suggested inflammation . A CSF test showed no evidence of meningitis and had a clear appearance . Computed tomography (CT) scans showed a defect in the cribriform plate (He was then transferred to our hospital. His SpOrm plate .Because he had fever, cough, and fatigue, we performed chest CT and a severe acute respiratory syndrome coronavirus-2 polymerase chain reaction test to screen for coronavirus disease 2019. The polymerase chain reaction test was performed twice and was negative both times. Interestingly, chest CT showed a consolidation and ground-glass opacity in posterior segments of the right upper lobes and superior segments of the bilateral lower lobes , indicatWe performed endoscopic transnasal CSF leak repair under general anesthesia. The bone defect and CSF leakage were found in the right frontal ethmoidal skull base . Two pieAfter this operation, the CSF leaks had stopped, the patient's temperature returned to normal, and the chest CT scan showed normal findings .Aspiration pneumonia occurs after the aspiration of microorganisms from the oral cavity or nasopharynx. It has been reported that the posterior segments of the upper lobes and superior segments of the lower lobes are typically involved in supine patients and that the posterior segments of the lower lobes are involved in upright patients , 3. The The chest CT in the case of CSF leaks associated with delayed identification of iatrogenic skull base injury during endoscopic sinus surgery showed imaging findings similar to those of aspiration pneumonia found in bedridden patients who are always in a supine position.If a patient with CSF leak after ESS experiences fever, cough, or fatigue, physicians should consider aspiration pneumonia in addition to meningitis.


However, the strong cerebrospinal fluid (CSF) signal in T2w images interferes with depicting the intracranial vessel wall. In this study, we propose a T2-prepared sequence for whole-brain IVWI at 3T with CSF suppression.T2 preparation and inversion recovery (T2IR) was used to suppress the CSF signal and was incorporated into the commercial three-dimensional (3D) turbo spin echo sequence-Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE). This new technique  was evaluated on nine healthy volunteers and compared with two other commonly used 3D T2-weighted sequences: T2w-SPACE and FLAIR-SPACE (FLAIR: fluid-attenuated inversion recovery). The signal-to-noise ratios (SNRs) of the vessel wall (VW) and CSF and contrast-to-noise ratios (CNRs) between them were measured and compared among these three T2-weighted sequences. Subjective wall visualization of the three T2-weighted sequences was scored blindly and independently by two radiologists using a four-point scale followed by inter-rater reproducibility analysis. A pilot study of four stroke patients was performed to preliminarily evaluate the diagnostic value of this new sequence, which was compared with two conventional T2-weighted sequences.A preparation module that combines T2IR-SPACE had the highest CNR (11.01 ± 6.75) compared with FLAIR-SPACE  and T2w-SPACE . The subjective wall visualization score of T2IR-SPACE was higher than those of FLAIR-SPACE and T2w-SPACE ; the two radiologists’ scores showed excellent agreement (ICC = 0.883).T2IR preparation module markedly suppressed the CSF signal without much SNR loss of the other tissues  compared with the IR pulse. Our results suggest that T2IR-SPACE is a potential alternative T2-weighted sequence for assessing intracranial vascular diseases.The T The T2Id system .2IR preparation module with 3D variable-flip-angle TSE- Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE) acquisition, called T2IR-SPACE, and achieved high resolution IVWI at 3.0T. The performance of the new sequence was assessed in a simulation study and an in vivo study in healthy volunteers and patients. The preliminary work for this study was partially reported in In the present study, we combined the T2IR-SPACE sequence comprises two parts  method  method . First, of -90xo  but with2IR-SPACE sequence. The simulation parameters were as follows: TR/TE = 2500/92 ms; echo spacing (ESP) = 4.4 ms; echo train length (ETL) = 77; TEprep = 200 ms; and TI = 950 ms. The T1 and T2 values were 4300 and 2200 ms for CSF (2IR module (TEprep and TI) is provided in the Supporting Material  and 3D T2-weighted vessel wall imaging with a FLAIR preparation pulse to suppress CSF (FLAIR-SPACE) were also simulated and compared with the proposed T2IR-SPACE sequence. The imaging parameters were adjusted to achieve the same spatial resolution and spatial coverage in the same scan time for all three sequences. The simulation parameters for T2w-SPACE were the same as those for T2IR-SPACE (2w-SPACE). For FLAIR-SPACE, the simulation parameters were TR/TE = 6250/345 ms, ESP = 4.4 ms, ETL = 195, and TI = 2100 ms. The recently developed techniques, such as delay alternating with nutation for tailored excitation (DANTE) prepared