Traditional and Nontraditional Cardiovascular Risk Factors in Hemodialysis Patients
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Approximately 50% of hemodialysis (HD) patients die from cardiovascular events. One of the main risk factors for cardiovascular events is hyperlipidemia. Progressive renal failure is associated with lipoprotein abnormalities and dyslipidemia. However, dyslipidemia may not appear as hyperlipidemia (a rise in plasma cholesterol and/or low-density lipoprotein (LDL)) in the majority of HD patients. Uremic dyslipidemia has an abnormal apolipoprotein profile and composition. It is characterized by reduced concentrations of apo A-containing lipoproteins in high-density lipoprotein (HDL) and increased concentrations of intact or partially metabolized triglyceride-rich apo B-containing lipoproteins in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL.
Common lipid abnormality in HD patients is hypertriglyceridemia. Other lipid abnormalities seen in HD patients are high serum lipoprotein levels and a decrease in HDL levels. Hypertriglyceridemia is caused by increased production of Apo B protein and a marked decrease in the metabolism of VLDL, primarily as a result of decreased endothelial cell debilitation of VLDL.
The lipoprotein abnormalities in HD patients are thought to be a significant factor in increased atherosclerosis. Serum total cholesterol, and particularly LDL-cholesterol, is known to be correlated with increased cardiovascular mortality in the general population. A similar correlation has also been reported in dialysis patients. However, it is today generally agreed that in the HD patient group, a low LDL cholesterol level is correlated with malnutrition and increased mortality.
Until recently, the treatment of hyperlipidemia in the HD patient group was based on adult hyperlipidemia guidelines, and it was generally thought that the approach to treatment and results in the general population would yield similar results in the HD patient group. However, in the same way that lipid abnormalities in the HD patient group differ from the general population, there are also various differences in terms of medical treatment. Treatment of hypertriglyceridemia, the most frequently observed lipid abnormality in this patient group, is advised since at above 500 mg/dl it can give rise to complications such as pancreatitis. Lifestyle changes plus fibrate or nicotinic acid are recommended for treatment of hypertriglyceridemia. However, medical treatment must be provided on the basis of a profit and loss calculation, bearing in mind the side-effects (myositis and rhabdomyolysis). The calculation of non-HDL cholesterol, used to measure the level of remnant lipoproteins, is useful in situations where LDL cholesterol is normal and triglyceride levels high. Studies have been published suggesting that this can initially reduce the frequency of cardiovascular events associated with the use of statin in the treatment of a high LDL cholesterol level. However, the AURORA study, a large prospective, randomized study published in 2009, showed that although rosuvastatin lowered LDL cholesterol in the HD patient group it did not lead to a decrease in cardiovascular mortality. From this important study and other similar research, different approaches may be expected in both the adult hyperlipidemia guideline and in guidelines regarding the HD patient group from those in the general population.
Cardiovascular diseases are the principal cause of death in HD patients. Widespread vascular calcification especially in the coronary arteries is one of the main causes of cardiovascular disease (Braun et al., 1996; London et al., 2003, Sigrist et al., 2007). Vascular calcification can be observed in two regions of the arterial structure, the intima and the media (Shanahan et al., 1999). Arterial intimal calcification (AIC) is generally associated with atherosclerotic lesions, and with plaque formation and the development of occlusive lesions (Shanahan et al., 1999). AIC may also be observed in patients with normal renal function, and calcification of the atherosclerotic plaque increases the frequency of MI and thrombotic complications. Arterial medial calcification (AMC) is seen in muscular arteries and leads to a reduction in vascular wall elasticity more than to occlusive lesions (London et al., 2003). AMC is more associated with uremia. Both AIC and AMC may be observed in HD patients.
Although vascular calcification was determined in uremic patients many years ago, research into its etiopathology is still on-going. Factors held responsible in the etiopathology today include a rise in osteogenic proteins such as osteocalcin, osteonectin, alkaline phosphatase and collagen-I, low levels of calcification inhibitors such as matrix Gla-protein, osteopontin, fetuin, pyrophosphate and osteoprotegerin, genetic factors, use of high-dose vitamin D, high Ca-P levels, hyperparathyroidism, inflammation and hyperlipidemia (Fukagawa & Kazama, 2007; Rutsch et al., 2011; Shantouf et al., 2009; Slatopolsky et al., 1980; Tamashiro et al., 2001; Tukaj et al., 2000).
As previously discussed, while classic cardiovascular risk factors are more associated with development of AIC, uremia and associated factors are more involved in the development of AMC. London et al.’s study on the subject determined that high phosphorus and low albunim levels and excessive Ca consumption represented risk factors for AIC, in addition to classic risk factors such as advanced age, a history of atherosclerotic disease, cigarette use and a history of DM and high LDL and CRP levels. They also showed that in addition to these classic risk factors, parameters more associated with HD and prolonged HD were influential in the development of AMC. In addition, in contrast to AIC, AMC may also be observed at early ages (London et al., 2003)
While definitive diagnosis of vascular calcification is made with histopathological examination, since this is not possible in clinical practice, the K-DIGO guideline recommends x-ray imaging and echocardiographic examination in the diagnosis of vascular and valvular calcification (Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. 2010). In conclusion, the term vascular calcification is used for two different entities in HD patients, AIC and AMC. The reason why the term vascular calcification is used to refer to both these clinical conditions is that both AIC and AMC can frequently be seen in the HD patient group and that differentiation cannot be performed with routine examinations. However, what must not be forgotten is that although they appear to be similar, there are various differences in the etiology, clinical reflections and approaches to treatment in these two clinical conditions. While improvement of atherosclerotic risk factors (hyperlipidemia, etc.) and sufficient dialysis may be beneficial in AIC, sufficient dialysis is of particular benefit in the treatment and prevention of AMC
Chronic kidney disease (CKD) is a significant health problem, the prevalence of which is increasing all over the world. The main cause of death in this patient population is cardiovascular disease (CVD)-related mortality (K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients, 2005; Silva et al., 2012). As with the normal population, CVD can also be treated in CKD patients, representing a potentially preventable disease group. In 1998, the National Kidney Foundation (NKF) reported that CKD patients are a high-risk group for CVD. That report stated that a high prevalence of CVD had been determined in CKD patients, leading to mortality 10-30 times greater in the dialysis patient group in particular compared to the normal population. (Levey et al., 1998; Sarnak et al., 2003). Kidney function disorder is therefore a traditional risk factor held responsible in the development of CVD.
CVD risk factors in chronic kidney patients are divided into traditional and non-traditional (Sarnak et al., 2003). Traditional and non-traditional risk factors are given in the table. The main traditional risk factors are advanced age, diabetes mellitus, kidney disease, hypertension, family history, cigarette use, male gender, obesity, left ventricular hypertrophy and a sedentary lifestyle (Anderson et al., 1991; Mallamaci et al., 2002). However, there are studies showing that of the traditional risk factors known to be correlated with mortality in the normal population, the relationship between the mortality and HT and Hyperlipidemia in HD patients do not linear (Sarnak &Levey, 2000). The correlation between mortality and HT and elevated total cholesterol in this patient group is U-shaped (Lowrie & Lew, 1990; Zager et al., 1998). For this and similar reasons, a large number of studies have shown that traditional risk factors are inadequate in determining CVD risk in CKD (Cheung et al., 2000; Longenecker et al., 2002; Sarnak et al., 2003). Other studies have therefore investigated whether other factors may influence the development of cardiovascular events in the CKD patient group, and non-traditional risk factors have been developed. Hyperhomocysteinemia is the main non-traditional risk factor thought to affect the development of CVD in CKD. Several clinical studies have shown elevated homocysteine levels in the HD patient group and that hyperhomocysteinemia increases cardiovascular mortality (Bostom et al., 1997; Mallamaci et al., 2002; Manns et al., 1999; Sirrs et al., 1999). It is generally accepted today that oxidative stress and a progressive atherosclerotic process are correlated with development of cardiovascular events. Studies have also shown that this correlation also applies in the HD patient group. Oxidative stress may therefore be regarded as a non-traditional risk factor in the HD patient group (Boaz et al., 1999; Boaz et al., 1999). Inflammation (a rise in CRP) has been shown to be correlated with cardiovascular events in healthy individuals in prospective studies (Ridker et al., 1997). Studies also exist showing this relationship in the HD patient group (Zimmermann et al., 1999). As shown in the table 1, uremia-associated factors (anemia, impaired calcium-phosphorus metabolism, fluid electrolyte metabolism imbalance and dyslipidemia) may be added to the non-traditional risk factors in the HD patient group. As shown, dyslipidemia appears among both the traditional and non-traditional risk factors in the HD patient group. The reason is that, in contrast to the normal population, there are various lipid metabolism abnormalities in uremic patients and their being referred to as uremic dyslipidemia.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|
Advanced age | \n\t\t\tHyperhomocysteinemia | \n\t\t|
Diabetes mellitus | \n\t\t\tOxidative stress | \n\t\t|
Kidney disease | \n\t\t\tInflammation | \n\t\t|
Hypertension | \n\t\t\tAnemia | \n\t\t|
Family history | \n\t\t\tImpaired calcium-phosphorus metabolism | \n\t\t|
Cigarette use | \n\t\t\tFluid electrolyte metabolism imbalance | \n\t\t|
Male gender | \n\t\t\tMalnutrition | \n\t\t|
Obesity | \n\t\t\tAltered nitric oxide/endothelin balance | \n\t\t|
Left ventricular hypertrophy | \n\t\t\tElevated fibrinogen level | \n\t\t|
Sedentary lifestyle | \n\t\t\tOther thrombogenic factors | \n\t\t|
Dyslipidemia (Higher LDL cholesterol, Lower HDL cholesterol) | \n\t\t\tDyslipidemia | \n\t\t|
Family history of CVD | \n\t\t\t\n\t\t |
Traditional and Nontraditional Cardiovascular Risk Factors in Hemodialysis Patients
Severe lipid metabolism disorders arise in patients with kidney failure, and the lipid metabolism disorder peculiar to this patient group is known as uremic dyslipidemia (Tsimihodimos et al., 2011). However, both the pathogenesis of uremic dyslipidemia and its relationship with the atherosclerotic process that leads to the development of cardiovascular events are debatable. Studies have shown that there is abnormality in all lipoprotein fractions in uremic patients. Factors influencing these abnormalities include the degree of kidney function impairment, primary disease, presence of nephrotic syndrome, whether renal replacement therapy is administered, and if so whether HD or peritoneal dialysis (PD), drugs used (antihyperlipidemic drugs, sevelamer, calcineurin inhibitors, steroid, etc.), and the presence of malnutrition and inflammation (Attman et al., 2011; Kaysen 2009; Tsimihodimos et al., 2008; Tsimihodimos et al., 2011; Vaziri and Moradi., 2006). Abnormality in lipid metabolism commences in the early stages of CKD and contributes to the development of cardiovascular complications by initiating the atherosclerotic process. Factors contributing to lipid metabolism in stage 1-4 CKD are known to include type of primary kidney disease, degree of proteinuria and use of drugs affecting lipid metabolism. The main lipid metabolism abnormalities seen in renal patients in these stages are hypertriglyceridemia, a rise in triglyceride remnant-rich lipoproteins and lipoprotein a (Lp (a)) levels, and a decline in HDL-cholesterol levels. Moreover, with the exception of nephrotic syndrome, Total (T) cholesterol and LDL-cholesterol levels are generally at normal limits in stage 1-4 CKD patients (Tsimihodimos et al., 2008; Vaziri & Moradi., 2006; Vaziri, 2006) A rise in LDL-cholesterol levels has been determined in patients with nephrotic syndrome (Tsimihodimos et al., 2008; Vaziri, 2006).
Before discussing specific lipid metabolism disorders in HD patients, some general information about lipid metabolism will assist understanding of dyslipidemia in this patient group.
