Baseline characteristics
\r\n\tCases of Corrosion in PA industrial equipment and plants are presented and discussed, based on the author's experience and knowledge.
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Despite routine use of ASA before CABG, and lifelong following the revascularization, patients who undergo CABG remain at high risk of long-term events in any vascular bed (cerebrovascular, cardiovascular, peripheral). The handicap of management of antiplatelet agents in the perioperative period of cardiac surgery requires close collaboration between cardiologists, surgeons and anaesthesiologists. It is necessary to avoid thrombotic complications maintaining the antiagregation, but balancing bleeding complications. [1]
Combined antiplatelet therapy employing agents from different pharmacological classes is characterised by good safety and efficacy profiles.
Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Antiplatelet therapy and antithrombotic therapy have been demonstrated to favorably modify clinical outcome, and recent trials of revascularization in ACSs have demonstrated a reduction in the frequency of major cardiac events.[2-14]
Multiple clinical trials showed the favorable benefit/risk ratio of clopidogrel over aspirin justifying the indication for using clopidogrel in a wide range of at risk patients and in long-term prevention in various manifestations of atherosclerosis.[2-9]
Antiplatelet and antithrombin therapy can have synergistic actions that reduce the risk of spontaneous or revascularization, especially percutaneous coronary intervention (PCI)–related events. On the other hand, all effective antithrombotic agents also increase the risk of bleeding, especially bleeding that results from vascular access or associated with surgery, including coronary artery bypass grafting (CABG).
The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial demonstrated that the combination of clopidogrel and aspirin was superior to aspirin alone for patients hospitalized with non–ST-elevation ACSs.[5] The therapy was in addition to the current standard of care, including heparin or low-molecular-weight heparin, antianginal therapy, and revascularization.[5, 6, 15].
Actually the field of the indications of use of the Clopidogrel is being continuously updated. There are different type of patients who benefit from antiplatelet therapy [16, 17] Moreover the combination of two antiagregant drugs (mainly ASA and clopidogrel) in high risk patients is a practice more and more extended [18] and dual antiplatelet therapy is recommended and has to be maintained at least 12 months after drug eluting stent placement [19].
On the other hand, in patients undergoing coronary artery bypass grafting, immediate postoperative antiagregant regimens are only regulated for routinely use Aspirin.
Antiplatelet therapy is critical in the management of coronary artery disease. For patients undergoing coronary artery bypass graft surgery (CABG), controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic complications.
Despite > 30 years of experience with antiplatelet agents during CABG, questions remain regarding their perioperative safety and efficacy. The results of continuing randomized controlled trials should further clarify the role of perioperative aspirin and clopidogrel therapy and help redefine the modern antiplatelet management of coronary artery bypass patients.
Following surgery, extensive evidence supports the use of aspirin, in doses of 100 - 325 mg daily, to be administered in 48 h postoperatively and continued indefinitely. Less is known regarding the use of clopidogrel following CABG, although it is now recommended as postoperative antiplatelet therapy in patients with recent acute coronary syndromes.[20]
It is very important to identify the optimal timing and dose ofAaspirin following CABG, and to assess the role of postoperative Clopidogrel therapy.
The recommendations regarding the treatment with Clopidogrel in coronary artery sugery do not take into consideration the cost-benefit ratio which reflect the usefulness from economic point of view, probably because of a the complexity of factors of this equation.
To compare the efficacy and safety of Clopidogrel with Aspirin and Aspirin plus Clopidogrel in patients undergoing surgical coronary revascularisation in the immediate postoperative period and 1 year after coronary artery bypass grafting depending on the type of the lesion, on the type of the surgical procedure and on the associated risk factors for gastrointestinal bleeding.
To evaluate the importance and utility of antiplatelet therapy with Clopidogrel early postoperatively in the intensive care unit (ICU) for the prevention of postoperative complications
To establish the prognostic implications of the type of the perioperative antiagregant regimen in patients with CABG and to determine which therapy can reduce hospital stay after cardiac surgery and improve the quality of life of these patients.
To determine the indications for using Clopidogrel or Aspirin or Aspirin plus Clopidogrel in coronary artery surgery depending on the cost-benefit ratio and its economic implications.
Randomized,, open label three years clinical trial with open study period, carried out on 1200 pts undergoing coronary artery bypass grafing divided in three parallel groups: Group A: Clopidogrel po 75 mg/day, Group B: Aspirin po 75 mg/day and Group C: Aspirin 75mg plus Clopidogrel 75mg once daily.
The main phases of the study protocol were: (Figure 1)
Enrollment phase – there were enrolled one thousand and two hundred patients undergoing CABG, in the immediate postoperative period
Active treatment phase – after randomisation all patients received antiagregant therapy:
Group A with Aspirin 75 mg daily
Goup B with Clopidogrel 75 mg daily
Group C with combination of Aspirin 75 mg with Clopidogrel 75 mg.
The treatment began the second day postoperatively and lasted no less than 1 year postoperatively.
follow –up phase – all patients were evaluated clinically and paraclinically daily for the first ten days and at one, three, six months and one year postoperatively. Patients were followed for a minimum of 1 to a maximum of 3 years, regardless of discontinuation of the study drug. Follow-up assessments took place at 1, 3, 6, and 12 months for all patients and at 1, 2 and 3 years for patients randomized early in the study.
The study included all patients undergoing coronary artery bypass grafting, who underwent surgery in an Emergency Institute for Cardiovascular Diseases between January 1st 2008 and May 1st 2011 who did not have the non – eligibility criterias.
Patients were over the age of 21, and able to provide informed consent and agreed to comply with all protocol-specified procedures.