T2w-SPACE and AntiDrive were also compared with our proposed T2IR-SPACE  equipped with a 32-channel head coil. Nine healthy volunteers  without known cerebrovascular disease were recruited for the volunteer study. Four patients  with symptoms of stroke and a diagnosis of intracranial arterial stenosis based on earlier MR angiography or computed tomography angiography were recruited for the pilot study. The patients were recruited during initial hospitalization within 30 days of symptom onset. Two more volunteers  were recruited to compare DANTE prepared T2IR-SPACE, T2w-SPACE, and FLAIR-SPACE. The imaging parameters were the same as those in the simulation and were summarized in For each volunteer, IVWI using whole-brain coverage was performed using T2IR-SPACE, T2w-SPACE, and FLAIR-SPACE, respectively) were conducted for two patients. The other two patients underwent only T2IR-SPACE and T2w-SPACE scans because they could not endure the long scan times. The imaging parameters were the same as those in the volunteer study.In the patient study, three scans ; Segment 2 included the basilar artery (BA) and V3–4 segments of VA; Segment 3 included C4–7 segments of ICA. Image quality was assessed using a four-point scale: 0 (poor), more than 50% of the vessel walls were invisible; 1 (acceptable), more than 50% of the walls were visible, but with noticeable blurring or limited SNR and CNR between the vessel wall and CSF; 2 (good), vessel walls were continuously visible but were slight blurred; 3 (excellent), vessel walls were clearly depicted with good SNR, CNR and sharpness. Scores >1 were regarded as diagnostic.Qualitative image analysis was performed at a workstation  by two experienced radiologists  independently. The 3D image sets of T2IR-SPACE, FLAIR-SPACE and T2w-SPACE images were co-registered on the workstation using 3D image fusion functionality . 2D cross-sectional wall images were reconstructed by an experienced MRI scientist (Z.N.) using multiplanar reconstruction for each arterial segment; five vessel segments were reconstructed for each subject. Care was taken to ensure location matching among different scans. The SNR of the vessel wall and adjacent CSF and the contrast-to-noise ratio (CNR) between them were measured using region-of-interest (ROI) analysis. Based on the aforementioned 2D images, the ROI was manually prescribed on the images where the vessel walls were clearly visualized in all three sequences, and the mean signal intensities (S) of these sequences were obtained. The SNR is defined as SNR = S/σ, where S is the mean signal intensity of a certain tissue (VW or CSF) and σ is the noise measured as the standard deviation from an artifact-free air region of the nasal cavity. The CNR between the VW and CSF is defined as CNR = SNRVW-SNRCSF.Quantitative analysis was performed at the following three vessel segments surrounded by CSF with different flow rate: the M1 segment of the MCA of both the left and right sides, BA, and internal carotid artery cavernous segment  of both the left and right sides. Tp < 0.05/2 = 0.025 (Bonferroni correction). The data were presented as means ± standard deviation.Statistical analyses were performed by using SPSS software . The intra-reader correlation coefficient (ICC) was obtained from a two-way random model. The ICC value was interpreted as excellent, good, fair, and poor when it was between 0.75 and 1, between 0.6 and 0.74, between 0.4 and 0.59, and less than 0.4, respectively. Paired two-tailed Wilcoxon signed-rank test was performed on the data sets to determine the significance of the differences. The significance level was set at 2IR-SPACE (xy) modulated by T2 decay during the T2IR module, in which, the Mxy of CSF decreases slightly because of its long T2 value and the Mxy of vessel wall is close to zero at the end of the T2IR module; (II) a second z recovering from the −z axis during TI; (III) Mxy during the SPACE acquisition that performs around the null point of CSF; and (IV) recovery of the Mz during Trec. The signal evolution for FLAIR-SPACE  Mxy during the SPACE acquisition around the null point of CSF; and (III) recovery of Mz during the remainder of the TR. T2w-SPACE signal evolution (xy during the SPACE acquisition and (II) recovery of Mz during the remaining time of TR. xy during the SPACE acquisition in T2IR-SPACE, FLAIR-SPACE, and T2w-SPACE, respectively. The CSF signals were well suppressed in both T2IR-SPACE and FLAIR-SPACE (both < 0.05). The signal intensity of the vessel wall in T2IR-SPACE (∼0.2) was almost twice that in FLAIR-SPACE (∼0.1). Although T2w-SPACE had the highest vessel wall signal (∼0.25) among these three sequences, the unsuppressed CSF signal (∼0.5) resulted in a low contrast between the vessel wall and CSF.The simulated signal evolutions within one TR were plotted after ten repetitions of the pulse sequence until the signal evolutions reached the steady-state for subsequent repetitions. The signal