Lipids are transported in plasma by means of water-soluble molecules known as lipoproteins. In addition to their transport characteristics, various enzymes in the lipid metabolism also serve as chemical reaction platforms converting transported lipids into one another. Lipoproteins possess a core consisting of non-polar lipids such as triglyceride and cholesterol and a surrounding structure consisting of polar lipids such as apolipoprotein and phospholipid. Thanks to the structural and catalytic functions of apolipoproteins in the structure of lipoprotein, by interacting with one another or various receptors they permit specific lipid species to be added to or removed from this lipoprotein. The main plasma lipoproteins are known as HDL, LDL, IDL and VLDL, depending on their functions and molecular structures (Dominiczak&Caslake., 2011; Vaziri, 2006).
Various changes take place in uremic dyslipidemia with the start of HD therapy. However, the lipoprotein and apolipoprotein profile in HD patients resembles that in pre-dialysis patients (Attman et al., 1993). The main lipid abnormality in this patient group is a rise in triglyceride and triglyceride-rich remnant lipoprotein levels. Other lipid abnormalities are a rise in Lp (a) levels and a decrease in HDL. LDL levels are generally within normal limits. However, as with other lipoproteins, LDL is not homogeneous and there are variations in size, density and composition (Tsimihodimos et al., 2008; Wiemer et al., 2002).
Studies have shown that HD therapy has various effects on lipid profile. This gives rise to various differences, even though pathogenesis and lipid profile phenotype in HD patients are similar to the pre-dialysis period. One factor associated with HD therapy is membrane type. In one study, six weeks after transition from low flux membrane to high flux membrane, Blankestijn et al. observed a decrease in triglyceride and VLDL levels and an increase in HDL levels (Blankestijn et al., 1995). Docci et al. showed that polysulfone membranes have a more positive effect on lipid profile compared to cuprophan membranes (Docci et al., 1995). There are also studies showing that high flux polysulfone membranes reduce oxidized LDL (Wanner et al., 2004). Schiffl and Lang analyzed the effect of dialysate purity on dyslipidemia. They showed that ultrapure dialysis fluids brought about an improvement in dyslipidemia (Schiffl & Lang, 2010). Apart from dialysate purity, the effects of acetate or bicarbonate use on lipid profile have also been evaluated. It has been shown that use of bicarbonate dialysate can have positive effects on lipid profile (Jung et al., 1995). Another parameter thought to affect lipid profile during HD is heparin use. Heparin is known to cause lipoprotein lipase to be released from the endothelial surface. Chronic heparin use therefore leads to a decrease in lipoprotein lipase. Lipoprotein lipase is known to serve in the catabolism of triglyceride-rich lipoproteins such as chylomicrons and VLDL. The decrease in lipoprotein lipase in chronic heparin use gives rise to impairment in triglyceride-rich lipoprotein catabolism (Tsimihodimos et al., 2008). Studies analyzing the effect of unfractionated (UF) heparin on lipoprotein metabolism have produced controversial results. Mahmood et al. reported that heparin use during HD has no effect on lipoprotein lipase levels (Mahmood et al., 2010). However, there are also studies reporting that use of heparin has negative effects on both lipoprotein lipase and on lipid parameters (Daubresse et al., 1976; Schrader et al., 1990; Shoji et al., 1992 ). Another contentious issue is whether there is a difference in the use of unfractionated (UF) heparin and low molecular weight heparin (LMWH) in the effect on lipid parameters. Leu et al. determined a significant fall in T. cholesterol, LDL and Apo B levels after a transition from UF heparin to LMWH in hyperlipidemic HD patients (Leu et al., 1998). Yang et al., on the other hand, showed that the use of LMWH in diabetic hyperlipidemic HD patients caused a decrease in triglyceride and VLDL levels (Yang et al., 1998). Wiemer et al. showed that the use of LMWH brought about a decrease in oxidized LDL and triglyceride levels (Weimer et al., 2002). However, in an evaluation of the effects on lipid parameters of type of HD membrane and heparin type used, Katopodis et al. showed that both membrane and type of heparin have no effect on lipid parameters (Katopodis et al., 2004). Today, the effect of both heparin use and type of heparin on lipid parameters is debatable. We think that there is a need for studies analyzing the effect of HD therapy on lipoprotein metabolism in the HD patient group.
As previously mentioned, hypertriglyceridemia is the most commonly seen lipid abnormality in both pre-dialysis and dialysis patients. Triglyceride-rich lipoprotein metabolism disorders give rise to an increase in triglyceride in CKD patients. The main triglyceride-rich lipoproteins are chylomicron and VLDL. Chylomicron and VLDL transport cholesterol from the intestine and liver to regions where it will be stored (adipose tissue) or used for energy (muscle cells). However, in order for chylomicron and VLDL to be able to do this they are exposed to various maturation processes. One of these is taking Apo E from HDL 2. Apo E enables binding to lipoprotein lipase and VLDL receptors. Another maturation process is taking Apo C-II from HDL 2. Apo C-II is a lipoprotein lipase activator. Apo C-III is a lipoprotein lipase inhibitor. Lipoprotein lipase enables the hydrolysis of chylomicron and VLDL and the fatty acids in them to be used by tissues (Tsimihodimos et al., 2011; Vaziri & Moradi., 2006; Vaziri, 2006). Through lipoprotein lipase, VLDL leads to a 70% decrease in hydrolyzed triglyceride content and the formation of remnant VLDL (IDL). IDL transfers Apo E and Apo C-II in plasma to HDL. After the transfer of the remaining triglycerides to HDL through the mediation of cholesteryl ester transfer protein (CETP), they are lipolyzed through mediation of hepatic triglyceride lipase.
Triglyceride metabolism defects emerge because of a rise in synthesis and/or a decrease in clearance. Lipoprotein lipase is very important in triglyceride and triglyceride-rich lipoprotein clearance. Vaziri et al. showed a decrease in lipoprotein lipase gene expression in several tissues in uremic patients (Vaziri & Moradi., 2006). There may be several causes of a decrease in lipoprotein lipase levels and efficacy in HD patients. One is the heparin use discussed in detail above (Daubresse et al., 1976; Schrader et al., 1990; Shoji et al., 1992). UF heparin use leads to a decline in lipoprotein lipase levels. Another cause is a reduced lipoprotein lipase activator (Apo C-II) and inhibitor (Apo C-III) ratio in HD patients (Chan et al., 2009; Moberly et al., 1999). Studies have shown that impaired Ca-P metabolism and secondary hyperparathyroid lead to a decrease in lipoprotein lipase activity (Akmal et al., 1990; Vaziri et al., 1997). In addition, physical inactivity, insulin resistance and an abnormal T4 (thyroxin) to-tri-iodothyromin (T3) conversion contribute to a decrease in lipoprotein lipase activity (Vaziri & Moradi., 2006). Another cause of reduced clearance is a decrease in hepatic lipase activity. Studies have shown a decrease in hepatic lipase activity in uremic patients. A decrease in hepatic lipase activity causes a decrease in the clearance of chylomicron remnants and IDL and a rise in plasma levels (Klin et al., 1996). Down regulation of VLDL receptor in various tissues is one cause of increased VLDL in plasma (Vaziri & Liang., 1997). Apart from decreased clearance, a rise in synthesis from the liver also contributes to hypertriglyceridemia. Insulin resistance is thought to be one of the factors leading to hypertriglyceridemia in HD patients by increasing hepatic VLDL production (Tsimihodimos et al., 2011). Another reason for increased triglyceride synthesis is the use of acetate dialysate, even though this is not used today. The acetate in the dialysate represents the source for fatty acid synthesis by passing into the blood (Vaziri, 2006). In addition to the use of heparin in HD therapy, various therapy-related factors are thought to cause modifications in triglyceride and triglyceride-rich lipoproteins. Use of a high flux membrane has been shown to reduce triglyceride levels in some studies, and to have no effect in others (Ottosson et al., 2001; Wanner et al., 2004).
Another frequently seen impairment of lipid metabolism in the CKD patient group, which includes HD patients, is a reduction in HDL cholesterol and impaired HDL metabolism. Impairments in HDL metabolism appear in the form of decreased Apo AI, impaired HDL maturation, increased HDL triglyceride and a rise in plasma pre β HDL (Pahl et al., 2009; Quaschning et al., 2001; Vaziri, 2006 ). The main function of HDL is to collect excess cholesterol from peripheral tissues and transport it to be metabolized in the liver (Genest et al., 1999). In addition, the fact that HDL levels decrease as a response to information suggests that it has an inhibitor effect on inflammation (Quaschning et al., 2001; Vaziri 2006). This inhibitor effect also occurs on platelet adhesion and LDL oxidation (Navab et al., 2001). As previously mentioned, another function of HDL is to represent a source for Apo CII and Apo E, which occupy an important place in the metabolism of triglyceride-rich lipoprotein. The most important proteins in the structure of HDL are Apo AI and Apo AII. Apo AI is an activator of lecithin cholesterol acyl transferase (LCAT), which occupies an important place in HDL metabolism. LCAT performs an important function in HDL maturation and in the mediated uptake of HDL from the peripheral tissue to be metabolized in the liver (Kaysen, 2009; Guarnieri et al., 1978; McLeod et al., 1984). Apo AII is a hepatic lipase activator permitting the metabolism of HDL-origin triglyceride (Vaziri, 2006). Okuboet al. showed that the level of Apo AI and Apo AII is low in uremic patients, and that the fall in Apo AI is related to a rise in catabolism and the fall in Apo AII to a decrease in production (Okubo et al., 2004). Low levels of Apo AI and Apo AII are one of the causes of low HDL in HD patients (Attman et al., 2011; Attman et al., 1993) Another reason for lowered HDL and impairment in its metabolism is LCAT deficiency (Guarnieri et al., 1978; Kaysen 2009; McLeod et al., 1984). A decrease in hepatic lipase activity in uremic patients has already been discussed. The role of hepatic lipase in the metabolism of HDL is to assist the hydrolysis and removal of HDL triglyceride content. When it is deficient, a rise in HDL triglyceride takes place (Klin et al., 1996). Cholesterol ester transfer protein (CETP) takes triglycerides by transferring cholesterol esters from HDL to LDL (Davidson and Toth, 2007; Madeleine et al., 2009; Vaziri, 2006). Kimura et al. showed a high CTEP level in HD patients (Kimura et al., 2003). Elevated CTEP may cause a rise in HDL triglyceride in this patient group (Vaziri, 2006). Studies have shown that the HD procedure itself has an effect on HDL-cholesterol levels in HD patients. One such study was performed by Jung et al. Those authors evaluated the effect of citrate and bicarbonate dialysate use on HDL-cholesterol levels and showed that bicarbonate dialysate use increased HDL-cholesterol levels (Jung et al., 1995). Another parameter affecting HDL-cholesterol level is the use of a low flux or high flux dialyzer. Studies have shown that use of a high flux membrane increased Apo AI and HDL-cholesterol levels (Blankestijn et al., 1995; Docci et al., 1995). In conclusion, with both its relation with CKD and the effect of HD therapy, the level of HDL-cholesterol, which has antiatherogenic, anti-inflammatory and antiplatelet functions, declines in the HD patient group, and various impairments arise in the metabolism.
