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Hemostatic and inflammatory markers in obese youths: effects of exercise and adiposity.

OBJECTIVES: To determine the relation of hemostatic markers to cardiovascular fitness and adiposity and the effect of physical training (PT) on these markers. STUDY DESIGN: Seventy-four obese teenagers were randomly assigned to 8 months of lifestyle education (LSE), LSE plus moderate-intensity PT, or LSE plus high-intensity PT. Measures included fibrinogen, plasminogen activator inhibitor-1 (PAI-1), D-dimer, C-reactive protein (CRP), fitness, percent body fat (%BF), and visceral adiposity (VAT). RESULTS: At baseline, fibrinogen and CRP were significantly correlated with %BF and VAT (0.27 </= r </= 0.51), and fitness (r = -0.39, r = -0.43, respectively); PAI-1 with %BF (r = 0.30) and VAT (r = 0.48); D-dimer with fitness (r = -0.24). Although PT produced significant changes in fitness and adiposity, there were no significant group differences in the hemostatic markers. Change in PAI-1 was significantly correlated with its baseline value (r = -0.47) and change in %BF (r = 0.38). Changes in D-dimer and CRP were significantly correlated with their respective baseline values (r = -0.68,r = -0.48, respectively). CONCLUSIONS: Unfavorable levels of fitness and adiposity were associated with higher levels of hemostatic markers, putting individuals with this profile at greater risk for future cardiovascular disease. No evidence was provided that 8 months of PT had a direct influence on these markers in obese youths.

Adipose Tissue↗

Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease.

Recombinant factor VIIa (rF.VIIa) is a two-chain procoagulant enzyme (Mr, approximately 50,000) active only when complexed with tissue factor in the extrinsic clotting system. We administered human rF.VIIa to hemophilic and von Willebrand disease (vWD) dogs to determine its hemostatic effectiveness and survival in the circulation. Hemophilia A dogs lacking factor VIII demonstrated an immediate increase in plasma rF. VIIa and prompt stoppage of hemorrhage at bleeding time (BT) sites. In seven studies in two dogs, the range of dose of rF. VIIa was 50-220 micrograms/kg, with an apparent 7- to 11-fold increase in plasma factor VII and a mean recovery in plasma of 34%. The t1/2 was 2.8 +/- 0.5 hr. The BT was normalized except in an animal given the minimum dose. In four studies in two hemophilia B dogs lacking factor IX, BT was normalized. The elevation in plasma factor VII was by a factor of 8-30, with a mean recovery of rF.VIIa in plasma of 44%. In two studies in a homozygous vWD dog lacking von Willebrand factor, which is needed for platelet function, BT was not corrected even though large doses of rF. VIIa were given. The human rF. VIIa protein was immunogenic for dogs. These studies indicate that factor VIIa corrects the hemostatic defect in dogs with hemophilia A and B, diseases primarily of the intrinsic clotting system, but does not correct the hemostatic defect in vWD.

Animals↗

Lysophosphatidylcholine acts as an anti-hemostatic molecule in the saliva of the blood-sucking bug Rhodnius prolixus.

Blood-sucking arthropods possess a variety of anti-hemostatic factors in their salivary glands to maintain blood fluidity during feeding. In this work we demonstrate the anti-hemostatic properties of lysophosphatidylcholine (lysoPC) isolated from the salivary glands of Rhodnius prolixus. First, we examined salivary glands of fourth and fifth instar nymphs for their phospholipid composition. The lumen displayed an accumulation of its phospholipid content, mainly phosphatidylcholine and lysoPC, with a 6-fold increase for the latter. To determine the presence of phospholipids in the saliva, fourth instar nymphs were fed with a32P-enriched blood meal. After 28 days their saliva was collected and subjected to lipid extraction, thin-layer chromatography, and autoradiography. The results showed the presence in the saliva of the same phospholipids present in the lumen. We then examined possible biological roles of these phospholipids when compared with other known effects of lysoPC. The luminal lipid extract and purified lysoPC from the lumen and saliva were tested for inhibition of washed rabbit platelets' aggregation induced by alpha-thrombin and platelet-activating factor. Both the luminal lipid extract and salivary lysoPC showed an increasing inhibition of aggregation, which correlated with the response of the platelets to standard lysoPC (up to 13 microg/ml). Next, salivary lysoPC was incubated with porcine arterial endothelial cells for 24 h. After incubation, culture medium was assayed for nitric oxide and showed increased nitric oxide production, similar to control cells exposed to standard lysoPC (up to 20 microg/ml). Together these data demonstrate the presence of lysoPC in the saliva of Rhodnius prolixus and its potential anti-hemostatic activities.