Treatment protocol phases
Patients were excluded from enrolment in the study if any of the following criteria were met:
Active internal bleeding or risk of hemorrhagic diathesis
Q-wave myocardial infarction within 24 hours prior to randomization
Cardiogenic shock.
Serum Creatinine ≥ 3.0 mg/dl
severe hepatic failure with ALT or AST > 3x ULN
Previous use of a GPIIb/IIIa antagonist within 7 days
Need for long-term anticoagulant or NSAID use
Failed PCI within 2 weeks prior to randomization
Active participation in another clinical trial
Failure to comply with the hospital protocol
The occurrence of adverse events (skin reactions, gastrointestinal symptoms, active internal bleeding)
Failure to comply with the hospital protocol/ absence to follow-up
The protocol was approved by the institute management, and every patient signed the informed consent form.
The essential inclusion criteria (gender,mean age, comorbidities, number of grafts per patient, the type of the grafts (arterial or venous) and the mean left ventricular ejection fraction, left ventricular diastolic performance and left atrial dimensions (diameters and area), the duration of treatment and assessment criteria were similar in the three treatment groups (p<0.0001). All patients received standard therapy including beta blockers, IEC, statins throughout the study period. The patients with exclusive arterial revascularisation also received calcium channel blockers agents but their number was similar in the three groups of study.
Clinical and laboratory parameters were initially assessed, at baseline and at each visit until the end of the study period.
The clinical measurements included: NYHA class for heart failure, presence of angina pectoris, ventricular rhytm, patient compliance and quality of life.
Laboratory parameters included: the usual blood tests (platelet count, hemoglobin, hematocrit, aminotransferases, LDH, biochemistry cholesterol and tryglycerides levels), electrocardiogram(with the evaluation of rhythm, frequence and ST-T elevation), 24 hours ECG Holter monitoring for silent ischemia, stress efort test at 1,3,6 months and 1 year postoperatively and when angina occurred (Bruce or Bruce modified protocol), echocardiography (with assessment of the LV dimensions, ventricular sistolic and diastolic performance, ventricular walls contractility - segmental kinetics, mitral regurgitation degree) and coronarography at 1 year when the other tests where positive for ischemia. Also, at each visit were recorded the occurrence of major and minor bleeding episodes, gastrointestinal symptoms, skin reactions, thrombocytopenia and lab tests abnormalities.
24 hours ECG Holter used a 12 channels monitoring with the evaluation of conduction or rhythm disturbances or occurrence of silent ischemia.
Treadmill stress test was done at 1, 3, 6 months and at 1 year postoperatively and used Bruce or Bruce modified protocol. If the stress test or Holter monitoring diagnosed ischemia at one follow up visit, this was the indication for performing coronarography.
Early development of graft occlusion was diagnosed based on clinical criteria and through electrocardiogram, Holter monitoring, thoracic and transesophageal echocardiography. The appearance of gastrointestinal bleeding was diagnosed using clinical evaluation, endoscopy and colonoscopy.
The looked at all-cause mortality and major cardiac events, namely cardiac mortality, myocardial infarction or need for target lesion revascularization. The most important endpoints used for the estimation of the medium term prognosis were:
The primary endpoint (efficacy endpoint) was a composite outcome cluster of 30-day mortality, myocardial infarction, in-hospital and at 1 year occurrence of graft occlusion (efficacy endpoints), total hospital stay and immobilization (measured in days), Intensive Care Unit length of stay and cost, quality of life. Quality of life was appreciated using a scale from one to ten calculated on the base of a questionnaire filled by the patients at each visit
The secondary endpoints at 30 days looked at in-hospital major peripheral or bleeding complications (including surgical bleeding complications, transfusion of at least two units of blood, intracranial bleeding, retroperitoneal bleeding, overt hemorrhage), neutropenia (<1.5 x 109 per litre), thrombocytopenia (<100 x 109 per litre), early discontinuation of the study drug due to a non-cardiac adverse event (including death of non-cardiac origin) (safety endpoint).
The data collected represented the fields of a database in the Visual Fox Pro computer program. Data were processed by means of computers, using the Excel, EpiInfo, Systat and SPSS programs for multivariate regression analysis and relative risk and correlation coefficient calculation
No confirmatory statistical hypothesis was pre-specified, but a detailed analysis plan was defined before the database was locked. This analysis plan was based on generating risk ratios and CIs (CI=confidence index) for the pairwise comparisons of primary interest. These comparisons were presented with the two - sided 95% CI of the relative risk and with normal p values. For the primary endpoints Kaplan-Meier curves were constructed and log-rank tests were done. For each endpoint, a two-sided 95% CI was also calculated and an overall Chi square test, comparing the three treatment groups was done [19, 21, 25].
The frequency of the primary efficacy plus safety endpoint for the Aspirin group as a reference group was 17,7%. On the basis of phase-II studies we assumed that the experimental groups with Clopidogrel and Aspirin plus Clopidogrel would result in better, or at least similar outcomes when compared with standard treatment. The sample size and power calculations were therefore based on non-inferiority of the experimental group versus the reference group. The study has 80% power to exclude, with 95% confidence (one-sided), a 1% higher rate of the primary endpoints compared with the reference group, provided the point estimate in the experimental treatment group was 1,7% lower for the efficacy endpoint and 2% lower for the efficacy and safety endpoint. [2-11, 13-18, 22]
The study included 1200 patients undergoing coronary artery bypass grafing with arteries (internal mammar, radial, gastroepiploic) or inverted saphenal veins. The patients were randomised to receive Clopidogrel 75 mg daily or Aspirin 75 mg daily or Aspirin plus Clopidogrel 75mg daily one day after surgery and in the postoperative period for no less than 1 year.. The patients undergoing also venticular remodelling for aneurysms were not taken in our study.