LDL is the major source of extracellular cholesterol. In HD patients, as with CKD patients without pre-dialysis proteinuria, cholesterol and LDL levels are normal or low (Kharrat et al., 2012; Shoji et al., 1992; Vaziri, 2006). Although the LDL level is normal or low, the level of small dense LDL with its atherogenic potential is high (Alabakovska et al., 2002; Kaysen, 2009). Additionally, there is an increase in oxidized LDL, thought to be correlated with atherogenic and cardiovascular mortality. As shown in several previous studies, Mahrooz et al. demonstrated high oxidized LDL levels in HD patients (Mahrooz et al., 2012, Samouilidou et al., 2012). However, the findings from studies regarding the relation between oxidized LDL levels and mortality and morbidity are controversial. Asamiya et al. showed that the oxidized LDL/LDL-cholesterol ratio is higher in patients with coronary artery calcification (Asamiya et al., 2012). Sevinç ok et al. reported that neither oxidized LDL nor non-oxidized LDL values are correlated with mortality (Sevinc ok et al., 2012). Pawlak et al. reported low oxidized LDL in HD patients but high antibodies against oxidized LDL, and that the oxidized LDL/oxidized LDL antibody ratio might be a new marker for cardiovascular events (Pawlak et al., 2012). Mention has already been made of studies showing that LDL is small and dense in HD patients. Noori et al. determined no correlation between conventional lipid parameters and mortality, but showed that very small LDL particle concentration is correlated with mortality (Noori et al., 2011). Kimura et al. showed that small size LDL is correlated with coronary artery disease (Kimura et al., 2011). In conclusion, LDL levels are normal or low in the HD patient group while LDL fractions (oxidized LDL, small dense LDL) with their atherogenic potential are higher in this patient group.
Lipoprotein (a) (Lp (a)) is a LDL-like particle. It is distinguished from LDL by the presence of apolipoprotein (a) (Apo (a)). Apo a binds to Apo B-100 with disulfide bonds. Because of Apo (a)’s similarity to plasminogen it is thought to contribute to thrombogenesis by inhibiting fibrinolysis of Lp (a) (Milionis et al., 1999; Tsimihodimos et al., 2011). There have been many studies regarding the correlation between elevated Lp (a) and cardiovascular events in the normal population (Rader &Brewer., 1992; Schaefer et al., 1994). There have also been several studies on the subject in HD patients, with high levels being shown in these (Dieplinger et al., 1993; Hirata et al., 1993; Kronenberg et al., 1995). Several clinical studies have evaluated the relation between Apo (a) size and Lp (a) level. Correlations have been determined between Apo (a) low molecular-weight (LMW) isoforms and elevated Lp (a) levels, and also between high-molecular-weight (HMW) isoforms and low Lp (a) levels (Boerwinkle et al., 1992; Kraft et al., 1992). The relationship between Apo (a) phenotype and elevated Lp (a) in HD patients is questionable (Hirata et al., 1993; Kronenberg et al., 1995). One of these studies, by Milionis et al., determined elevated Lp (a) and Apo (a) levels in HD patients (Milionis et al., 1999). Kronenberg et al.’s study supported these findings (Kronenberg et al., 1995). However, Kronenberg et al.’s 1999 study showed that LMW Apo (a) phenotype is an independent predictor for CAD (Kronenberg et al., 1999). The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study showed that Lp (a) levels are high in young, white patients and correlated with cardiovascular events. However, that study also stated that Apo (a) size is not correlated with elevated Lp (a) and cardiovascular events (Longenecker et al., 2002). In conclusion, while the correlation between elevated Lp (a) and Apo (a) size in the HD patient group is still unclear, elevated Lp (a) in particular is thought to be a cardiovascular risk factor.
Hyperlipidemia is known to be one of the most important cardiovascular risk factors in the normal population (Gordon et al., 1977). However, the relationship between dyslipidemia and mortality in HD patients is controversial. Cheung et al. determined that several traditional risk factors, including T. cholesterol, were not correlated with mortality in HD patients (Cheung et al., 2000). A cross-sectional study by Stack et al. produced similar results (Stack & Bloembergen). However, some studies have reported a correlation between dyslipidemia and mortality (Hahn et al., 1983; Nishizawa et al., 2003). As already discussed, whether renal replacement is performed with CRD patients, and whether that replacement is HD, modifies lipid metabolism disorders. No dyslipidemia-mortality correlation has been determined in certain patient populations (cancer patients, hospitalized patients, etc.) including the HD patient group (Shoji et al., 2011). This reverse relationship is therefore known as ‘reverse epidemiology’ (Kalantar-Zadeh et al., 2004). Hypercholesterolemia, high body mass index (BMI) and hyperhomocysteinemia lead to shortening in long-term survey in the normal population. But in the HD patient these factors lead to an increase in short-term survey. Researchers have described this to malnutrition inflammation (MIA) syndrome (Stenvinkel et al., 1999). MIA syndrome is known to be correlated with atherosclerosis and mortality in HD patients. Presence of hypercholesterolemia, high BMI and hyperhomocysteinemia in this patient group shows that nutrition status may be good. Improvement in MIA in these patients may cause a decrease in mortality (Nurmohamed &Nubé, 2005). In conclusion, these traditional risk factors for HD patients should be reviewed and new treatment objectives set out.
It is today recognized that there is a correlation between hyperlipidemia and cardiovascular events in individuals with normal renal functions and that cardiovascular mortality can be reduced by treating hyperlipidemia. It has been shown in several randomized, controlled meta-analyses that reducing LDL cholesterol with statin therapy brings about a significant decrease in CAD and myocardial infarction (MI) in the normal population (Baigent et al., 2005). However, in the same way that impairments in lipid metabolism in HD patients differ from those in individuals with normal renal functions, so there are various differences in dyslipidemia treatment in these patients. This section discusses dyslipidemia treatment and its effect on mortality and morbidity in the light of major studies.
The use of statin has been shown to have a lowering effect on mortality and morbidity in hyperlipidemic patients without renal function disorder. Statin use in pre-dialysis CKD patients is known, with its LDL-cholesterol reducing effect and an effect independent of the lipid lowering effect known as pleotropic effect, to reduce mortality and morbidity and to slow renal progression (Deshmukh & Mehta., 2011; Olyaei et al., 2011). Statins’ pleotropic effects may be listed as a decrease in endothelial cells’ permeability to LDL, an increase in vasodilator response, a decrease in endothelial adhesion molecules and an antioxidant effect (Vaughan et al., 2000). The use of statin in HD patients is controversial. One study on the subject by Saltissi et al. showed that simvastatin significantly reduces non-HDL cholesterol levels (Saltissi et al., 2002). Chang et al. determined that simvastatin has an anti-inflammatory effect as well as a lipid-reducing one in HD patients (Chang et al., 2002). These and similar studies have shown that statins have a lipid-reducing effect in HD patients, as well as the presence of pleotropic effects (Nishikawa et al., 1999; Soliemani et al., 2011; van den Akker et al., 2003). One piece of research to investigate the effect on mortality of statin therapy was the Deutsche Diabetes-Dialyse-Studie (4D) study. This was a prospective, randomized study involving 178 HD centers. It included more than 1000 diabetic HD patients and observed 21% MI -associated mortality in the group receiving atorvastatin and the control group. However, sudden cardiac death-related cardiac mortality levels approaching 50% developed in both groups. The researchers suggested that sudden cardiac deaths might be related to arrhythmia and were not reduced by the use of statin (Wanner et al., 2005). Another major piece of research, the AURORA study published in 2009, included 2776 HD patients. That study showed that despite a significant fall in LDL cholesterol with rosuvastatin, there was no significant decrease in cardiovascular mortality (Fellström et al., 2009). Finally, the SHARP study was conducted with 9270 patients with CKD (3023 dialysis patients). In that study, simvastatin + ezetimibe (4193 simvastatin plus ezetimibe from the start, 457 beginning with simvastatin alone and then plus ezetimibe after one year) was administered to one arm, and placebo (4191 plus at the beginning, 429 plus one year after) to the other. Average duration of monitoring was 4.9 years. Major cardiovascular events (non-fatal myocardial infarction or coronary death, non-hemorrhagic stroke, or arterial revascularization) were observed in 11.3% of the simvastatin plus ezetimibe group, and in 13.4% of the placebo group. A 17% fall in major atherosclerotic events was observed with a decrease of 0.85 mmol/L in LDL. In addition, this decrease in risk did not alter depending on whether the patients enrolled received dialysis therapy or not. In other words, in contrast to the 4D and AURORA studies, a decrease in major cardiovascular events was brought about with statin therapy in that study (Baigent et al., 2011).
Ezetimibe is a selective intestinal cholesterol absorption inhibitor. Prevention of cholesterol absorption in addition to inhibition of cholesterol synthesis has been shown to reduce cardiovascular mortality in recent years. For that reason, studies have begun being performed regarding the use of ezetimibe alone in patients with a high risk of side-effects from ezetimibe plus low-dose statin combinations or statin for the purpose of reducing side-effects frequently observed with statins, particularly at increased doses (myopathy/myositis, hepatitis, etc.). In the HD patient group, in which the effect of statin on mortality and morbidity is controversial, studies with low patient numbers have shown that ezetimibe produces a reliable and effective fall in cholesterol (Hattori & Hattori., 2010; Ahmed & Khalil., 2010). Finally, the SHARP study showed that simvastatin plus ezetimibe produced a significant decrease in atherosclerotic cardiovascular events (Baigent et al., 2011).
Fibrates have been used for many years, particularly in the treatment of hypertriglyceridemia. In the HD patient group, hypertriglyceridemia exhibits a pronounced impairment of lipid metabolism. HD would therefore seem to represent a potential patient group for fibrate use. However, since fibrate metabolites are eliminated by the kidney, and since these metabolites give rise to serious side-effects such as myopathy and rhabdomyolysis by accumulating with a decrease in glomerular filtration rate, use in this patient group is limited. However, one study including some 9000 patients published in 2012 showed that fibrate use is quite safe and effective in diabetic patients with moderate renal damage. Patients with a GFR above 30 were included in that study, however (Ting et al., 2012). There are not many studies concerning the use of fibrate in HD patients. One such study is that by Makówka et al. The study included 27 chronic HD patients and lasted for 63 days. It determined a significant fall in T cholesterol, LDL and triglyceride with fenofibrate therapy and a significant rise in HDL. AST and ALT levels remained normal in patients receiving fenofibrate, while CPK levels rose significantly compared to basal values but then remained stable (Makówka et al., 2012). Prospective randomized studies involving large patient numbers evaluating the reliability and efficacy of fibrate use in the HD patient group are now needed.
Nicotinic acid is a water-soluble vitamin B complex (vitamin B3) that has been used in the treatment of hypertriglyceridemia for many years. It produces a fall in triglyceride, LDL and VLDL levels and a rise in HDL. However, hepatoxicity and flushing are side-effects that limit its use. While there have been pharmacokinetic studies in HD patients, studies showing its effectiveness in the treatment of dyslipidemia are restricted to a very small number of cases (Reiche et al., 2011). There are no studies showing its effect on mortality and morbidity. Restrepo Valencia and Cruz reported a fall in T. cholesterol and triglyceride levels and a rise in HDL after nicotinic acid therapy in 3 HD and 6 PD patients (Restrepo Valencia &Cruz., 2008). Shahbazian et al. reported a rise in HDL cholesterol in 48 HD patients after 8-week nicotinamide therapy (Shahbazian et al., 2011).
Sevelamer hydrochloride is a non-calcium containing phosphorus-binding resin used in the treatment of hyperphosphatemia in HD patients. The Dialysis Clinical Outcomes Revisited (DCOR) and Renagel in New Dialysis (RIND) studies showed that it provides a better survey that calcium-containing phosphorus-binders (Block et al., 2007; Suki et al., 2007). Sevelamer prevents the absorption of intestinal cholesterol. Studies have shown it has positive effects on lipid parameters in HD patients (Yamada et al., 2005; Qunibi, 2005). Iimori et al. showed that dyslipidemia improved significantly with treatment with sevelamer and that mortality declined (Iimori et al., 2012). However, the use of sevelamer in the treatment of dyslipidemia in HD patients has not been accepted due to the lack of wide-ranging and long-term studies.