Animals↗

Comparison of two topical collagen-based hemostatic sponges during cardiothoracic procedures.

The need for topical hemostasis during cardiothoracic procedures continues to fuel the development of additional hemostatic products with a focus on minimizing cost and increasing efficacy. The efficacy of a recently approved collagen-based topical hemostatic agent (Hemostagene, Coletica, S.A., Lyon, France) was tested in a prospective randomized trial of 60 consecutive patients undergoing cardiothoracic surgical procedures. Comparisons to a control collagen sponge (Helistat, Integra Life Sciences, Inc., Plainsboro, NJ) were made and hemostasis was considered successful if bleeding was controlled in 10 min or less. We employed a unique hemorrhage grading scale to more closely assess the relative effectiveness of these different topical agents. Overall, Hemostagene and Helistat achieved a successful hemostasis rate of 75% and 77%, respectively, with no statistically significant difference. The Hemostagene sponge was deemed easier to handle when compared to control. During the study, neither of the products was associated with complications attributable to the topical sponge. In conclusion, Hemostagene had improved handling characteristics yet was equal to Helistat at topical hemostasis, adding an alternative to the topical hemostatic market.

Blood Coagulation↗

A new instrument for hemostatic vascular management in endoscopic surgery: diode laser (STATLase-SDL) and its handpiece (dual hook).

OBJECTIVE: The authors described experimental data in hemostatic vascular transection using a STATLase-SDL with a 780-865 nm GaA/As diode wavelength and its handpiece, Dual Hook (DH). SUMMARY BACKGROUND DATA: The STATLase-SDL and DH are newly developed devices for endoscopic surgery. It seems that the device has improved hemostatic cutting ability. METHODS: The DH was applied to the abdominal aorta (< 2 mm) of Japanese white rabbits (n = 15) under general anesthesia. Tissue temperature during laser transection and interluminal bursting pressures were measured. Histopathological examinations at the cut end were carried out by hematoxylin-eosin (H&E) and elastica Van Gleson's (EVG) stainings. To investigate short-term effects 11 days postoperatively, the cut ends of the vessels were examined histologically in the heminephrectomy group. RESULTS: The DH hemostatistically cut through arteries up to 2 mm in diameter. Temperatures at the inner hook and in adjunct tissue were higher than 160 degrees C, while that at the outer hook was lower than 80 degrees C. The bursting pressures immediately after transection was 307.2 +/- 35.2 mm Hg at a laser power of 8 W (n = 5), and 295.6 +/- 28.7 mm Hg at 10 W (n = 5). Histological examination of the transected sites on the vessels revealed well-opposed tissue welding of the vascular wall. Absence of fragmentation in the welding of the internal elastic lamina is crucial for closure of the vessel stump. Up to 11 days postoperatively, there were no direct complications related to the use of the DH. CONCLUSIONS: The STATLase-SDL and DH have good hemostatic cutting ability and might be suitable for endoscopic surgery.

Angioscopes↗

Hemostatic factors, inflammatory markers, and progressive peripheral atherosclerosis: the Edinburgh Artery Study.

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.

Aged↗

Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management.