The baseline characteristics were similar in the three arms of the study (Table 1). Overall, the study populations were similar to those of previous trials on antiagregants.
\n\t\t\t | \n\t\t\t\t | \n\t\t\t||
Mean (SD) age (years) | \n\t\t\t62,3 (12) | \n\t\t\t62,5 (13) | \n\t\t\t62,4(12) | \n\t\t
Age"/>70 years | \n\t13,85% | \n\t14,21% | \n\t14,43% | \n
Women | \n\t25,94% | \n\t26,18% | \n\t26,62% | \n
Family history of heart disease (%) | \n\t49,62% | \n\t50,12% | \n\t49,75% | \n
Dislipidemia (%) | \n\t75,06% | \n\t75,81% | \n\t76,37% | \n
Prior myocardial infarction (%) | \n\t33,50% | \n\t33,91% | \n\t34,58% | \n
NYHA class "/>II | \n20,15% | \n20,70% | \n20,89% | \n
Prior stroke (%) | \n\t6,29% | \n\t6,73% | \n\t6,96% | \n
Peripheral arterial disease | \n\t9,82% | \n\t9,72% | \n\t10,45% | \n
Atrial fibrillation | \n\t6,04% | \n\t6,48% | \n\t6,47% | \n
Hypertension | \n\t65,49% | \n\t66,58% | \n\t64,92% | \n
Diabetes mellitus | \n\t25,19% | \n\t25,43% | \n\t25,12% | \n
Current smoker | \n\t26,45% | \n\t26,43% | \n\t25,87% | \n
Re-intervention (previous coronary artery surgery) | \n\t8,82% | \n\t8,98% | \n\t8,95% | \n
Baseline characteristics
The medications used chronically by the patients at the time of randomization were similar in the Aspirin, Clopidogrel and Aspirin plus Clopidogrel treatment arms and are are listed in Table 2
\n\t\t | \n\t\t\t | \n\t\t||
Digoxin | \n\t\t23,68% | \n\t\t23,94% | \n\t\t24,13% | \n\t
ACE inhibitors | \n\t\t67,25% | \n\t\t68,58% | \n\t\t63,68% | \n\t
Angiotensin II inhibitors | \n\t\t24,43% | \n\t\t23,69% | \n\t\t25,12% | \n\t
Beta blockers | \n\t\t89,92% | \n\t\t89,28% | \n\t\t90,29% | \n\t
Aspirin before surgery | \n\t\t61,46% | \n\t\t63,84% | \n\t\t65,17% | \n\t
Calcium channel blockers | \n\t\t25,44% | \n\t\t25,93% | \n\t\t26,37% | \n\t
Diuretics | \n\t\t19,90% | \n\t\t20,70% | \n\t\t20,39% | \n\t
Aldactone | \n\t\t21,91% | \n\t\t21,94% | \n\t\t20,89% | \n\t
Lipid lowering agents | \n\t\t89,92% | \n\t\t93,76% | \n\t\t94,28% | \n\t
Number of patients who received concomitant medications during stay in hospital
61,46% of patients received Aspirin before surgery in group A, respectively 63,84% in group B and 65,17% in group C.
The primary efficacy and efficacy plus safety endpoints and their individual components in the treatment groups are shown in Table 3.
The clinical diagnosis at the time of randomization was similar in the three treated arms of the study:
Over half of the patients presented with unstable angina (49,62% in group A, 51,63% in group B and 53.48% respectively in group C).
Approximately one in five-six patients had experienced a recent myocardial infarction (16.37% in group A, 21,94% in group B and 22.39% respectively in group C).
About a third presented with stable angina or another diagnosis requiring antiagregant regimen (aproximatively 33,6% in each treatment arm - 33.75% in group A, 33,66% in group B, 33,58% in group C).
The data base was done using Visual Fox Pro programme. The main variables used were:
Prediction variables :
patient ID Data
preoperative diagnosis
surgical risk (calculated using a scale from 1 to 10 taking into account different preoperative parameters: age, co-morbidities, severity of cardiac lesions (NYHA class), type and duration of surgical intervention, associated risk factors)
type of surgical intervention
specific variables related to the surgical performance: duration of surgical intervention, intraoperative complications
ICU duration and complications occured
• Outcomes variables:
presence and type of postoperative complications
death and its causes.
The statistical analysis was performed using the SYSTAT and SPSS programmes for:
Measurement of the power of association between the prediction variables and outcomes using different tests depending on the type of variables:
for qualitative variables: CHI square test or Fischer exact test
for quantitative variables: T test (Student test), ANOVA test or U test depending on samples volumes and Kruskal Wallis nonparametric tests or other methods of statistical correlation as analysis of simple linear and multivariate regression
Relative Risk calculation and the 95% confidence limits for treatment groups
Cost-benefit ratio calculation for using different antiplatelets agents after coronary artery bypass grafting. It was determined using a special programme, which used the data from the database and different economic data from specialized departments from our Institute, in order to perform the assessment of the efficiency of different antiplatelet therapies following coronary artery surgery.