Also known as trimethyl-aminobutyric acid, carnitine is a naturally-occurring vitamin-like substance. Carnitine serves in several important metabolic pathways. One of the most important of these is that it lowers the level of free fatty acid necessary for triglyceride synthesis and beta-oxidation of fatty acids (Guarnieri et al., 2001). Since the kidneys are an important site of carnitine synthesis, that synthesis decreases in the event of kidney failure (Bellinghieri et al., 2003). Studies exist showing that carnitine therapy has a positive effect on lipid parameters in HD patients, while others report no positive effect (Emami Naini et al., 2012; Naini et al., 2012; Hurot et al., 2002; Guarnieri et al., 2007). For that reason, carnitine is not definitively accepted in the treatment of dyslipidemia in HD patients.
Heparin-induced extracorporeal LDL precipitation (HELP) is a form of lipid apheresis particularly used in the treatment of familial hyperlipidemia. The number of case reports in the literature is limited, although a significant lipid decrease has been observed with HELP. One of this limited number of studies in the literature is that by Bosch et al. A pronounced fall in LDL was observed with 29 sessions of HELP in 5 HD patients (Bosch et al., 1993). Another study by Bosch et al. reported quite good results with HELP in 3 HD patients (Bosch et al., 1993). Eisenhauer et al. achieved a significant fall in LDL cholesterol with HELP in 6 HD patients (Eisenhauer et al., 1991). In the light of these case reports, we think that HELP may be a useful form of treatment, especially in HD patients with familial hyperlipidemia and with no response to drug therapy.
The K-DOQI treatment of hyperlipidemia guideline was published in 2003 because of the variation in dyslipidemia in HD patients (Kidney Disease Outcomes Quality Initiative (K/DOQI) Group, 2003) Until then, there had been recommendations resembling an adult hyperlipidemia guideline in the studies performed. In essence, the recommendations of that guideline are as follows;
In order to prevent serious complications such as pancreatitis in patients with a triglyceride level above 500 mg/dl, primary focus must be on triglyceride-lowering therapy. Diet, fibrate and nicotinic acid can be used in treatment.
If the triglyceride level is below 500 mg, treatment should be adjusted according to LDL levels. If LDL is above 100 mg/dl, LDL-lowering therapy (diet and statin) is recommended.
If LDL is normal while triglyceride is elevated, there is generally a rise associated with lipid remnants. The amount of remnant lipoprotein can generally be estimated with a calculation of non-HDL cholesterol. Non- HDL cholesterol is calculated as the difference between T. cholesterol and HDL cholesterol. Treatment is recommended in patients with non-HDL cholesterol above 130 mg/dl.
As already stated, because of the insufficient number of studies, the dyslipidemia treatment guideline in chronic kidney patients was adapted to the adult hyperlipidemia treatment guideline. However, it is clear that treatment in HD patients requires a different approach. We therefore think that this guideline published in 2003 should be updated in the light of more recent studies.
The pathogenesis of dyslipidemia in the HD patient group, which has various impairments in lipid metabolism, has not yet been fully clarified. New studies regarding that pathogenesis are therefore needed. In addition, new studies regarding what the aim of treatment in dyslipidemia and the parameter to be targeted should be (triglyceride, LDL, IDL, VLDL or non-HDL cholesterol?). Finally, treatment adapted to the adult hyperlipidemia treatment guideline because of a lack of sufficient studies must clearly be turned into a lipid guideline aimed at HD patients in the light of newly published studies.
Wheat (
Grain yield is the final result of plant growth and development and hence most, if not all, genes are supposed to contribute towards yield either indirectly or directly. Consequently, achieving increased grain yield is a non-trivial task, and the accumulative knowledge from wheat breeding suggests that we would require concurrent improvements of both the ‘source’ and ‘sink’ tissues. Traditional breeding largely depends on empirical phenotypic selection, which has already resulted in the development and release of a large number of high-yielding varieties. However, time consumption, labour intensity, environmental dependence, and low efficiency are prime barriers that nowadays hinder conventional/traditional wheat breeding. High-yielding wheat varieties can result from the uncovering of novel genetic variation, better selection techniques, or the identification of superior genotypes with novel or improved characteristics caused by favourable combinations of superior alleles at multiple loci. In recent years, an impressive number of advancements in genetics and genomics have been made in wheat. Owing to the tremendous effort of IWGSC, the ‘gold standard’ reference genome has become available for wheat cultivar ‘Chinese Spring’. The most comprehensive assembly of this reference line has been recently released in 2018 which gave access to a total of 107,891 high-confidence genes [9]. The genome sequences may assist the identification of important genes at an unprecedented level which is a key aspect in wheat breeding. Different types of molecular markers, such as RFLP, AFLP, SCAR, STS, SSR, CAPS, and GBS-SNPs, have been identified and mapped on the different chromosomes of wheat and highly dense genetic maps have also been developed (available at https://wheat.pw.usda.gov/GG3/) which are being utilised in various genetic studies in wheat [10, 11]. To date, more than 15 different high-throughput GBS strategies have been developed and utilised in various crops including wheat [12]. Moreover, several SNP arrays/assays have also been developed which are flexible in terms of data point and sample number customization, which contributes to its high-density scanning and robust call rates compared to PCR and NGS-based markers. Several high-density SNP genotyping arrays have been utilised for genetic dissection of different traits and marker-assisted breeding in wheat namely the Illumina Wheat 9 K iSelect SNP array [13], the Illumina Wheat 90 K iSelect SNP genotyping array [14], the Wheat 15 K SNP array [15], the Wheat 55 K SNP array, the Axiom Wheat 660 K SNP array, the Axiom HD Wheat genotyping (820 K) array [16], the Wheat Breeders’ 35 K Axiom array [17], and the Wheat 50 K
Here in this chapter, we summarise the recent progress in understanding the genetics of grain yield and other related traits together with the new strategies, such as gene cloning and mining of superior alleles, transgenic technologies, genome editing technologies, genomic selection (GS), genome-wide association studies (GWAS)-assisted GS, and haplotype-based breeding (including haplotype-based GWAS and haplotype-based GS), which altogether make it available for genomics-assisted breeding (GAB) in crop improvement and to break the yield ceiling in wheat.
Grain yield is a complex polygenic trait, significantly associated with grain number per spike, grain weight, harvest index, number of productive tillers, plant height, days to heading/flowering, etc. The trait is also influenced by the environment and shows a significant level of genotype × environment interaction with low heritability. Previous studies showed that increased yield potential in the major wheat-growing countries was largely associated with increased grains per square meter, harvest index, and biomass, and reduced plant height [4, 5]. Moreover, it has been revealed that the use of dwarfing genes (
As discussed above, several studies have reported hundreds of QTLs in different mapping populations evaluated under different environments. An innovative approach i.e., meta-QTL analysis has emerged which helps in refining the QTL positions by combining the QTL results from independent studies and identifying the most stable and consensus QTLs [34]. The power of this approach lies in detecting regions of the genome that are most often involved in trait variation and reducing the QTL confidence intervals, thus facilitating the identification and characterisation of underlying candidate genes. For the first time in 2010, Zhang and his colleagues [35] conducted a meta-QTL analysis of major QTLs for grain yield and yield-related traits and identified 12 significant MQTLs on chromosomes 1A, 1B, 2A, 2D, 3B, 4A, 4B, 4D, and 5A, few of which also included important known genes, such as
MAS allows a more effective selection of target genotypes which further enable certain traits to be ‘fast-tracked’, resulting in faster line development and variety release. MAS is a more cost-effective approach that can replace phenotyping and thereby allows selection in off-season nurseries as well. Another advantage of using MAS is that the total number of genotypes that need to be tested can be reduced significantly in early generations which allow more efficient use of field or glasshouse space which is generally limited [48]. MAS remains a valid option for major gene or QTL, whereas QTL cloning or gene cloning may become a more routine activity assisted by increased utilisation of high-throughput phenotyping techniques [49], sequencing [50], and identification of high-confidence candidate genes through ‘omics’ profiling [51]. Cloned QTL/gene may provide new opportunities for a more targeted search for novel alleles in wild wheat germplasm and mutants (Table 1).
Genes/QTLs | Chromosome | Products/enzymes | Associated yield-related traits | References |
---|---|---|---|---|
2A, 2B, 2D | Sucrose synthase | Endosperm development | [52] | |
2A | Cell wall invertase | Kernel weight | [53] | |
5D | Cell wall invertase | Kernel weight | [54] | |
7A | Zinc-finger protein | Thousand grain weight, number of grains per spike, spike length, peduncle length and spikelet’s per spike | [55] | |
6D | Glutamine synthetase | Mineral nutrient and grain size | [56] | |
7A | Indole-3-glycerol-phosphate synthase | Thousand grain weight | [57] | |
7A | Snakin/GASA protein | Grain length | [58] | |
7D | Glutamine synthetase | Thousand grain weight, grain length | [59] | |
3D | Cytokinin oxidase/dehydrogenase | Grain size, grain filling rate, grain weight | [60] | |
3A | Cytokinin oxidase | Grain weight and leaf chlorophyll content | [61] | |
6A | Trehalose 6-phosphate phosphatase | Grain weight | [62] | |
2A | FLO2 protein | Thousand grain weight, grain size | [63] | |
1A, 1B, 1D | Plant-specific protein kinase | Plant height, length of peduncle, penultimate node, thousand grain weight | [64] | |
4A, 4B,4D | Sucrose non-fermenting 1-related protein kinases | Thousand grain weight, spike length | [65] | |
4A | Fructan 6-fructosyltransferase | Thousand grain weight | [66] | |
6A | E3 ubiquitin ligase | Grain weight, grain size | [25] | |
3D | Cytokinin oxidase/dehydrogenase | Thousand grain weight | [67] | |
5A | Putative protein phosphatase | Grain length | [68] | |
7A | F-box protein of 429 amino acids | Total spikelet number per spike | [69] | |
3A | Indole-3- acetic acid-glucose hydrolase | Thousand grain weight | [24] | |
7B | E3 ubiquitin ligase | Kernel size | [70] | |
3A | Tryptophan amino transferase | Plant height, spike number | [71] | |
5A | NAC transcription factor | Spike number, grain number per spike, and thousand grain weight | [72] | |
3A | Serine carboxypeptidases | Grain size, grain weight | [73] | |
7A | Transcript elongation factor | Grain number | [74] | |
7A | Pheophytin pheophorbide hydrolase | Thousand grain weight, grain filling | [75] | |
3B | Histone-like transcription factor | Number of spikes per plant | [76] | |
6B | Histone-like transcription factor | Number of spikes per plant | [77] | |
7A, 7B, 7D | Cytochrome P450 CYP78A3 | Seed size | [78] |
Cloned genes/QTLs regulating various yield-related traits in wheat.
At present, tremendous sequence information is available in public databases as a result of the sequencing of diverse wheat crop genomes, including reference lines and wild progenitors. This information can be used for mining the novel and superior alleles of agronomically important genes from gene pools to appropriately deploy for the development of high-yielding cultivars. Allele mining also provides insights into the molecular basis of trait variations and identifies the sequence variants associated with superior alleles. Moreover, it helps in the development of allele-specific molecular markers, assisting the introgression of novel alleles via MAS.