BACKGROUND: Cardiac surgery involving cardiopulmonary bypass (CPB) leads to fulminant activation of the hemostatic-inflammatory system. The authors hypothesized that heparin concentration-based anticoagulation management compared with activated clotting time-based heparin management during CPB leads to more effective attenuation of hemostatic activation and inflammatory response. In a randomized prospective study, the authors compared the influence of anticoagulation with a heparin concentration-based system (Hepcon HMS; Medtronic, Minneapolis, MN) to that of activated clotting time-based management on the activation of the hemostatic-inflammatory system during CPB. METHODS: Two hundred elective patients (100 in each group) undergoing standard cardiac surgery in normothermia were enrolled. No antifibrinolytic agents or aprotinin and no heparin-coated CPB systems were used. Samples were collected after administration of the heparin bolus before initiation of CPB and after conclusion of CPB before protamine infusion. RESULTS: There were no differences in the pre-CPB values between both groups. After CPB there were significantly higher concentrations ( < 0.05) for heparin and a significant reduction in thrombin generation (25.2 +/- 21.0 SD vs. 34.6 +/- 25.1), d-dimers (1.94 +/- 1.74 SD vs. 2.58 +/- 2.1 SD), and neutrophil elastase (715.5 +/- 412 SD vs. 856.8 +/- 428 SD), and a trend toward lower beta-thromboglobulin, C5b-9, and soluble P-selectin in the Hepcon HMS group. There were no differences in the post-CPB values for platelet count, adenosine diphosphate-stimulated platelet aggregation, antithrombin III, soluble fibrin, Factor XIIa, or postoperative blood loss. CONCLUSION: Compared with heparin management with the activated clotting time, heparin concentration-based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.

Adult↗

Use of a new hemostatic scalpel in plastic surgery.

This assessment of a new hemostatic scalpel in plastic surgery is based on one surgeon's personal experience with this instrument in 348 cases representing a variety of procedures. With its improved hemostatic capabilities the hemostatic scalpel may offer the following advantages: better visualization of the surgical field, enhanced precision, and more delicate control. Considerable time and experience are necessary, however, before the scalpel can be used safely and competently.

Breast↗

Association between carotid atherosclerosis and hemostatic markers in patients with cerebral small artery disease.

The purposes of this study were to investigate the association between carotid atherosclerosis and hemostatic markers, and to elucidate the difference in hemostatic markers between intima-media thickening and plaque formation in patients with cerebral small artery disease. We investigated carotid atherosclerosis by assessing diffuse intima-media thickness measurements and localized plaque using B-mode ultrasonography, and we measured the concentrations of plasma fibrinogen, beta-thromboglobulin and platelet factor 4 as markers for platelet activation, and the activity of plasma von Willebrand factor as a marker for endothelial damage. The intima-media thickness was significantly associated with age, male sex, the concentrations of plasma beta-thromboglobulin and platelet factor 4, and the activity of plasma von Willebrand factor. The plaque score showed a significant association with male sex, the concentration of fibrinogen, and the activity of plasma von Willebrand factor. These results may indicate that underlying mechanisms are not the same between the intima-media thickness and plaque formation. We suggest that hemostatic markers could reflect the severity of carotid atherosclerosis in patients with cerebral small artery disease, and that preventive antiplatelet therapies against brain infarction might be necessary for patients with severe carotid atherosclerosis.