The calculation of the cost-benefit ratio for each type of treatment and for routinely use clopidogrel in CABG was done taking into account the following parameters:
parameters related to the type of the treatment
cost of the treatment for each patient
number of supplementary echographic and endoscopic examinations per patient
number of bleeding episodes and cost per patient
global cost/ patient
parameters related to surgical intervention
early postoperative mortality rates for surgical intervention (global and specific depending on individual risk and type of the antiagregant regimen)
in hospital and at 1 year graft occlusion/myocardial infarction/severe bleeding on subgroups of patients taking into account the individual risk
immediate and long term postoperative complications rates depending on the type of the antiagregant regimen
ICU length of stay and cost
quality of life at 1 month and 1 year postoperatively on risk subgroups and on type of surgical interventions depending on the type of the antiagregant regimen
Parameters related to the patient
age
gender
co-morbidities
associated risk factors.
Using the above mentioned parameters, the special programme calculated a risk score per patient on types of treatment and the cost of routinely use clopidogrel in cabg patients, which was used then for estimation of the cost-benefit ratio associated with the type of the antiagregant regimen
Data were grouped on types of surgical interventions according to the exposure level to the risk factors. For each exposure level there were introduced the number of patients taking Clopidogrel (cases) and the number of patients who have not taken Clopidogrel (controls). The confounders were controlled by stratification.
Data interpretation was performed taking into account the following hypothesis:
a cost-benefit report >1 was considered unfavourable from economic point of view; for these patients the routine use of Clopidogrel as antiplatelet therapy after coronary artery bypass surgery was considered as having uncertain indication;
a cost-benefit report =1 was considered neutral and included the patients subgroups classified as relative indication for the routine use of clopidogrel as antiplatelet therapy after coronary artery bypass surgery, risks and benefits of using that therapy it being appreciated on case to case basis, depending on the risk and benefit for each patient;
a cost-benefit report <1 was considered favourable from economic point of view; for these patients the routine use of Clopidogrel as antiplatelet therapy after coronary artery bypass surgery was considered as having a standard indication, being recommended in each case.
Statistic methodology
Statistical analysis and cost-benefit report calculation
The main conclusion of our study was that using Clopidogrel single or associated with Aspirin for antiplatelet treatment in the immediate postoperative period in CABG patients is more effective than Aspirin alone, with a better cost-benefit report. The cost benefit report associated with using Aspirin plus Clopidogrel was almost two times higher than with Aspirin alone (Figure 4)
The incidence of myocardial infarction and death following graft thrombosis was 21% in Aspirin group,12% in Clopidogrel group and respectively 7% in aspirin plus Clopidogel group.
Cost-benefit report depending on the type of antiplatelet treatment in CABG patients
Relative risks and 95% confidence indexes for primary efficacy composite endpoints (30 days mortality, myocardial infarction, inhospital graft oclusion, hospital stay and immobilization (days), Intensive Care Unit length of stay and cost, quality of life) were different depending on the patients age, NYHA class, LVEF, the severity of associated MR, but, in all cases were lower among patients treated with Clopidogrel associated with Aspirin than among those treated with Aspirin alone
Also, there were different depending on the patients age, NYHA class, LVEF and associated severe mitral regurgitation.
Conventional statistical testing for Clopidogrel plus Aspirin versus Clopidogrel alone versus Aspirin alone resulted in p values of 0,0002 and 0,0003 respectively for the primary efficacy plus safety composite endpoints.
Relative risks and 95% Confidence Indexes for primary efficacy composite endpoints in the study groups
At hospital discharge and at 30 days, the combined efficacy and safety outcome endpoints were smaller in Clopidogrel plus Aspirin group.
For the primary efficacy plus safety endpoint (30 day mortality, inhospital graft oclusion or inhospital major bleeding), the rates were smaller for Clopidogrel plus Aspirin group, as the rates of in-hospital death
In-hospital graft oclusion and myocardial infarction occurred rarely in patients treated with Clopidogrel plus Aspirin compared with the patients treated with Aspirin alone. Major hemorrhagic events were similar in the study groups. Concerning the duration of the hospitalisation and imobilisation, there were a little bit smaller in Clopidogrel plus Aspirin group. (Figure 6)
Frequency of composite and single endpoints at hospital discharge and at 30 days
On long term, the incidence of death, myocardial infarction, and revascularization occurring at one year following CABG was greater in Aspirin group compared with Clopidogrel and Clopidogrel plus Aspirin groups (15% versus 12% versus 10%)
The Kaplan Meier curves for primary efficacy and safety endpoints showed a smaller probability for death, myocardial infarction or graft oclusion in Clopidogrel plus Aspirin group (Figure 7).
Early after treatment, the curves for Clopidogel associated or not with Aspirin started to separate from the one of Aspirin alone. At 30 days, differences in the primary endpoints between the three groups were already present.
Until the end of the follow up, for the primary efficacy endpoint and for the primary efficacy plus safety endpoint, event rates were abut two times higher for Aspirin group compared with Clopidogrel plus Aspirin group with log rank tests highly significant and significant p values (p<0,0001).
The Kaplan Meier curves for primary efficacy and safety endpoints
Concerning antiagregany therapy complications, the dates on in-hospital strokes are summarized in Figure 8.
There were no significant differences between the three groups regarding major hemorrhage and thrombocytopenia. Minor hemorrhage occurs more frequently in patients taking Aspirin. Total stroke and ischemic stroke rates were similar in the three groups. A few hemorrhagic conversions were seen in each of the tthree treatment groups. More minor or major bleeding complications and blood transfusions were also seen in the aspirin alone or associated with clopidogrel groups compared with clopidogrel alone group, although these differences were not significant.
Significantly more major bleeding complications (p=0,0001), more transfusions (p=0,002) and a higher rate of thrombocytopenia (p=0,001) were seen in patients with associated treatment with anticoagulants, in patients older than 75 years and in diabetics, the rate of major bleeding complications was three times higher in those with associated anticoagulant therapy (4%versus 14% and 2% versus 7% respectively
Hemorhagic and ischemic postoperative complications in the study groups.