Considerable progress has been made in the past for manipulation of genes from diverse sources, including wild relatives and progenitors, and transferring them into wheat to confer increased grain yield, transgenesis can be employed as a powerful alternative for increasing the grain yield through exploiting the genes/traits which does not occur naturally in the wheat species. Transgenic plants refer to plants that contain a gene(s) that has been artificially inserted from an unrelated plant or a completely different species. The increase in grain yield potential through transgenesis involves an ideotypic detail of potential targets for transformation. In 2017, Nadolska-Orczyk and his colleagues [79] reported potential targets for transgenesis which can result in the increased grain yield in wheat. These include ‘transcription factors, regulating spike development, which mainly affect grain number; genes involved in metabolism or signalling of growth regulators—cytokinins, gibberellins, and brassinosteroids—which control plant architecture and consequently stem hardiness and grain yield; genes determining cell division and proliferation mainly impacting grain size; floral regulators influencing inflorescence architecture and consequently seed number, and genes involved in carbohydrate metabolism having an impact on plant architecture and grain yield’. Furthermore, modulated expression of flowering genes, which control vernalization and photoperiod-dependent floral induction, may be good for winter or spring wheat varieties [79, 80]. Besides, augmenting photosynthetic rates of laminar and non-laminar organs and the capability to access and utilise a greater amount of resources, such as nutrients or water, may also be potential targets for transgenesis in wheat for grain yield improvement [81, 82]. Besides, information about specific genotypes as well as climatic and agronomic conditions and consideration of the fact that the majority of the genes are members of multigene families is required for successful implementation of selected potential genes in breeding programs [79].
Transgenic wheat has the capacity to transform agriculture, but progress has been very limited as no transgenic wheat cultivar could be commercially approved so far because of consumers’ concerns. Few promising reports are available where newly developed transgenic wheat showed a significant grain yield advantage [72, 83]. Over-expression of a nitrate-inducible transcription factor (NAC TF) in wheat enhanced root growth and the ability to uptake nitrogen, therefore, increased nitrogen accumulation and grain yield by 10% (on a single plant basis) [72]. In another study, Gonzalez and his colleagues [83] reported that transgenic wheat lines carrying a mutated version of the sunflower TF (
Targeted genome editing has emerged as a powerful tool for studying gene function, correcting defective genes, or introducing novel functionality. Its mechanism involves sequence-specific double-strand breaks (DSBs) in the target DNA, with edits incorporated during the endogenous repair. In the earlier phase of genome editing, to induce the desired double-strand breaks at the target site, the engineering for zinc-finger nucleases (ZFNs) [85] or meganucleases [86] attracted the attention of the researcher community. These genome-editing systems needed specialised competence to produce artificial proteins consisting of customizable DNA-binding domains (sequence-specific), each linked to a non-specific nuclease for target DNA cleavage, and offered researchers with extraordinary tools to perform genetic manipulation. Later, the identification of a novel class of a
In 2012, an inexpensive, simple, easy to use, and effective genome-editing system that is clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) was introduced which revolutionised the field of genome editing [89]. The use of this powerful tool allows producing genome-edited plants in a very short period. CRISPR technology can be efficiently utilised for both precisely eliminating the negative regulator genes and augmenting the activity of positive-regulator genes that affect the trait of interest. Nevertheless, there are only a couple of reports available for validation of the CRISPR technique in wheat compared to other crops, such as rice [90]. In these reports, different genes were targeted by CRISPR/Cas9 to address the major biotic, and abiotic stresses along with improving a few agronomic traits in wheat [90]. An exciting advantage of using the CRISPR/Cas9 technology is the possibility of simultaneously editing multiple target genes using a single CRISPR construct. For instance, Wang and his colleagues [91] practiced this multiplexed genome editing in hexaploid wheat for targeting three different genes viz.
Many crucial agronomic traits are determined by a few base changes or point mutations in a gene [97, 98, 99]. CRISPR/Cas9 mediated gene replacements or gene modifications through homology-directed repair (HDR) has been reported as a practicable approach to correct the point mutations in the target DNA/gene and has the capability for accelerating crop improvement [100, 101]. Yet, the low efficiency of template DNA delivery and the rare occurrence of HDR (endogenous) has always been a difficult task in attaining success in plants. Furthermore, the CRISPR/Cas9 system is amenable for gene knock-in or knock-out, but cannot covert base into another. These challenges highlighted the demand for alternative powerful approaches that can result in precise and stable genome editing in crops. In 2016, a novel approach that is ‘Base editing’ was emerged which allows precise base (nucleotide) substitutions in a programmable manner, without requiring a donor template or disruption of a gene [102]. A base editor is a fusion of catalytically inactive Cas9 domain (Cas9 variants, Cas9 nickase, or dCas9) and an adenosine or cytosine domain that converts one base to another. Nucleotide substitutions or single-base changes may generate elite trait variations in crops which assist in accelerating crop improvement. The base-editing system can revert an SNP or single-base change without gene disruption. In recent years, many adenine and cytosine base editors have emerged as powerful tools for precise genome modifications (A to G or C to T) in eukaryotic genomes [102]. The potential of this approach has been demonstrated in several crops, including wheat [103, 104, 105, 106]. As aforementioned, HDR efficiency is comparatively low in plant cells, so knock-ins of DNA fragments to target sites are challenging. Recently in 2019, Anzalone and co-workers developed a more efficient genome-editing technology that is ‘Prime editing’ which consists of CRISPR-Cas9 nickase–reverse transcriptase fusions programmed with pegRNAs (prime-editing guide RNAs) that enable precise genome editing without inducing DSBs or requiring a donor DNA template (mandatory for genome editing via HDR) in mammalian cells [107]. The prime editors have been adapted for use in wheat via optimization of the codon, promoter, and editing conditions [108]. This optimised suite of prime editors enabled InDels and point mutations in wheat and rice at higher frequencies [108]. Development of new technologies and tools, newly discovered CRISPR/Cas systems, are being continuously reported, inferring that the CRISPR toolbox for wheat genome engineering would expand further in the near future. Researchers have also focused on the development of efficient approaches for eliminating transgenes from genome-edited plants, such as (a) transient expression of DNA and RNA [109], (b) use of CRISPR/Cas9 ribonucleoprotein complexes [110], (c) use of CRISPR-S—an active interference element [111], and (d) programmed self-elimination of the CRISPR/Cas9 constructs [112] to generate transgene-free genome-edited plants. The elimination of transgenes offers the following two advantages—(i) elimination of Cas9 construct from genome-edited plants prevents the induction of genetic changes at undesired loci, (ii) elimination of the transgenes is likely a prerequisite for getting regulatory approval of genome-edited crops for commercial applications. In the future, CRISPR technology may be supposed to accelerate wheat biology research, ultimately facilitating the development of high-yielding wheat varieties.
The genetic complexity of grain yield and other yield-related traits limit the power of QTL mapping and association mapping in identifying small effect loci [113]. A powerful breeding strategy that is genomic selection (GS) has been introduced to circumvent this problem which implements whole-genome markers for predictions, and thus can efficiently complement QTL mapping and association analysis in dissecting the complex genetic base of grain yield-related traits in wheat [114, 115]. High-throughput/next-generation genotyping technologies have accelerated the adoption of GS by enabling the development of large sets of DNA marker data at reasonable costs [116]. GS is a potential GAB tool that predicts genomic-estimated breeding values (GEBVs) of individuals (from the breeding population) with genotypic data available via prediction models constructed based on a training population (TP) with available phenotypic and genotypic information [117]. As aforementioned, using the prediction models, the GEBVs of unobserved individuals are predicted, circumventing the omission of the small-effect genomic region (markers) that would fail a threshold (significance) test. Though the effect of each marker is small, a large volume of genotypic information covering the whole genome still has the power to explain all the genetic variance. GS complements conventional breeding approaches and can potentially decrease the requirement of large-scale phenotyping and hasten the rate of genetic gain via shorter breeding cycles [118, 119]. The performance of GS relies mainly on the prediction accuracy, defined as the ‘Pearson’s correlation between the selection criterion and the true breeding value to select individuals with unknown phenotypes’ [120, 121]. Other factors that affect the GS accuracy include gene effects, level of linkage disequilibrium (LD), statistical models, the genetic composition of the TP, relationship between validation population (VP) or selection individuals and TP, and heritability of the target traits [120]. The major objective of GS is to decrease the cost of phenotyping and hasten genetic gains, use of high-throughput phenotyping tools and platforms that enable high-density phenotyping of hundreds to thousands of individuals across time and space using proximal or remote sensing, can increase the intensity and accuracy of selection and, eventually the selection response, as well as reduce phenotyping costs. The main idea of high-throughput phenotyping is to exploit secondary traits, such as canopy temperature, and green normalised difference vegetation index (NDVI) are closely related to grain yield that may be advantageous in early-generation testing of individuals. Data recorded on secondary traits (genetically correlated to grain yield) can be incorporated in multivariate pedigree and GS models, improving indirect selection for GY [122, 123, 124]. Moreover, GS can also be applied to gene bank accessions for germplasm enhancement. Accessions stored in germplasm bank represents an under-exploited rich genetic resource for wheat breeders, superior alleles can be extracted from these accessions which may be exploited for grain yield improvement in wheat [125, 126]. In general, lengthy pre-breeding programs are needed to develop lines that possess favourable alleles/genes from the wild accessions with superior agronomic performance and that may be utilised as parents in breeding programs. Using GS, germplasm enhancement breeding programs can be directly started using wild accessions and landraces. In a recent GS-based study, NGS technologies with multi-environment phenotyping were used to study the contribution of exotic genomes to 984 pre-breeding lines. Significant positive contributions of exotic germplasm to pre-breeding lines derived from crosses of CIMMYT’s best elite lines with exotics were reported [127]. Genomic selection studies conducted in wheat for grain yield and related traits are presented in Table 1. The prediction accuracy of GS for different grain yield-related traits has varied from 0 to 0.98% in wheat (Table 2).
Population type and size* | Number of genotyped markers | Traits | Accuracy of GEBV used | References |
---|---|---|---|---|
Advanced breeding lines from CIMMYT (254) | 41,371 GBS-SNPs | TGW, DTH, and GY | 0.28–0.45 | [128] |
Two DH populations (165 and 159) | 1975 and 1483 SNPs (90K SNP) | GNPS | 0.10–0.42 | [129] |
European winter wheat lines (2325) | 12,642 SNPs (9K SNP) | GY | 0.5–0.65 | [130] |
Winter wheat population (273) | 40,267 SNPs (90K SNP) | GY, TGW, PH and DTH | 0.33–0.67 | [131] |
Inbred breeding lines (557) | 12,083 GBS-SNPs | DTH and GY | 0.57 | [132] |
Advanced elite spring wheat lines (287) | 15,000 SNPs (90 K SNP) | GY, TGW and GN | 0.38–0.63 | [133] |
Lines from multiple families (659) | 9500 DArT-GBS-SNPs | GY | 0.38–0.41 | [134] |
Winter wheat breeding population from multiple families (861) | 6600 DArT-GBS-SNPs | GY | 0.39–0.48 | [135] |
Inbred breeding lines (557) | 12,083 GBS-SNPs | GY | 0.65–0.76 | [136] |
Hybrids obtained by crossing 18 males and 667 females (1888) | 13,005 SNPs (90 K and 15 K) | GY, DTH and PH | 0.5–0.55 | [137] |
Winter wheat lines (1100) | 27,000 GBS-SNPs | GY | 0.23–0.55 | [138] |
European winter and spring cultivars (210) | GBS-SNPs | 44 spike morphology traits | 0.2–0.5 | [139] |
Elite wheat lines (4368) | 2038 GBS-SNPs | DTH, DTM, PH and GY | 0.35–0.44 | [140] |
Bread wheat lines (10375) | 18,101 GBS-SNPs | GY and TGW | 0.59–0.98 | [141] |
Double haploid lines (282) | 7426 GBS-SNPs | GY and TGW | 0.47–0.54 | [142] |
Bread wheat lines (3771) | 8519 GBS-SNPs | DTH, DTM and GY | 0–0.75 | [143] |
Soft red winter wheat lines (239), Double haploid (100), and Recombinant inbred lines (156) | 2721 SNPs (9 and 90K) | GY, DTH, TGW, GNPS, and PH | − 0.14-0.43 | [144] |
F4:6 generation and double haploid winter wheat breeding lines (1114) | 7300 DArT-GBS-SNPs | GY | 0.45 | [145] |
Winter wheat lines (3282) | 18,728 GBS-SNPs | GY | 0.25 | [122] |
>6400 breeding lines | 78,662 GBS-SNPs | GY | 0.41 | [146] |
Advanced breeding lines (456) | 11,089 GBS-SNPs | GY | 0.33–0.66 | [147] |
Association mapping panel (456), two F5 populations (61 and 501), two DH populations (447 and 759) | 16,233 GBS-SNPs | GY | 0.21 | [148] |
Advanced bread wheat lines (4302) | 8443 GBS-SNPs | GY | 0.35–0.43 | [149] |
Winter wheat lines (1325) | 11,154 SNPs (15 K) | GY | 0.57 | [150] |
Genomic selection studies conducted in wheat for grain yield and related traits.