Adult↗

Hemostatic changes after dietary coenzyme Q10 supplementation in swine.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10). We elucidated the effect of CoQ10 on certain hemostatic parameters that may influence the progression of heart disease. Twelve Yorkshire swine were randomized to receive diet supplementation with either CoQ10 or placebo for 20 days. Blood samples were obtained at baseline and at the end of the feeding period. At the end of the protocol, there were no significant differences in hemostatic parameters in the placebo group. A significant increase in total serum CoQ10 level (from 0.39 +/- 0.06 to 0.96 +/- 0.04 microgram/ml, p < 0.001) was noted after the feeding period in the CoQ10-supplemented group. We observed significant inhibition of ADP-induced platelet aggregation (-9.9%) and a decrease in plasma fibronectin (-20.2%), thromboxane B2 (TXB2, -20.6%), prostacyclin (-23.2%), and endothelin-1 (ET-1, -17.9%) level. There were no changes in the plasma concentrations of the natural antithrombotics [antithrombin-III (AT-III), protein S, and protein C] after CoQ10 supplementation. CoQ10 supplementation in a dose of 200 mg daily is associated with mild antiaggregatory changes in the hemostatic profile. Clinical beneficial effects of CoQ10 may be related in part to a diminished incidence of thrombotic complications.

Angiotensin III↗

The use of a combination nail elevator and hemostat clamp. New instruments for nail avulsion.

Nail avulsion surgery is frequently accomplished using a hemostat clamp with or without a nail elevator device. Two new instruments have been developed that combine the useful design specifications of the hemostat clamp with the nail elevator device. Specifically, one blade of the hemostat is replaced with either a nail elevator spatula or a Freer septum elevator allowing nail elevation, clamping, and removal with a single instrument. Use of either device is more efficient because nail avulsion is completed using a single instrument thereby reducing procedural steps and handling and sterilization costs. Furthermore, these instruments may reduce the risk of trauma to the nail bed and matrix during nail avulsion. The instruments and their use are described.

Humans↗

Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I).

BACKGROUND: The long-term associations of established risk factors for coronary heart disease (CHD), for example cholesterol, are well known, but not for the less familiar hemostatic variables. OBJECTIVES: To establish whether associations between hemostatic variables and CHD first identified nearly three decades ago have persisted long-term. METHODS: The first Northwick Park Heart Study (NPHS-I) recruited 2167 white men and 941 white women, average age at entry 48 years, on whom measures of factor (F) VII activity (VIIc) and plasma fibrinogen were carried out, both at entry and at follow-up approximately 6 years later. RESULTS: During a median follow-up of 29 years, 231 male and 36 female CHD deaths were recorded from notifications by the Office for National Statistics. VIIc at recruitment was significantly related to CHD mortality, corrected rate ratio, RR, per 1 SD increase 1.56 (95% CI 1.29, 1.88) in men and RR 1.78 (95% CI 1.17, 2.72) in women. Recruitment fibrinogen was also strongly related to CHD mortality in men, RR 1.63 (95% CI 1.33, 1.99) but not in women, RR 0.75 (95% CI 0.40, 1.43). The associations persisted after controlling for confounders and were confirmed using 6-year follow-up measurements and in analyses omitting deaths within 10 years of recruitment. CONCLUSIONS: The hemostatic system contributes to CHD mortality, and its effect is stable over time. For VIIc, the effect was similar in men and women, while for fibrinogen it appeared to be present only in men.

Adolescent↗

Hemostatic imbalance in active and quiescent ulcerative colitis.