The probability of early graft oclusion and perioperative myocardial infarction was smaller with Clopidogrel alone or associated with Aspirin versus Aspirin alone, the associated relative risks being negative because the studied drugs worked as protection factors for these perioperative complications. (Figure 9)
As we seen before, the relative risks for the most severe antiagregant therapy complications, hemoragic stroke were similar in the three study groups
Relative risk for early graft thrombosis, acute myocardial infarction or hemorrhagic stroke
Multiple clinical trials showed the favorable effects of Clopidogrel alone or combined with Aspirin extending the indication for using Clopidogrel in a wide range of at risk patients and in long-term prevention in various manifestations of atherosclerosis.
In recent years, enormous growth in the use of coronary stenting procedures has resulted in a significant decrease in restenosis rates, while acute and sub-acute stent thrombosis remain a significant potential complication. It has been shown, however, that the risk of acute and sub-acute stent thrombosis is greatly reduced by the administration of antiplatelet therapies following stenting. Much clinical experience with combination of aspirin and ticlopidine has been gained, however ticlopidine has been shown to be associated with rare risk of haematological adverse events.
The CLASSICS study demonstrated the safety and efficacy of clopidogrel (with or without loading dose) in combination with aspirin for use following coronary stenting.
A large randomized trial has demonstrated that the acute administration of clopidogrel—a long-acting antiplatelet therapy—to patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) can reduce subsequent risk for death, myocardial infarction, or stroke by 20% when continued for a mean duration of nine months [21]. However, single-center case series have demonstrated that, in patients requiring coronary artery bypass graft surgery, the use of Clopidogrel is associated with increased risk of perioperative bleeding and a need for transfusion [22- 26].
This risk appears to be time dependent. For example, post-hoc data analysis from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial revealed that bleeding risks were increased when patients had CABG surgery within 5 days of clopidogrel treatment but not when surgery was delayed for >5 days after treatment with clopidogrel [21]
These findings are reflected in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the acute management of patients with NSTE ACS, which endorse the acute use of clopidogrel but also recommend withholding clopidogrel for at least 5 days before CABG surgery (27).
Adherence in community practice to this guidelines recommendation is very unclear. has not been characterized previously. There are studies trying to characterize patterns of Clopidogrel use before CABG and to examine the time-dependent risks for postoperative transfusion among NSTE ACS patients treated at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative [15, 28- 29].
Combined antiplatelet therapy was also studied in a lot of trials and most of them showed good safety and efficacy profiles. Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Antiplatelet therapy and antithrombotic therapy have been demonstrated to favorably modify clinical outcome, and recent trials of revascularization in ACSs have demonstrated a reduction in the frequency of major cardiac events[2-14].
The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.
Actually the field of the indications of use of the antiagregant therapy is being continuously updated.The role of the aspirin in the primary prevention has extended its prescription based on related factors of cardiovascular and/or neurological risk. Moreover the combination of two antiagregant drugs (mainly Aspirin and clopidogrel) in high risk patients is a practice more and more extended [18]. Dual antiplatelet therapy has to be maintained at least 12 months after drug eluting stent placement and, in this patient a specific protocol of antiaggregation in type, combination and duration need to be applied [30, 31].
For patients undergoing coronary artery bypass graft surgery, controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic complications. There are also of this systematic reviews trying to evaluate the risks and benefits of preoperative aspirin and clopidogrel therapy, to identify the optimal timing and dose of aspirin following CABG, and to assess the role of postoperative clopidogrel therapy.[20]Following surgery, extensive evidence supports the use of aspirin, in doses of 100 - 325 mg daily, to be administered in 48 h postoperatively and continued indefinitely. Less is known regarding the use of clopidogrel following CABG, although it is now recommended as postoperative antiplatelet therapy in patients with recent acute coronary syndromes.Despite > 30 years of experience with antiplatelet agents during CABG, questions remain regarding their perioperative safety and efficacy. The results of continuing randomized controlled trials should further clarify the role of perioperative aspirin and clopidogrel therapy and help redefine the modern antiplatelet management of coronary artery bypass patients.
Also, the optimal aspirin dose for the prevention of cardiovascular events remains controversial.[32]: Daily aspirin doses of 100 mg or greater were associated with no clear benefit in patients taking aspirin only and possibly with harm in patients taking clopidogrel. Daily doses of 75 to 81 mg may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially for those receiving dual antiplatelet therapy.
The response to aspirin and/or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting is characterised by individual variability, but, overall combined clopidogrel and aspirin overcome single drug resistances, were are safe for bleeding and improve venous graft patency. [33]
At first sight, clopidogrel appears to be undesirable for cardiac surgeons: antiplatelet therapy can increase the risk of bleeding during coronary artery bypass graft surgery (CABG).1 Traditionally, many surgeons have felt that, with impeccable technique, their personally constructed grafts would be nearly ‘immune’ to thrombosis, even without antiplatelet therapy. However, it could theoretically reduce the risk for early vein graft failure, which is predominantly thrombosis related.
