Classification of abnormalities of glucose tolerance in cystic fibrosis on OGTT.
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\r\n\tCreating decent living conditions for all people and at the same time decouple economic growth from the increasing use of virgin resources and environmental impacts will be the major challenge in this millennium. This is also the essence of the United Nations 2030 Sustainable Development Goals. There are many approaches suggested for solving these problems. One is to change consumption behaviour from material products to services. Another solution is to find technological solutions to create more closed loops for materials and use fewer virgin resources. All solutions will require more of the central resource, namely energy, and the hope is that energy will be obtained from clean renewable sources. A central question is if this complex equation has solutions or if there are barriers for the development which are unforeseen today. Another important question is how long a transition to a more sustainable use of resources will take.
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\r\n\tResource efficiency thus involves using the Earth's limited virgin resources in a sustainable manner while at the same time creating liveable cities and minimising impacts on the environment. It allows us to create more with less and to deliver greater value with less input. An increasing consumption of virgin resources will inevitable create international conflicts as every nation will defend its own interests.
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\r\n\tThe new situation for resource use is that material and product flows have become more and more globalized which make them difficult to control.
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\r\n\tThe central aim of this book is to view resource efficiency from a more complex perspective looking at several resources and the causal links between them in order to point out more new pathways towards a more sustainable use of resources.
Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic condition seen in the Caucasian population, affecting approximately 1/2500 live births in Australia [1]. It is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, located on the long arm of chromosome 7 [1] and expressed in the epithelial cells of lungs, pancreas and sweat glands and other organs. Cystic fibrosis–related diabetes (CFRD) is one of the most important complications of the disease as it is known to have a significant impact on morbidity and mortality [2]. Patients with CF ultimately die from recurrent respiratory tract infections and respiratory failure which may be hastened by abnormalities of glucose tolerance affecting respiratory function and nutrition.
\nThe pathophysiology of CFRD is likely multifactorial and complex. Historically CFRD was thought to be the result of progressive pancreatic destruction by secretions of the exocrine pancreas, pancreatic autodigestion and replacement with nonfunctioning fatty tissue, amyloid deposits or fibrotic tissue [3, 4]. This theory was supported by ultrasound findings in patients with CF of an “echogenic” and atrophied pancreas which progresses with age. MRI has also been used to study the pancreas of patients with CF. Sequeiros et al. attempted to determine the pancreatic volume of patients with CF using MRI and compare with Type 1 diabetic patients and controls. In over 70% of patients with CF, the pancreas could not be visualised and this was irrespective of glycaemic status [5]. Pancreatic tissue on autopsies of patients with CF has also noted to have fewer islet cells and replacement with fibrotic tissue. Histologically, patients with CFRD have a relative decrease in the number of islet cells and insulin-containing cells within the islets, relative to the non-CFRD cohort [4, 6].
\nHowever, recent information supports the theory that destruction of the physical pancreas does not entirely explain the glycaemic abnormalities in patients with CF. Insulin deficiency has been shown to occur in young children and infants with CF [7], and even infants have been reported to have CFRD [8]. This has also been demonstrated in animal models of CF. In both the pig and ferret CF models, the animals demonstrate abnormal insulin secretion from birth, suggesting that CFTR may play a more direct role in insulin secretion [9, 10]. In the pig model, newborn pigs were noted to develop hyperglycaemia even when there was no significant islet cell destruction [10]. Recent studies of the CFTR potentiator ivacaftor (Kalydeco™), which improves gating defects and thus should not have any impact on fatty or fibrotic tissue, have demonstrated an improvement in glucose abnormalities [11, 12]. This suggests that the intrinsic abnormality in the CFTR protein may play a role in glycaemic control in CF.