OBJECTIVE: In healthy conditions, factors inducing or inhibiting coagulation and factors inducing or inhibiting fibrinolysis are in balance. In ulcerative colitis, hypercoagulation is presumed, which may explain part of the clinical features of this disease. Therapy strategies affecting hemostasis may improve the course of ulcerative colitis. This study was conducted to evaluate the balance of coagulation and fibrinolysis in the course of treatment of active ulcerative colitis. METHODS: Patients with active ulcerative colitis were studied by serial determination of markers of the coagulation cascade (thrombin-antithrombin complexes and fibrin degradation products [FbDP]) and the fibrinolytic cascade (fibrinogen degradation products [FgDP]). Parameters of inflammation were also measured (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], albumin, platelet count, and fibrinogen). Disease activity was assessed by endoscopic and histopathological scores. Follow-up measurement was performed in the course of treatment at the third or fourth month after baseline. Measurements were compared with healthy controls. RESULTS: Thirty-three patients and 22 healthy controls were included. During active ulcerative colitis, inflammatory parameters (CRP, ESR, platelet count) and hemostatic parameters (thrombin-antithrombin complexes, fibrinogen, FgDP, and FbDP) were elevated in comparison with healthy controls. Albumin was decreased and antithrombin-III remained unchanged. During treatment, disease activity decreased significantly endoscopically and histopathologically (p < 0.001). CRP, ESR, platelet count, and fibrinogen also decreased significantly. The hemostatic balance, expressed as the ratio between the plasmin-dependent generation of FgDP and coagulation-dependent generation of FbDP, increased from 0.69 to 1.12 during treatment, mainly because of a decrease of FbDP. In healthy controls, this ratio was CONCLUSIONS: The coagulation and fibrinolytic cascades were activated in active ulcerative colitis, with a hemostatic imbalance in favor of coagulation. This hypercoagulability persisted in 20% (7/33) of patients with ulcerative colitis in remission. The decrease of FbDP and the increase in the FgDP/FbDP ratio during reconvalescence of ulcerative colitis showed that the coagulation cascade was more activated than the fibrinolytic cascade in active disease.

Adult↗

Hemostatic and fibrinolytic indices in neonatal foals with presumed septicemia.

Thirteen coagulation tests evaluating hemostatic and fibrinolytic indices and serum cytokine and plasma endotoxin concentrations were obtained in 34 foals with a positive sepsis score (septic group) and 46 age-matched healthy foals. Compared to healthy foals, the prothrombin, activated partial thromboplastin, and whole blood recalcification times were significantly longer in septic foals. The fibrinogen and fibrin degradation products concentrations, percent plasminogen, alpha-2 antiplasmin, and plasminogen activator inhibitor activities, and tumor necrosis factor and interleukin-6 activities were greater in septic foals. Protein C antigen and antithrombin III activity were significantly lower in septic foals. Blood cultures were positive for growth and endotoxin was detected in 19 of 29 and 15 of 30 septic foals, respectively. In septicemic foals with detectable endotoxin in the plasma, the prothrombin and activated partial thromboplastin times were significantly longer and the plasminogen and antithrombin III activities were significantly less than in septic foals in which endotoxin was not detected. Twenty-three of the 34 septic foals did not survive. Septic foals that did not survive were most likely to have a positive blood culture in which a gram-negative organism was isolated. Histopathologic evidence of hemorrhage was evident in 11 foals at postmortem examination and thrombosis was identified in 2 foals. The prothrombin time was significantly longer in foals that had multisite hemorrhage at postmortem examination. The results of this study indicate that clinically relevant alternations in hemostatic and fibrinolytic indices occur in neonatal foals with septicemia and that derangements can be correlated with the presence of endotoxin in plasma. Derangements in hemostatic or fibrinolytic indices were helpful in identification of septic foals with increased risk of coagulopathy, but were not helpful in predicting hemorrhage as compared to thrombus formation. Survival of septicemic foals was correlated with gram-negative bacteremia, but not with the presence of endotoxin or coagulopathy.

Aging↗

Genetically engineered biologically based hemostatic bioassay.

Real-time direct measures of hemostatic parameters in vivo are required for optimizing the dynamic delivery of coagulation modifying pharmacotherapies. Typical sensors of physiologic functions in vivo, however, have only a restricted array of sensory inputs, and thus limited capacity to monitor thrombotic and hemostatic activity. To overcome this limitation we have developed a genetically engineered excitable cell line that can be potentially used for an implantable thrombin biosensor. Specifically, we have generated stem cell-derived cardiac myocyte aggregates overexpressing the human thrombin receptor, protease activated receptor-1 (PAR-1), which exploit the inherent electropotential input-output relationship of the cells to detect local changes in thrombin activity. In vitro, the signaling activity of PAR-1 cardiac myocytes was highly responsive to thrombin, inducing a sixfold increase in intracellular cAMP as compared with a twofold increase in control cells. In vivo, the engineered myocytes also detected alterations in local coagulation potential. Specifically, PAR-1 engineered cells implanted in vivo detected local increases in thrombin with a doubling in chronotropic activity compared with a 50% increase in control aggregates. Overall these studies demonstrate the potential of genetic engineering to expand the physiologic signals recognized by excitable cells, and may facilitate the translation of this approach for the real-time monitoring of hemostatic function in vivo.