Figures in parenthesis are the population size.
GY, GNPS, DTH, DTM, PH, and TGW refer to grain yield, grain number per spike, days to heading, days to maturity, plant height, and thousand grain weight, respectively.
As discussed above, GWAS estimates marker effects throughout the genome on the target association panel (diverse germplasm) based on prediction models. Based on LD, GWAS may identify new functional variants, including novel MTAs and genes for many agronomically important traits in diverse germplasm. According to a comprehensive simulation study in plants, the use of a few major MTAs/QTLs/genes (each explaining ≥ 10% of the phenotypic variance) as fixed effects in GS models can increase the accuracy of GS for complex quantitative traits [151]. Although, the potential to combine robust and consistent associations identified from GWAS as fixed effects in GS models to increase prediction accuracy for complex traits such as grain yield has not been investigated comprehensively in wheat. The first report of integrating the genetic architecture of GY (revealed through GWAS) into prediction models in wheat has come from the work by Sehgal and co-workers, most recently in 2020 [149]. Firstly, using a haplotype-based genome-wide association study, they identified 58 MTAs for GY. Out of these 58 MTAs, 16 were ‘environment-specific’ with large effects and eight MTAs were consistent across trials and environments. These consistent MTAs were then used as fixed effects in the prediction models which resulted in a 9–10% increase in prediction accuracy for GY [149]. It is suggested that the utility of GS incorporating GWAS results may be noteworthy for GY when GWAS results detect highly robust and significant genomic regions.
Due to low heritability and persistent ‘genotype × environment’ interactions, improving grain yield (GY) is a difficult task for the global plant breeding community, especially under stressful environmental conditions [152, 153, 154]. As discussed earlier, GWAS-assisted GS has proven to be an effective method for deciphering the genetic architecture of complex traits, population improvement, and the development of better varieties with a higher yield. However, the problem of ‘missing heritability’, which is widespread in single marker-based GWAS, is not addressed by this approach. The alternative approach to boost the power of GWAS is by constructing haplotypes between neighbouring SNPs on a chromosome. As specific sets of alleles are observed on a single chromosome, haplotypes are inherited jointly with the limited probability of contemporaneous recombination. Haplotypes are implemented in crop improvement in two ways—retrospective and prospective [155]. Plant breeders have to choose the advantageous haplotypes that lead to desirable phenotype(s) for the trait(s) of interest during the long-term selection process. As a result, these advantageous haplotypes in elite crop germplasm can be found utilising the genome resequencing technique to sequence an elite gene pool [156]. Later, molecular markers that characterise these beneficial haplotypes can be produced, and all of these haplotype-defining markers can then be utilised to pick the most ideal combination of haplotypes that govern a certain phenotype. Furthermore, by identifying lines with unique recombination in chromosomal blocks of relevance, these haplotype-related markers can be utilised to distinguish between favourable and unfavourable genetic variation. On the other hand, haplotypes can be employed in a prospective approach, in which a vast collection of ancestral and wild germplasm of specific crop species (not just elite breeding pools) is re-sequenced to find haplotypes with a wider range of genetic variation [153, 155]. The genome-wide haplotypes are employed in this strategy to find novel haplotypes in a wide variety of natural germplasm. For the discovery of QTLs/genes, recent GWA studies based on empirical and simulation data (i.e., better p-values) and allelic effect estimation have demonstrated that haplotype blocks have higher mapping accuracy and power than individual SNPs [153, 155, 156, 157, 158, 159, 160]. Haplotype superiority can be explained by a number of factors. Stephens and his colleagues [161] showed that haplotype blocks are more informative than SNP markers because of their multi-allelic character in nature. The scientists found that haplotype variants were more common than SNPs, implying that recombination and recurrent mutation events occurred within and among haplotype genes (Figure 1). In addition, as compared to individual SNPs, haplotype-based analysis is predicted to reduce the false positives and shows the intricate mechanism of causal haplotypes [162]. Similarly, the haplotype-assisted GS depicts the complex relationships between genotypic information and phenotypes more accurately than individual SNPs. As a result, this method could eventually aid in improving selection gain per unit of time. Because haplotypes can better capture LD and genomic similarities in various lines and may capture local high-order allelic interactions, they may improve the accuracy of genomic prediction [163]. Furthermore, by depicting population structure in the calibration set, prediction accuracy might be enhanced. The superiority of haplotype-based predictions over SNP-based predictions for all studied traits, including yield, test weight, and protein content, was established in a recent GS study that compared the prediction ability computed from haplotypes and SNPs in a set of 383 advanced lines and cultivars of wheat [164]. Based on evidence revealing higher haplotype-assisted genomic prediction efficiency than SNPs, researchers are increasingly embracing haplotype-assisted genomic prediction in crop development programmes.
Flow diagram indicating how haplotype-based GWAS and haplotype-based GS, when combined with high-throughput genotyping, have the potential to improve gene identification precision and accuracy (modified from Bhat et al. [
Significant progress has been made in wheat in developing various genomics resources, including high-throughput molecular markers, dense genetic maps, and next-generation genotyping platforms. The availability of high-quality wheat genome information has also enabled many next-generation sequencing-based approaches for genetic mapping, allele mining, and identification of candidate genes which have enhanced the precision, pace, and efficiency of trait mapping. At present, trait-associated markers, high-throughput genotyping platforms, and expertise are available for deploying genomics-assisted breeding in wheat. We believe that in the coming years, extensive deployment of genome editing, transgenic technology, genomic selection, haplotype-based breeding in combination or alone would be undertaken for crop improvement and breaking the yield ceiling. Various steps involved in generating high-yielding wheat genotypes using genomics-assisted breeding technologies are represented in Figure 2.
Flowchart demonstrating the steps involved in generating high-yielding wheat genotypes using different genomics-assisted breeding strategies.
Thanks are due to the Head, Department of Molecular Biology and Genetic Engineering, G. B. Pant University of Agriculture and Technology, Pantnagar, (India) for providing necessary facilities.
The authors declare no conflict of interest.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Sanna",coverURL:"https://cdn.intechopen.com/books/images_new/10492.jpg",editedByType:"Edited by",editors:[{id:"327116",title:"M.D.",name:"Andrea",middleName:null,surname:"Sanna",slug:"andrea-sanna",fullName:"Andrea Sanna"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10302",title:"Aortic Aneurysm",subtitle:"Clinical Findings, Diagnostic, Treatment and Special Situations",isOpenForSubmission:!1,hash:"edb4662797c08616dc42b7796f1d17fe",slug:"aortic-aneurysm-clinical-findings-diagnostic-treatment-and-special-situations",bookSignature:"Ana Terezinha Guillaumon and Daniel Emilio Dalledone Siqueira",coverURL:"https://cdn.intechopen.com/books/images_new/10302.jpg",editedByType:"Edited by",editors:[{id:"251226",title:"Prof.",name:"Ana Terezinha",middleName:null,surname:"Guillaumon",slug:"ana-terezinha-guillaumon",fullName:"Ana Terezinha Guillaumon"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10537",title:"Frontiers in Clinical Neurosurgery",subtitle:null,isOpenForSubmission:!1,hash:"908c7edd9fcb3cbafbf42d30232db9a0",slug:"frontiers-in-clinical-neurosurgery",bookSignature:"Xianli Lv, Guihuai Wang, James Wang and Zhongxue Wu",coverURL:"https://cdn.intechopen.com/books/images_new/10537.jpg",editedByType:"Edited by",editors:[{id:"153155",title:"Dr.",name:"Xianli",middleName:null,surname:"Lv",slug:"xianli-lv",fullName:"Xianli Lv"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9818",title:"Bariatric Surgery",subtitle:"From the Non-Surgical Approach to the Post-Surgery Individual Care",isOpenForSubmission:!1,hash:"6083018185852f95759958b4d9e5e33b",slug:"bariatric-surgery-from-the-non-surgical-approach-to-the-post-surgery-individual-care",bookSignature:"Nieves Saiz-Sapena and Juan Miguel Oviedo",coverURL:"https://cdn.intechopen.com/books/images_new/9818.jpg",editedByType:"Edited by",editors:[{id:"204651",title:"Dr.",name:"Nieves",middleName:null,surname:"Saiz-Sapena",slug:"nieves-saiz-sapena",fullName:"Nieves Saiz-Sapena"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9790",title:"Surgical Management of Head and Neck Pathologies",subtitle:null,isOpenForSubmission:!1,hash:"8ae195fe1164fd55b69b775d596f1e8a",slug:"surgical-management-of-head-and-neck-pathologies",bookSignature:"Ho-Hyun (Brian) Sun",coverURL:"https://cdn.intechopen.com/books/images_new/9790.jpg",editedByType:"Edited by",editors:[{id:"184302",title:"Dr.",name:"H. Brian",middleName:null,surname:"Sun",slug:"h.-brian-sun",fullName:"H. Brian Sun"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:142,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"26862",doi:"10.5772/27413",title:"Titanium as a Biomaterial for Implants",slug:"titanium-as-a-biomaterial-for-implants",totalDownloads:16274,totalCrossrefCites:52,totalDimensionsCites:128,abstract:null,book:{id:"938",slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Carlos Oldani and Alejandro Dominguez",authors:[{id:"70012",title:"Dr.",name:"Carlos",middleName:null,surname:"Oldani",slug:"carlos-oldani",fullName:"Carlos Oldani"},{id:"73445",title:"MSc.",name:"Alejandro",middleName:"Anibal",surname:"Dominguez",slug:"alejandro-dominguez",fullName:"Alejandro Dominguez"}]},{id:"58199",doi:"10.5772/intechopen.71963",title:"Virtual and Augmented Reality in Medical Education",slug:"virtual-and-augmented-reality-in-medical-education",totalDownloads:3107,totalCrossrefCites:21,totalDimensionsCites:41,abstract:"Virtual reality (VR) and augmented reality (AR) are two contemporary simulation models that are currently upgrading medical education. VR provides a 3D and dynamic view of structures and the ability of the user to interact with them. The recent technological advances in haptics, display systems, and motion detection allow the user to have a realistic and interactive experience, enabling VR to be ideal for training in hands-on procedures. Consequently, surgical and other interventional procedures are the main fields of application of VR. AR provides the ability of projecting virtual information and structures over physical objects, thus enhancing or altering the real environment. The integration of AR applications in the understanding of anatomical structures and physiological mechanisms seems to be beneficial. Studies have tried to demonstrate the validity and educational effect of many VR and AR applications, in many different areas, employed via various hardware platforms. Some of them even propose a curriculum that integrates these methods. This chapter provides a brief history of VR and AR in medicine, as well as the principles and standards of their function. Finally, the studies that show the effect of the implementation of these methods in different fields of medical training are summarized and presented.",book:{id:"6211",slug:"medical-and-surgical-education-past-present-and-future",title:"Medical and Surgical Education",fullTitle:"Medical and Surgical Education - Past, Present and Future"},signatures:"Panteleimon Pantelidis, Angeliki Chorti, Ioanna Papagiouvanni,\nGeorgios Paparoidamis, Christos Drosos, Thrasyvoulos\nPanagiotakopoulos, Georgios Lales and Michail Sideris",authors:[{id:"211650",title:"M.D.",name:"Panteleimon",middleName:null,surname:"Pantelidis",slug:"panteleimon-pantelidis",fullName:"Panteleimon Pantelidis"},{id:"211654",title:"Ms.",name:"Angeliki",middleName:null,surname:"Chorti",slug:"angeliki-chorti",fullName:"Angeliki