\nThe timeframe during which patients with CF develop glycaemic abnormalities and CFRD has significant variability, and the specific CFTR class abnormality does not entirely account for this unpredictability. Non-CFTR genetic modifiers may play a key role in determining this risk. Patients with CF who have a family history of Type 2 diabetes are known to have an increased risk of CFRD [13, 14]. Polymorphisms in
In normal insulin physiology, insulin secretion occurs in two phases—the first phase results from exocytosis of preformed insulin granules which is the result of a voltage-dependent calcium channel being triggered by blood glucose elevations [16–18]. The second phase requires maturation of insulin granules and lasts minutes to hours [19, 20]. Oral glucose ingestion results in a limited and delayed first-phase insulin peak when compared with intravenous administration [21, 22]. Overall, the amount of insulin secreted appears to be amplified when glucose is given orally, rather than intravenously. Incretins (glucagon-like peptide and gastric inhibitory peptide) are secreted from neuroendocrine cells of the gastrointestinal system and increase insulin secretion and decrease glucagon secretion. The secretion of incretins is hypothesised to be the result of the action of oral glucose within the gastrointestinal tract [21]. The role of incretins in CFRD has not yet been fully elucidated, and it is unclear whether or not patients with CFRD have abnormal levels of incretins. However, the diet of CF patients may play a role in the development of CFRD. In patients with Type 2 diabetes mellitus (DM), those prescribed orlistat, a lipase inhibitor, had diminished fat digestion which resulted in greater postprandial hyperglycaemia [23]. In a randomised crossover trial, Perano et al. demonstrated that adolescent patients with CF, who did not take appropriate pancreatic enzyme supplementation, experienced amplified postprandial hyperglycaemia [24]. Barrio postulates in her review that inadequate enzyme supplementation in patients with CF results in fat malabsorption, which may hasten gastric emptying, thereby inhibiting the normal augmentation of insulin response by the neuroendocrine cells [25]. Exogenous incretin therapy has proven beneficial in patients with Type 2 DM, but it has also been associated with weight loss in this cohort, an undesirable outcome for patients with CF [26]. Hyperglycaemia is known to promote beta-cell apoptosis, and as such, postprandial hyperglycaemia from dysfunctional incretin secretion in CF may potentiate the glycaemic abnormalities demonstrated and hasten the progression to CFRD.
\nCFRD is distinct from both Type 1 and Type 2 diabetes. CFRD is not an autoimmune condition like Type 1 DM and is not associated with autoantibodies found in Type 1 DM. Moreover, Type 2 DM is primarily a disorder of insulin resistance, whereas glucose abnormalities in CF are primarily the result of insulin deficiency, which is present even in CF patients with normal glucose tolerance on oral glucose tolerance test (OGTT) [7]. One of the features of CFRD that differentiates it from other forms of diabetes is the variation in glucose tolerance demonstrated over time [27]. Although abnormalities of glucose tolerance are known to progress and the complications of diabetes increase in the degree of abnormal glycaemia, some patients with the diagnosis of CFRD will have OGTT results that normalise [27]. The role of insulin resistance has been less well defined although there is emerging evidence of its importance. Ahmad et al. illustrated that patients with CF actually had an increase in peripheral insulin sensitivity compared to healthy controls matched for age and body mass index. They concluded that this increase in peripheral sensitivity in CF patients was a metabolic compensation for insulin deficiency [28]. Moran et al. replicated these findings in exocrine-insufficient CF patients without diabetes. However, once CFRD had developed, there was an increase in peripheral insulin resistance [29]. The mechanism by which this may occur could be the result of a downregulation of GLUT-4 insulin-sensitive channels secondary to chronic hyperglycaemia [30] (“glucose toxicity”). Insulin resistance is also thought to vary over time which could explain the variability of glucose tolerance seen in patients with CF, including a normalisation of previously abnormal glucose tolerance on OGTT. It is often cited that glucose abnormalities worsen during pulmonary exacerbations (due to cytokine and stress hormone release), but the data to support this suggestion is limited and was not found in the study by Widger et al. [31]. This group performed OGTT in patients with a pulmonary exacerbation and then repeated the OGTT when well. Although the sample size was small, 8/9 patients remained within their glycaemic category even when recovered from their pulmonary exacerbation. However insulin resistance is known to increase during periods of corticosteroid usage, overnight feeds [32, 33], pregnancy and during puberty [34–36]. In the latter case, insulin resistance is thought to increase as a result of a physiological elevation in growth hormone [34], and this may account for the increased detection of CFRD in this age group.