There are three different principal mechanisms that play a role in vein graft failure during postoperative periods: early (<1 month): thrombosis; related to technical factors, Intermediate (1 to 12 months): intimal hyperplasia and Later postoperative (>12 months): accelerated atherosclerosis [34]
Concern about possible hemorrhagic complications arising from use of oral antiplatelet agents in immediate proximity to coronary artery bypass graft (CABG) surgery leads many clinicians to avoid or discontinue these agents preoperatively. Recent evidence suggests that.the modest hemorrhagic risk may be acceptable, given the clinical benefits of sustained antiplatelet therapy in preventing graft occlusion and ischemic complications pre- and post-CABG. [35]
Also, other analysis provide insight into patterns of clopidogrel use and outcomes in the setting of CABG performed on patients with NSTE ACS [36] and found that as many as 30% of patients currently receive clopidogrel before CABG surgery, and, of these, nearly 90% have surgery within 5 days of treatment, contrary to the ACC/AHA guidelines recommendations. These data demonstrating a modest increase in transfusion risk in part reflect a more stable estimate of risks based on a much larger case sample in the CRUSADE Initiative.
The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) were similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.[26]
Data from the Antiplatelet Trialists’ Collaboration support the use of antiplatelet therapy (mostly data for aspirin) after CABG and further data support the initiation of aspirin within 48 hours of CABG. The CURE trial provides the opportunity to explore the combined use of aspirin and clopidogrel for those undergoing CABG.[26]
Clopidogrel offers multiple advantages in acute and chronic use in coronary intervention. The favorable benefit/risk ratio of clopidogrel over aspirin established by CAPRIE, combined with its characteristics related to rapid onset of action, loading dose, pre-treatment efficacy and ease of use, justify the consideration of using clopidogrel in a wide range of at risk patients and in long-term prevention in various manifestations of atherosclerosis / atherothrombosis.
Combined antiplatelet therapy employing agents from different pharmacological classes after CABG was characterised by good safety and efficacy profiles. The absence of interaction, and the potential synergistic effect when used with other antithrombotic agents, will allow clinicians to optimise treatment in acute situations. Combination therapy, using clopidogrel and other drugs commonly administered for a range of cardiovascular and other disorders, appears safe after CABG.
Despite routine use of ASA before CABG, and lifelong following the revascularization, patients who undergo CABG remain at high risk of long-term events in any vascular bed (cerebrovascular, cardiovascular, peripheral). The incidence of death, MI, and revascularization occurring at one and three-year following a CABG is greater than 15%.3. Therefore, patients who undergo CABG could benefit from long-term therapy that provides improved protection against all types of atherothrombotic events such as myocardial infarction, ischemic strokes, and vascular death.
First, our comparisons of clinical outcomes by treatment strategy were observational. Although we adjusted all comparisons for baseline clinical factors, we cannot exclude any persistent unmeasured confounding. Nonetheless, because a randomized clinical trial evaluating the benefits and risks of different antiagregant regimen of patients undergoing CABG is unlikely to be undertaken, this study is the first to provide insight into the scope of this issue at a national level.we considered the diagnostic of ischemia using stress test, Holter monitoring and, in case of a positive result, invasive coronarography as sufficient. Second, we did not collect data on the incidence of re-exploration at 2 or three years after CABG, although we had some information about that and we did nor perform routinely coronarography at 1 year postoperatively to all patients.
Antiplatelet therapy with Clopidogrel plus Aspirin in the immediate postoperative period in patients with CABG was associated with an better cost-benefit report, proving to be more effective than Aspirin alone.
Taking into account both efficacy and safety, the combined antiplatelet therapy with Clopidogrel and Aspirin emerged as the best treatment in this trial.
The favourable cost/benefit ratio of Clopidogrel over Aspirin established by this study, combined with its characteristics related to rapid onset of action, loading dose, pre-treatment efficacy and ease of use, justify the consideration of routinely using Clopidogrel in CABg patients and in long-term prevention in various manifestations of atherosclerosis
Taking into account cost-benefit report when comparing antiplatelet strategies after CABG,treatment with Aspirin alone was associated with an cost benefit report almost 1 in terms of reducing mortality and graft oclusion, Clopidogrel alone with a little bit more than one and the asociated therapy had an cost benefit ratio about 3, emerged as the best treatment inthis trial. It should be regarded as an attractive alternative pharmacological antiplatelet strategy in the immediate postoperative period in CABG patients,deserving further studies
Special thanks to cardiac surgeons and anesthesiologists from the Emergency Institute for Cardiovascular Diseases „C.C.Iliescu”, Bucharest, Romania
Creativity is difficult to define, as the evolution of the concept of creativity throughout history since antiquity shows. The word creativity is derived from the Latin word
Nevertheless, in the Renaissance, creativity in art and in science was closely related. Many people, not least Leonardo Da Vinci [3], combined scientific and artistic approaches in their work. However, the further development of science increasingly encouraged the specialisation and division of individual scientific disciplines, not to mention the disintegration of science and art. Various studies have reinforced this division, for example, studies of the differences between the right and left halves of the human brain [4]. It is thought that the right side of the brain is primarily responsible for emotions, intuition and thus creativity, while the left side supports more analytical skills such as learning, memorising and processing information. Based on the individual differences between the right and left hemispheres of the brain, a person should therefore be more gifted in either the arts or sciences or in a more holistic or analytical view of the world. This dichotomy was put forward by C.P. Snow in his public discussion
However, contemporary creativity research, especially that of Mihaly Csikszentmihalyi [7], reveals common psychological processes that occur during creative activity. The psychological state of a person working creatively is characterised by optimal attention and involvement in the process, a state described by the word flow [7]. In order to enter a flow state, the individual can be supported by a suitable environment, music and discussion of the planned work and goal, which have been explored within art therapy [8, 9]. A suitable environment is important to the creative process so that the individual can remain in the creative process for as long as possible, not be distracted and be fully engaged and immersed in the creative process.