Chorti"},{id:"220557",title:"Ms.",name:"Ioanna",middleName:null,surname:"Papagiouvanni",slug:"ioanna-papagiouvanni",fullName:"Ioanna Papagiouvanni"},{id:"220558",title:"Mr.",name:"Georgios",middleName:null,surname:"Paparoidamis",slug:"georgios-paparoidamis",fullName:"Georgios Paparoidamis"},{id:"220559",title:"Mr.",name:"Georgios",middleName:null,surname:"Lales",slug:"georgios-lales",fullName:"Georgios Lales"},{id:"220560",title:"Mr.",name:"Thrasyvoulos",middleName:null,surname:"Panagiotakopoulos",slug:"thrasyvoulos-panagiotakopoulos",fullName:"Thrasyvoulos Panagiotakopoulos"},{id:"220561",title:"Mr.",name:"Christos",middleName:null,surname:"Drosos",slug:"christos-drosos",fullName:"Christos Drosos"},{id:"220562",title:"Dr.",name:"Michail",middleName:null,surname:"Sideris",slug:"michail-sideris",fullName:"Michail Sideris"}]},{id:"50915",doi:"10.5772/63266",title:"Doped Bioactive Glass Materials in Bone Regeneration",slug:"doped-bioactive-glass-materials-in-bone-regeneration",totalDownloads:3504,totalCrossrefCites:13,totalDimensionsCites:34,abstract:"In the arena of orthopaedic surgery, autograft is considered to be the gold standard for correction of fracture repair or other bone pathologies. But, it has some limitations such as donor site morbidity and shortage of supply, which evolved the use of allograft that also has some disadvantages such as immunogenic response to the host, low osteogenicity as well as possibilities of disease transmission. Despite the benefits of autografts and allografts, the limitations of each have necessitated the pursuit of alternatives biomaterials that has the ability to initiate osteogenesis, and the graft should closely mimic the natural bone along with regeneration of fibroblasts. A variety of artificial materials such as demineralised bone matrix, coralline hydroxyapatite and calcium phosphate-based ceramics such as hydroxyapatite (HA), β-tricalcium phosphate (β-TCP) and bioactive glass have been used over the decades to fill bone defects almost without associated soft tissue development. Most of them were having only the properties of osteointegration and osteoconduction. Only bioactive glass possesses osteogenic property that stimulates proliferation and differentiation of osteoprogenitor cells and in some cases influencing the fibroblastic properties. But, this material has also some disadvantages such as short-term and low mechanical strength along with decreased fracture resistance; but, this was further minimised by ion doping that positively enhanced new bone formation. There are many metal ions such as magnesium (Mg), strontium (Sr), manganese (Mn), iron (Fe), zinc (Zn), silver (Ag) and some rare earths that have been doped successfully into bioactive glass to enhance their mechanical and biological properties. In some of the cases, mesoporous bioactive glass materials with or without such doping have also been employed (with homogeneous distribution of pores in the size ranging between 2 and 50 nm). These biomaterials can be served as scaffold for bone regeneration with adequate mechanical properties to restore bone defects and facilitate healing process by regeneration of soft tissues as well. This chapter encompasses the use of bioactive glass in bulk and mesoporous form with doped therapeutic ions, their role in bone tissue regeneration, use as delivery of growth factors as well as coating material for orthopaedic implants.",book:{id:"5164",slug:"advanced-techniques-in-bone-regeneration",title:"Advanced Techniques in Bone Regeneration",fullTitle:"Advanced Techniques in Bone Regeneration"},signatures:"Samit Kumar Nandi, Arnab Mahato, Biswanath Kundu and Prasenjit\nMukherjee",authors:[{id:"60514",title:"Dr.",name:"Samit",middleName:null,surname:"Nandi",slug:"samit-nandi",fullName:"Samit Nandi"}]},{id:"37120",doi:"10.5772/29607",title:"Trigeminocardiac Reflex in Neurosurgery - Current Knowledge and Prospects",slug:"the-trigeminocardiac-reflex-in-neurosurgery-current-knowledge-and-prospects",totalDownloads:3438,totalCrossrefCites:10,totalDimensionsCites:27,abstract:null,book:{id:"749",slug:"explicative-cases-of-controversial-issues-in-neurosurgery",title:"Explicative Cases of Controversial Issues in Neurosurgery",fullTitle:"Explicative Cases of Controversial Issues in Neurosurgery"},signatures:"Amr Abdulazim, Martin N. Stienen, Pooyan Sadr-Eshkevari, Nora Prochnow, Nora Sandu, Benham Bohluli and Bernhard Schaller",authors:[{id:"78171",title:"Prof.",name:"Bernhard",middleName:null,surname:"Schaller",slug:"bernhard-schaller",fullName:"Bernhard Schaller"},{id:"78525",title:"Mr.",name:"Amr",middleName:null,surname:"Abdulazim",slug:"amr-abdulazim",fullName:"Amr Abdulazim"},{id:"78530",title:"Dr",name:"Pooyan",middleName:null,surname:"Sadr-Eshkevari",slug:"pooyan-sadr-eshkevari",fullName:"Pooyan Sadr-Eshkevari"},{id:"126039",title:"Dr.",name:"Martin",middleName:"Nikolaus",surname:"Stienen",slug:"martin-stienen",fullName:"Martin Stienen"},{id:"126040",title:"Dr.",name:"Nora",middleName:null,surname:"Prochnow",slug:"nora-prochnow",fullName:"Nora Prochnow"},{id:"126041",title:"Dr.",name:"Benham",middleName:null,surname:"Bohluli",slug:"benham-bohluli",fullName:"Benham Bohluli"}]},{id:"26863",doi:"10.5772/26362",title:"The Bearing Surfaces in Total Hip Arthroplasty – Options, Material Characteristics and Selection",slug:"the-bearing-surfaces-in-total-hip-arthroplasty-options-material-characteristics-and-selection",totalDownloads:9530,totalCrossrefCites:10,totalDimensionsCites:21,abstract:null,book:{id:"938",slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Hamid Reza Seyyed Hosseinzadeh, Alireza Eajazi and Ali Sina Shahi",authors:[{id:"66361",title:"Dr.",name:"Alireza",middleName:null,surname:"Eajazi",slug:"alireza-eajazi",fullName:"Alireza Eajazi"},{id:"74857",title:"Dr.",name:"Hamid Reza",middleName:null,surname:"Seyyed Hosseinzadeh",slug:"hamid-reza-seyyed-hosseinzadeh",fullName:"Hamid Reza Seyyed Hosseinzadeh"},{id:"173207",title:"Dr.",name:"Alisina",middleName:null,surname:"Shahi",slug:"alisina-shahi",fullName:"Alisina Shahi"}]}],mostDownloadedChaptersLast30Days:[{id:"65467",title:"Anesthesia Management for Large-Volume Liposuction",slug:"anesthesia-management-for-large-volume-liposuction",totalDownloads:6203,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The apparent easiness with which liposuction is performed favors that patients, young surgeons, and anesthesiologists without experience in this field ignore the many events that occur during this procedure. Liposuction is a procedure to improve the body contour and not a surgery to reduce weight, although recently people who have failed in their plans to lose weight look at liposuction as a means to contour their body figure. Tumescent liposuction of large volumes requires a meticulous selection of each patient; their preoperative evaluation and perioperative management are essential to obtain the expected results. The various techniques of general anesthesia are the most recommended and should be monitored in the usual way, as well as monitoring the total doses of infiltrated local anesthetics to avoid systemic toxicity. The management of intravenous fluids is controversial, but the current trend is the restricted use of hydrosaline solutions. The most feared complications are deep vein thrombosis, pulmonary thromboembolism, fat embolism, lung edema, hypothermia, infections and even death. The adherence to the management guidelines and prophylaxis of venous thrombosis/thromboembolism is mandatory.",book:{id:"6221",slug:"anesthesia-topics-for-plastic-and-reconstructive-surgery",title:"Anesthesia Topics for Plastic and Reconstructive Surgery",fullTitle:"Anesthesia Topics for Plastic and Reconstructive Surgery"},signatures:"Sergio Granados-Tinajero, Carlos Buenrostro-Vásquez, Cecilia\nCárdenas-Maytorena and Marcela Contreras-López",authors:[{id:"273532",title:"Dr.",name:"Sergio Octavio",middleName:null,surname:"Granados Tinajero",slug:"sergio-octavio-granados-tinajero",fullName:"Sergio Octavio Granados Tinajero"}]},{id:"42855",title:"Critical Care Issues After Major Hepatic Surgery",slug:"critical-care-issues-after-major-hepatic-surgery",totalDownloads:8935,totalCrossrefCites:2,totalDimensionsCites:2,abstract:null,book:{id:"3164",slug:"hepatic-surgery",title:"Hepatic Surgery",fullTitle:"Hepatic Surgery"},signatures:"Ashok Thorat and Wei-Chen Lee",authors:[{id:"52360",title:"Prof.",name:"Wei-Chen",middleName:null,surname:"Lee",slug:"wei-chen-lee",fullName:"Wei-Chen Lee"},{id:"157213",title:"Dr.",name:"Ashok",middleName:null,surname:"Thorat",slug:"ashok-thorat",fullName:"Ashok Thorat"}]},{id:"72175",title:"Fontan Operation: A Comprehensive Review",slug:"fontan-operation-a-comprehensive-review",totalDownloads:1299,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"Since the first description of the Fontan operation in the early 1970s, a number of modifications have been introduced and currently staged, total cavopulmonary connection with fenestration has become the most commonly used multistage surgery in diverting the vena caval blood flow into the lungs. The existing ventricle, whether it is left or right, is utilized to supply systemic circuit. During Stage I, palliative surgery is performed, usually at presentation in the neonatal period/early infancy, on the basis of pathophysiology of the cardiac defect. During Stage II, a bidirectional Glenn procedure is undertaken in which the superior vena caval flow is diverted into the lungs at an approximate age of 6 months. During Stage IIIA, the blood flow from the inferior vena cava (IVC) is rerouted into the pulmonary arteries, typically by an extra-cardiac conduit along with a fenestration, generally around 2 years of age. During Stage IIIB, the fenestration is closed by transcatheter methodology 6–12 months after Stage IIIA. The evolution of Fontan concepts, the indications for Fontan surgery, and the results of old and current types of Fontan operation form the focus of this review.",book:{id:"9585",slug:"advances-in-complex-valvular-disease",title:"Advances in Complex Valvular Disease",fullTitle:"Advances in Complex Valvular Disease"},signatures:"P. Syamasundar Rao",authors:[{id:"68531",title:"Dr.",name:"P. Syamasundar",middleName:null,surname:"Rao",slug:"p.-syamasundar-rao",fullName:"P. Syamasundar Rao"}]},{id:"45712",title:"Serdev Sutures® in Middle Face",slug:"serdev-sutures-in-middle-face",totalDownloads:4952,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"2989",slug:"miniinvasive-face-and-body-lifts-closed-suture-lifts-or-barbed-thread-lifts",title:"Miniinvasive Face and Body Lifts",fullTitle:"Miniinvasive Face and Body Lifts - Closed Suture Lifts or Barbed Thread Lifts"},signatures:"Nikolay Serdev",authors:[{id:"32585",title:"Dr.",name:"Nikolay",middleName:null,surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"55812",title:"Postural Restoration: A Tri-Planar Asymmetrical Framework for Understanding, Assessing, and Treating Scoliosis and Other Spinal Dysfunctions",slug:"postural-restoration-a-tri-planar-asymmetrical-framework-for-understanding-assessing-and-treating-sc",totalDownloads:7701,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Current medical practice does not recognize the influence of innate, physiological, human asymmetry on scoliosis and other postural disorders. Interventions meant to correct these conditions are commonly based on symmetrical models of appearance and do not take into account asymmetric organ weight distribution, asymmetries of respiratory mechanics, and dominant movement patterns that are reinforced in daily functional activities. A model of innate, human asymmetry derived from the theoretical framework of the Postural Restoration Institute® (PRI) explicitly describes the physiological, biomechanical, and respiratory components of human asymmetry. This model is important because it gives an accurate baseline for understanding predisposing factors for the development of postural disorders, which, without intervention, will likely progress to structural dysfunction. Clinical tests to evaluate tri-planar musculoskeletal relationships and function, developed by PRI, are based on this asymmetric model. These tests are valuable for assessing patient’s status in the context of human asymmetry and in guiding appropriate exercise prescription and progression. Balancing musculoskeletal asymmetry is the aim of PRI treatment. Restoration of relative balance decreases pain, restores improved alignment, and strengthens appropriate muscle function. It can also halt the progression of dysfunction and improve respiration, quality of life, and appearance. PRI’s extensive body of targeted exercise progressions are highly effective due to their basis in the tri-planar asymmetric human