evolution for TIR-SPACE  compriseIR-SPACE  comprisevolution  has two 2IR-SPACE images while the signal of other tissues maintained a high level. The qualitative image analysis results are summarized in 2IR SPACE showed better overall image quality when visualizing the intracranial vessel wall . The inter-reader reliability was 0.883 . Representative images are shown in 2IR-SPACE images, while they were almost invisible at most segments on FLAIR-SPACE images because of their low SNRs (labeled by red arrows). Additionally, the intracranial vessel wall could not be differentiated in T2w-SPACE images because of the high CSF signal.The MR scans were successfully acquired in all the participants with adequate or excellent image quality. As expected, the CSF signal was effectively suppressed in all T2IR-SPACE showed the best image contrast between the vessel wall (VW) and CSF (CNR: 11.01 ± 6.75) among the three sequences. As expected, the SNRs of the VW and CSF from T2w-SPACE were the highest , but the high CSF signal made delineating the outer boundary of the intracranial vessel wall challenging. The CSF signal was effectively suppressed in both T2IR-SPACE and FLAIR-SPACE, but the T2IR-SPACE had a much higher vessel wall signal , resulting in a higher CNR between the VW and CSF . The CNRs approximately agreed with the Bloch simulation predictions shown in The quantitative results are summarized in 2IR-SPACE image than on the FLAIR-SPACE and T2w-SPACE images. 2IR-SPACE imaging  was diagnosed as probable vasculitis , concent imaging .2IR-SPACE and DANTE prepared T2w-SPACE, where T1w-SPACE was also scanned as a reference standard. Wall thickening was detected at the M2 segment of the right MCA in T2IR-SPACE (yellow arrow). This lesion was confirmed in T1w-SPACE but could not be visualized in DANTE-SPACE. We performed T2w-SPACE with AntiDrive in another healthy subject. The result is shown in 2IR-SPACE achieved high spatial resolution, large spatial coverage and, more importantly, remarkable CSF suppression and enhanced WM-CSF CNR. As shown in our preliminary results, T2IR-SPACE greatly improves the ability of conventional T2w-SPACE to differentiate vessel walls from CSF and is a potential alternative to T2w-SPACE for assessing intracranial vascular diseases.T2IR-SPACE had better intracranial wall visualization than the other two sequences in all vessel wall segments  segments of the MCA or adjacent to the brain parenchyma  of CSF rather than the velocity of CSF. Hence, this approach is insensitive to slow flow and flow direction. In T2w-SPACE with AntiDrive, the CSF signal is not well suppressed and the intracranial vessel wall is not visible. This is because the TR (2500 ms) is relatively long in T2w-SPACE, although the AntiDrive pulse inverts the Mz of CSF to the negative longitudinal axis at the end of the echo train, the CSF still recovers to a relatively high value during the long Trec. However, in T1w-SPACE, CSF signal is already low enough and lower than the brain parenchyma due to the short TR, and the application of AntiDrive pulse would further reduce the CSF signal and improve the T1 contrast. This is the reason why AntiDrive pulse is widely used in T1-weighted IVWI.Recently, DANTE prepared SPACE and SPACE with AntiDrive have gained popularity in IVWI due to their efficient CSF suppression and superior SNR efficiency . We comp0 field inhomogeneity. However, the composite pulse has a narrower bandwidth with limited RF amplitude when implemented on a human scanner and is thus sensitive to B1 field inhomogeneity.In this study, a composite 90° pulse was used instead of a hard pulse to tip the magnetization down with better immunity to B1-weighting imaging  compared with the IR pulse. Our results suggest that T2IR-SPACE is a potential alternative T2-weighted sequence for assessing intracranial vascular diseases.In the present study, we developed a new whole-brain Thttps://doi.org/10.5281/zenodo.4145224.The datasets used and analyzed during this study are available from the corresponding author on reasonable request and filling out NEL-Consent redirecting to “Zenodo” with the doi: The studies involving human participants were reviewed and approved by Institutional Review Board of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Institutional Review Board of Shenzhen Second People’s Hospital. The patients/participants provided their written informed consent to participate in this study.LZ and YaZ designed the sequence and experiments and drafted the manuscript. LZ performed the Bloch equation simulations. YQ and YiZ performed the subjective assessment. LW contributed to data collection. LR recruited the patients. NZ and LW measured the SNR and CNR. XL and YL contributed to the study design and helped revised the manuscript critically. XL and HZ conceived the study design and provided supervision of the whole project and critical review of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.