The principle of
The modern rapid development, especially of information technology or computer science, requires many developers and sophisticated users to have a thorough knowledge of the technological side, which in practice means at least knowledge of programming as well as creative use of this technology. In fact, the technology is evolving so fast that one cannot expect that the necessary knowledge to use this technology can be formed into specific tools that potential users can use without a deeper understanding of the technology. Therefore, only those who know how to develop the technology can understand how to use it creatively in other, sometimes entirely new ways. A typical example is computer game developers, the vast majority of whom are programmers by profession. For this reason, 20 years ago, interdisciplinary study programmes emerged around the world that combine both technological knowledge in a particular field and the creative use of that knowledge, often to create artistic products. This is the case, for example, in the field of new media art. One of the first degree programmes of this kind was the
I want to write about creativity in science and art from the perspective of my own experience. My main profession is computer scientist. After graduating from the University of Ljubljana in electrical engineering, I earned a Ph.D. in computer science [13] at the University of Pennsylvania in the United States. I did my Ph.D. in the GRASP Lab, where I specialised in computer interpretation of images or videos—a research area we call computer vision. This means that we use various computer methods to figure out what or what kind of objects are in an image, what shape they are, where they are in physical space, to try to determine their identity, recognise people, etc. Already during my Ph.D. studies, I was mainly concerned with three-dimensional interpretation of image information and started to use a special kind of geometric models, namely superquadrics [14]. Superquadrics are a generalisation of Lamé curves in three dimensions. They were introduced into computer graphics by Barr [15] and into computer vision by Pentland [16] to model rectangular and curved shapes. In my Ph.D. thesis [17], I developed a method for their reconstruction from depth images.
One of the advantages of superquadrics is that we can use just one equation to describe a wide variety of basic geometric objects, e.g. spheres, cubes, cylinders, etc.:
Eq. (1) is the implicit superquadric equation in object space. The size parameters
With superquadrics, we want to model the shape of an object in a kind of holistic and abstracted way, without the irrelevant details that might otherwise be important for identifying the object. Figure 1 shows stone sarcophagi whose shape was first captured underwater using multi-image photogrammetry, and the resulting 3D point cloud was then modelled using superquadrics [18]. With new and improved means of acquiring 3D data, 3D documentation of individual artefacts and entire environments is becoming increasingly important in heritage science. However, large 3D point clouds suitable for display and presentation must be segmented and modelled with appropriate geometric models to allow further analysis and understanding of the imaged scene.
Sarcophagi on the remains of a sunken Roman ship off the island of Brač in the Adriatic Sea, modelled with superquadrics [
My original method of superquadric recovery was based on iterative least squares minimisation of a fitting function that was too slow for a real-time application. Nevertheless, the method has been used in many very different applications, and my publications on superquadrics reached almost 2000 citations on Google Scholar. Interestingly, after a hiatus of almost 20 years when our lab stopped intensive work on superquadrics reconstruction and segmentation [14], we are working on it again as we try to speed up superquadrics reconstruction and segmentation by using deep neural networks [19].
I started teaching at the University of Ljubljana in 1988, and when the World Wide Web came along, I realised that it could be a good tool for presenting visual art, which I always liked very much. In 1995, together with my students, I built the Slovenian Virtual Gallery, a virtual space with paintings by famous Slovenian painters that could be explored by clicking in the direction of the desired movement or on the paintings themselves [20]. This first-generation virtual gallery was a success and received the highest rating—four stars in the Magellan Internet Guide, based on the depth, ease of exploration and Net appeal. At the same time, in 1995, my colleague Ken Goldberg of GRASP Lab, who was at the time at the University of Southern California, developed the influential art installation
Under Dragan’s influence, I soon began to create my own art installations. My most successful installation, inspired by Andy Warhol’s portraits of famous people, was the interactive installation
Ten years ago, in 2012, I started sculpting in stone and wood rather accidentally and out of a need to do more with my hands than just type and sit behind a computer screen. Perhaps my experience with 3D documentation of physical objects in the context of heritage science also had some influence on my desire to touch and feel real objects. After a few workshops under the guidance of academic sculptors Alenka Vidrgar and Dragica Čadež Lapajne, I began to work independently. My sculptural work so far was recently presented in my solo exhibition, which took place in DLUL Gallery in Ljubljana in autumn 2020 [24].
Like computer programming, sculpting requires concentration and thought, especially in direct carving, the technique I primarily use. While computer programming and research allow for easy experimentation and lots of trial and error, it’s impossible to glue a stone back together once it’s chipped. But my computer vision research has given me an experience that makes me see the objects around me mostly volumetrically—I can easily imagine how I would model them with superquadric blocks. Interestingly, superquadrics or superellipses were already used in furniture design and architecture by the Danish mathematician, designer, writer and poet Piet Hein [25]. Piet Hein designed a large public square
The superellipse-shaped fountain in the middle of Sergels Torg, Stockholm, Sweden [
I make my sculptures from regular blocks of stone, but more often from irregular rocks or large pebbles. In my sculptures, I often look for abstract and pure geometric forms that remind me of superquadrics, like the sculptures in Figures 3 and 4.
The sculpture titled big eye was created from the slab of Carrara marble on the top. The finished sculpture on the bottom has an elliptic indentation and a round hole, both examples of superquadrics.
The sculpture entitled Taschenleerer was created from the rock seen on the top. The outer shell of Taschenleerer is in the shape of a superquadric (bottom).
In the block of Carrara marble in Figure 3, I have made a large and shallow indentation in the form of an ellipse. Inside the depression is a round hole that goes all the way through the block of marble. Both subtractions of material could be modelled as superquadrics. The title of the sculpture is
I found the rock for the
I have also finished the stone differently. The outer surface is polished to bring out the texture of the stone, and the vertical side of the concave central part of the sculpture is chiselled with a tooth chisel.