model.",book:{id:"5816",slug:"innovations-in-spinal-deformities-and-postural-disorders",title:"Innovations in Spinal Deformities and Postural Disorders",fullTitle:"Innovations in Spinal Deformities and Postural Disorders"},signatures:"Susan Henning, Lisa C. Mangino and Jean Massé",authors:[{id:"204825",title:"Dr.",name:"Susan",middleName:null,surname:"Henning",slug:"susan-henning",fullName:"Susan Henning"},{id:"206242",title:"Dr.",name:"Lisa C",middleName:null,surname:"Mangino",slug:"lisa-c-mangino",fullName:"Lisa C Mangino"},{id:"206245",title:"Dr.",name:"Jean",middleName:null,surname:"Massé",slug:"jean-masse",fullName:"Jean Massé"}]}],onlineFirstChaptersFilter:{topicId:"202",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82020",title:"Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Novel Technique and Technology with Case Series",slug:"minimally-invasive-transforaminal-lumbar-interbody-fusion-a-novel-technique-and-technology-with-case",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105187",abstract:"Minimally invasive spine surgery (MIS) transforaminal lumbar interbody fusion (MI-TLIF) has been utilized to treat a variety of spinal disorders. Like other minimally invasive spine surgery techniques and technology, the MI-TLIF approach has the potential to limit the morbidity associated with larger exposures required for open surgery. The MI-TLIF approach has a number of advantages over many other minimally invasive spine surgery approaches including direct decompression of neural elements, collection of morselized autograph from the surgical site to achieve high fusion rates, restoration of spinal canal diameter, foraminal diameter, disk height, and reduction of spondylolisthesis. In this chapter, we discuss a novel technique for performing MI-TLIF developed by the senior author who is a leading minimally invasive spine surgeon. The technique and technology illustrated in this chapter were developed out of a recognition of a need to reduce the learning curve for performing MI-TLIF, as well as need for a cost-effective method that provides a high fusion rate, excellent clinical outcomes, and low complication rate. The indications, surgical planning, postoperative care, complications, and patient outcomes in a large series will be reviewed using this novel MI-TLIF technique.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"78335",title:"Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers",slug:"safety-and-efficiency-of-cervical-disc-arthroplasty-in-ambulatory-surgery-centers",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.99589",abstract:"Introduction Anterior cervical surgeries have been safely performed in ambulatory surgery centers since 1995 with the first cases being one level anterior cervical discectomies without fusion, then in 1996, one level anterior cervical discectomies with fusion (ACDF). When it is was certain that outpatient fusion was safe, the number of ACDF levels slowly and methodically were increased to the now standard outpatient maximum of four level ACDF. During this evolution, with the introduction of arthroplasty surgery, one level arthroplasties were considered appropriate for outpatient surgery and now two-level outpatient cervical arthroplasties are routine and some three level arthroplasties have been performed with no additional morbidity compared to one level procedures. The author first reported a series of 27 patients in 2010 who underwent cervical disc replacement at an ASC. (Wohns, R. Safety and cost-effectiveness of outpatient cervical disc arthroplasty. Surg. Neurol. Int. 1, 77, 2010). The average operative time was 40 minutes and the patients were observed over a period of three hours prior to discharge. None of the patients had major complications and there were no reports of worsening or persistent pain. The results of a Delphi study in 2018 compared the safety and efficiency of one-level and two-level arthroplasty procedures performed in an ASC and in a hospital setting. (Gornet et al. Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers vs Hospital Settings. Int’l J of Spine Surgery. Vol. 12, No.5, 2018, pp. 557-564). The study analyzed outcomes of 145 ASC patients, 348 hospital outpatients and 65 hospital inpatients and the conclusion was that both one and two-level arthroplasties may be performed safely in an ASC. Surgeries in ASCs are of shorter duration and performed with less blood loss without increased AEs. At the present time, there does not appear to be any contra-indication to performing the vast majority of cervical arthroplasties in an ambulatory surgery center (ASC). Furthermore, the cost of an outpatient arthroplasty is commonly 30% to 50% of the cost of hospital-based procedures.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Richard N.W. Wohns"},{id:"82255",title:"Minimally Invasive Laminectomy for Lumbar Stenosis with Case Series of Patients with Multi-level (3 or More Levels) Stenosis",slug:"minimally-invasive-laminectomy-for-lumbar-stenosis-with-case-series-of-patients-with-multi-level-3-o",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.105186",abstract:"Lumbar stenosis is the most common pathology seen and treated by spine surgeons. It is often seen in the elderly population who frequently have multiple medical co-morbidities. Traditional approaches remove the spinous process and detach paraspinous muscles to achieve adequate canal decompression. This approach can damage the posterior tension band leading to permanent muscle damage, scar tissue formation, iatrogenic flatback syndrome, and increase risk of adjacent segment disease requiring reoperation. Performing lumbar laminectomy in a cost-effective manner is critical in effectively treating patients with lumbar stenosis. This chapter reviews a minimally invasive muscle-sparing approach to treating lumbar stenosis. The technique is performed through a tubular retractor. Direct decompression of the spinal stenosis is achieved while preserving the paraspinous muscle attachments and spinous process. This technique has multiple advantages and can potentially reduce load stress on adjacent levels and subsequent adjacent level pathology leading to further surgical intervention. In addition, the procedure shows how facet fusion is performed using the patient’s own locally harvested drilled morselized autograph to achieve bilateral facet fusion. By fusing the facets, we have shown that restenosis at the operative level is less likely to occur. This chapter will review a case series of multilevel lumbar stenosis including clinical outcomes.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"80705",title:"Cervical Arthroplasty",slug:"cervical-arthroplasty",totalDownloads:38,totalDimensionsCites:0,doi:"10.5772/intechopen.102964",abstract:"Technological advances have allowed spine surgery to follow the trend toward minimally invasive surgery in general. Specifically, we have seen a corresponding rise in the popularity of cervical arthroplasty. For the treatment of cervical disc disease, arthroplasty is a less invasive option than the gold standard of cervical discectomy and arthrodesis, which by nature is more disruptive to surrounding tissues. Arthroplasty preserves the facets, maintains motion, and reduces the rate of adjacent segment breakdown. These factors counteract the negative impacts of fusion while maintaining the benefits. Arthroplasty implants themselves have become more streamlined to implant as well with less native bone destruction, and biomechanics more compatible with the native disc. While initial implants were ball and socket devices with complex fixation and plane-specific movements, later devices incorporated such motions as translation and compression. Viscoelastic components and materials more closely resembling native tissues afford a more biocompatible implant profile. Until cell-based therapies can successfully reproduce native tissue, we will rely on artificial components that closely resemble and assimilate them.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Jason M. Highsmith"},{id:"80605",title:"Minimally Invasive Treatment of Spinal Metastasis",slug:"minimally-invasive-treatment-of-spinal-metastasis",totalDownloads:42,totalDimensionsCites:0,doi:"10.5772/intechopen.102485",abstract:"Advancements in the treatment of systemic cancer have improved life expectancy in cancer patients and consequently the incidence of spinal metastasis. Traditionally, open spinal approaches combined with cEBRT (conventional external beam radiation therapy) allowed for local tumor control as well as stabilization and decompression of the spine and neural elements, but these larger operations can be fraught with one complications and delayed healing as well as additional morbidity. Recently, minimally invasive spine techniques are becoming increasingly popular in the treatment of spinal metastasis for many reasons, including smaller incisions with less perioperative complications and potential for expedited time to radiation therapy. These techniques include kyphoplasty with radiofrequency ablation, percutaneous stabilization, laminectomy, and epidural tumor resection through tubular retractors, as well as minimally invasive corpectomy. These techniques combined with highly conformal stereotactic radiosurgery have led to the advent of separation surgery, which allows for decompression of neural elements while creating space between neural elements and the tumor so adequate radiation may be delivered, improving local tumor control. The versatility of these minimally invasive techniques has significantly improved the modern management of metastatic disease of the spine by protecting and restoring the patient’s quality of life while allowing them to quickly resume radiation and systemic treatment.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Eric R. Mong and Daniel K. Fahim"},{id:"76620",title:"Minimally Invasive Lateral Approach for Anterior Spinal Cord Decompression in Thoracic Myelopathy",slug:"minimally-invasive-lateral-approach-for-anterior-spinal-cord-decompression-in-thoracic-myelopathy",totalDownloads:146,totalDimensionsCites:0,doi:"10.5772/intechopen.97669",abstract:"Myelopathy can result from a thoracic disc herniation (TDH) compressing the anterior spinal cord. Disc calcification and difficulty in accessing the anterior spinal cord pose an operative challenge. A mini-open lateral approach to directly decompress the anterior spinal cord can be performed with or without concomitant interbody fusion depending on pre-existing or iatrogenic spinal instability. Experience using stand-alone expandable spacers to achieve interbody fusion in this setting is limited. Technical advantages, risks and limitations of this technique are discussed. We conducted a retrospective chart review of all patients with thoracic and upper lumbar myelopathy treated with a lateral mini-open lateral approach. Review of the literature identified 6 other case series using similar lateral minimally invasive approaches to treat thoracic or upper lumbar disc herniation showing efficient and safe thoracic disc decompression procedure for myelopathy. This technique can be combined with interbody arthrodesis when instability is suspected.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Edna E. Gouveia, Mansour Mathkour, Erin McCormack, Jonathan Riffle, Olawale A. Sulaiman and Daniel J. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"July 5th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:20,paginationItems:[{id:"82526",title:"Deep Multiagent Reinforcement Learning Methods Addressing the Scalability Challenge",doi:"10.5772/intechopen.105627",signatures:"Theocharis Kravaris and George A. 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Kleczyk, Karin Hayes and Rajesh Mehta",slug:"evaluating-similarities-and-differences-between-machine-learning-and-traditional-statistical-modelin",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Machine Learning and Data Mining - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11422.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:59,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}}]},overviewPagePublishedBooks:{paginationCount:9,paginationItems:[{type:"book",id:"7723",title:"Artificial Intelligence",subtitle:"Applications in Medicine and Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7723.jpg",slug:"artificial-intelligence-applications-in-medicine-and-biology",publishedDate:"July 31st 2019",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"a3852659e727f95c98c740ed98146011",volumeInSeries:1,fullTitle:"Artificial Intelligence - Applications in Medicine and Biology",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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