Animals↗

The effects of long-term graft preservation on intraoperative hemostatic changes in liver transplantation. A comparison between orthotopic and heterotopic transplantation in the pig.

UNLABELLED: We compared hemostatic changes during OLT and HLT after various periods of graft storage, to investigate whether the host liver in HLT protects the recipient from hemostatic deterioration induced by severe graft storage damage. In particular, the mechanism of fibrinolytic deterioration was investigated. The effect of prostaglandin E1 (PGE1) on these parameters was also studied. MATERIAL AND METHODS: 69 pigs underwent either OLT (N = 32) or HLT (N = 37) with a graft stored for 2 hr (N = 31), 24 hr (N = 16), 48 hr (N = 7), or 72 hr (N = 15). PGE1 was given intravenously to both donor and recipient animals and was added to the preservation and flushing solutions. Fibrinolysis (euglobulin clot lysis time, t-PA activity and alpha 2-antiplasmin) and coagulation parameters (activated partial thromboplasmin time, prothrombin time, fibrinogen and platelet count) were measured at several intervals during transplantation. STATISTICS: Univariate non-parametric tests were used for analysis of coagulation and fibrinolysis parameters. For the three main variables- i.e., the type of transplantation, the use of PGE1, and the preservation time, multiple regression analysis was performed. RESULTS: Fibrinolytic activity increased during the anhepatic period of OLT. Graft reperfusion was followed by a rise in t-PA in both OLT and HLT. In HLT, t-PA quickly returned to normal, whereas a continuous increase was found in OLT. The coagulation parameters, in turn, remained unchanged during the anhepatic period and deteriorated in OLT compared to HLT. The duration of graft storage was directly related to the severity of the hemostatic changes, although this effect was more apparent in OLT than in HLT. CONCLUSIONS: Changes in hemostasis are more pronounced in OLT than in HLT. This suggests that the host liver protects the recipient from the effects of graft storage damage, even after long preservation times. Early postreperfusion fibrinolytic activity was presumably due to t-PA release from the graft both in OLT and HLT. The further rise t-PA in OLT might be caused by the release of cytokines from the graft, that subsequently evoke endothelial t-PA release. In HLT, t-PA and cytokines may be cleared by the native liver. No positive or negative effect of PGE1 on coagulation or fibrinolysis parameters was noticed.

Alprostadil↗

Cellular arrangement of human breast cancer cell lines determines hemostatic parameters.

Two in vitro models are compared to investigate whether cellular configuration or composition of the matrix in which the cells are cultured influences growth and/or prognostic parameters. T47D, MCF-7 and Hs578T breast cancer cell lines were cultured on two different matrices (agarose and collagen). Growth curves, biological markers (Ki-67, p53 and bcl-2) and the expression of hemostatic parameters were studied. The tested hemostatic parameters were urokinase-type plasminogen activator, tissue-type plasminogen activator and plasminogen activator inhibitor as fibrinolytic parameters and von Willbrand factor, tissue factor, antithrombin III, factor X and factor Xa as coagulation parameters. We found that T47D and MCF-7 formed spheroids in both matrices. Hs578T did not form spheroids; instead, the cells remained single cells in the agarose matrix and grew invasively through the collagen matrix. Expression of the biological markers was similar for spheroids and monolayers. In contrast, a clear difference in expression of hemostatic factors by spheroids and monolayers was found.

Biomarkers↗