I usually find a suitable name for my sculptures only after I have finished them, or during the work, when the final form has already taken shape in my mind. I was not familiar with the German word
I am trying to combine my knowledge of computer science with sculpture. I am investigating how a sculpture can be enriched with virtual content [29]. In the past, artists have often placed stone sculptures in a watery environment— either with standing water in which the sculpture was reflected or with flowing water in the form of various fountains that introduced a dynamic element. For the
TOP: The virtually augmented sculptures sun and galaxy from the light fountain series. A Kinect depth sensor and video projector are mounted above each sculpture. The projected light dots move as water drops across the sculptural surface. BOTTOM: The virtual water drops merge on the Gallaxy sculpture to form a spiral gutter, eventually flowing into the hole in the Centre. The short lines of light are the result of the longer exposure of the moving points of light.
The installation is also interactive, as the Kinect sensor continuously captures the 3D shape. When someone touches the sculpture, the 3D shape changes and the light dots move across the new 3D configuration. Hand movements can easily trigger a ‘splash’ of the projected light dots. In the video [30, 31], one can observe the virtual dynamic enrichment of the sculptures. In the sculpture
Creativity as a human phenomenon has also become the focus of scientific research in recent decades, with the aim of better understanding it and possibly promoting it through imitation of observed circumstances and identified conditions. The first major scientific study of creativity was begun at Stanford University in 1959, involving a large group of the most distinguished contemporary architects [32]. Stanford remains a centre for the study of creativity, and as part of the Hasso Plattner Institute of Design (Stanford d.school), workshops are held for students and faculty members on how to apply design thinking to scientific and scholarly research and to learn about creativity [33].
Several schemes or stages for creativity have been proposed, such as:
preparation (e.g. investigation in all directions),
incubation (i.e. unconscious processing),
illumination (e.g. flash of insight),
verification (e.g. a conscious and deliberate effort in the way of testing the validity of the idea).
However, pioneering psychologist Mihaly Csikszentmihalyi [34] has suggested an underappreciated but crucial aspect of the creative mindset: a predisposition to psychological androgyny. Indeed, based on interviews with 91 highly creative people from a variety of fields, Csikszentmihalyi has found that female artists and scientists tend to be much more assertive and self-confident, and that the men in the same sample are more preoccupied with their families and their sensitivity to subtle aspects of the environment that other men tend to dismiss as unimportant.
The second phase of the above scheme, incubation, usually requires some release from other obligations—in other words, leisure. Pieper [35], a mid-twentieth century German philosopher, already claimed that leisure is the basis for culture and creativity. Margared Mead [36], the famous anthropologist, noted that activities that can be freely pursued by people who make their living from another source are degraded and corrupted when pursued for gain. Workaholism, a trend and a malaise of modern developed societies, does not leave enough free time to devote to creative activities. However, the latest negative trend affecting more people is addiction to media and social networking, especially mobile phones. An addicted person tends to spend all available free time surfing the Internet, social networking sites, playing computer games, etc. and cannot engage in creative activities. Therefore, the call for regular, weekly unplugging and abstinence from screens is in vogue to gain more time, creativity and connection [37].
So, based on my own experiences, what similarities do I see between creativity in computer science and creativity in art?
In winter, I often look for river stones in the hopfields around our country house in the Savinja valley. In prehistory, the Savinja River changed its riverbed several times, leaving quite large and well-rounded stones in the ground, which come from the Smrekovec Mountains, the only place in Slovenia with extinct volcanic activity. Andesite, an extrusive volcanic rock, and its variants such as basalt and rhyolite are typical of Smrekovec (see e.g. Figure 6).
Foot of the Giant, 2017, 38 × 16 × 11 cm, Oligocene volcanic—effusive rock, andesite, with white phenocrysts of Na-Ca plagoclase and rare black hornblende within green chloritised glassy to microcrystalline groundmass with traces of fluid lava flow, formed during the time of effusive activity of the Smrekovec volcanism.
Despite many similarities, there are also some differences between creativity in science and in the visual arts. Although there are many advantages to knowing important people in your field of research, the evaluation criteria for published research papers are really quite objective. The means of reaching a wider audience, such as conferences and scientific journals, are basically open and democratic. However, a large circle of enthusiastic followers is even more important in the arts, as objective criteria for evaluating art are much harder to define. Opportunities to show and exhibit one’s own art are therefore rarer.
Creative work in either field requires, at least in my experience, concentrated, largely individual effort. In programming and academic writing, we like to isolate ourselves from the rest of the environment. For example, when programmers are not alone in a room, they often put on headphones to isolate themselves. A sculptor working on stone wears a mask and noise reduction ear muffs to isolate himself from dust and noise. This also isolates him from his surroundings, making conversation impossible.
It is important that the scientist/artist be able to put himself in a state of enthusiasm, for that is how he becomes most productive. In both areas, however, regular communication with the immediate and wider professional environment is necessary. If only to ensure that we are on the right track.
Franc Solina is the author of all photographs in this chapter, except where indicated otherwise.
IntechOpen publishes different types of publications
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Biosensors, Biomaterials and Tissue Engineering",value:9,count:1},{group:"subseries",caption:"Bioinspired Technology and Biomechanics",value:8,count:2},{group:"subseries",caption:"Bioinformatics and Medical Informatics",value:7,count:9}],publicationYearFilters:[{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2019",value:2019,count:5},{group:"publicationYear",caption:"2018",value:2018,count:3}],authors:{paginationCount:228,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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