\nChronic inflammation may play a key role in the development of glucose abnormalities in CF. Bismuth et al. demonstrated in their cohort of patients with CF that the erythrocyte sedimentation rate (ESR), a marker of inflammation, positively correlated with HbA1c and the area under the curve (AUC) for glucose in patients undergoing OGTT [37]. Significant and ongoing oxidative stress is one mechanism hypothesised to result in an inflammatory state and beta-cell apoptosis [38, 39]. One review postulated that the imbalance in inflammatory T-cell lymphocytes known to play a role in the development of other forms of diabetes may contribute to lung inflammation and thereby a chronic inflammatory states resulting in glucose abnormalities [40]. T-helper 17 (Th-17) lymphocyte cells secrete a pro-inflammatory cytokine-IL-17 known to be involve in pulmonary inflammation in CF and is known to be present in higher levels compared to controls in patients with Type 2 diabetes. Furthermore, studies also suggest that IL-17 may play an important role in the development of Type 1 diabetes [41] and may contribute to β-cell destruction. It has also been postulated that cytokines such as TNF-α may act directly on the insulin receptor by inducing insulin resistance, thereby inhibiting the potential action of insulin [42].
\nThe pathophysiology of CFRD is likely to be multifactorial but ultimately resulting from progressive insulin deficiency secondary to islet cell destruction and defective beta-cell secretion, combined with stressors that intermittently increase insulin resistance resulting in a further deterioration of glycaemic status. Certain patients may be more at risk if non-CFTR genetic modifiers are present [13, 14], and perhaps these patients are unable to compensate for the degree of histological pancreatic destruction and defective beta-cell functioning.
\nCFRD is known to occur in up to 50% of patients with CF by the age of 30 years [43] and the prevalence increases with age. CFRD can occur in young children with CF but is rare [8]. Recent studies suggest that CFRD affects approximately 9% in the 5–9 year age group [44] and a smaller proportion of children under 5 may also meet the CFRD diagnostic criteria. Yi et al. recently reported a series that suggested 5% of their cohort between 6 months and 5 years had CFRD [45]. Although a small proportion of young children have CFRD, the average age of onset is 20 years [46]. CFRD occurs more commonly in females with a prevalence of 17% in young female adults compared with 12% in males previously described [47].
\nChildren with CF are known to be insulin deficient from birth. Milner et al. demonstrated that children with CF in the first year of life had lower insulin levels than controls [7]. Insulin deficiency will progress over time and results in a gradual deterioration of glucose tolerance. As such, impaired glucose tolerance is much more common than CFRD and can affect up to 41% of children in the 6–9 year age group [48], compared with only 10% of this group being classified as CFRD. The risk of early CFRD is much higher in children with abnormal glucose tolerance on OGTT [48].
\nThe prevalence of identified CFRD has been shown to increase after the introduction of screening [49]. Unlike Type 1 or Type 2 diabetes which are often symptomatic, CFRD does not often present with symptoms of hyperglycaemia although this can occur in approximately one third of patients. Symptoms can include polyuria and polydipsia, but CFRD is more likely to present insidiously with the catabolic complications of insulin deficiency such as nutritional deterioration or decline in pulmonary function. When routine screening was introduced in Australia, the incidence of CFRD increased from 2.0 to 22.1 per 1000 person years between 2000 and 2008, which represents a tenfold increase [50]. A decline in the age of diagnosis has also been demonstrated after the introduction of routine screening; Noronha et al. reported a reduction in the mean age of diagnosis from 22.3 years to 13.5 years [49]. Routine screening from at least 10 years of age with an OGTT is recommended by most guidelines [51, 52].
\nThe risk factors for the development of CFRD are closely linked to the specific CFTR genotype and the severity of the CFTR protein dysfunction [53]. CFTR mutations are classified according to the resulting functional deficit [54]. Class 1 and class 2 mutations result in the total or partial absence of CFTR protein at the surface membrane due to defective/non-functional protein (Class 1, e.g. stop codon mutations) or due to defective transfer of the protein to the cell membrane, i.e. defective “trafficking” (Class 2, e.g. F508) [25]. Classes 3, 4, 5 and 6 have irregularities in regulation, conductance, prevalence and stability of CFTR at the membrane [55]. Of the latter, 4 classes, all except class 3, which is known as a gating mutation, have partial function. Those classes with no action have a more severe phenotype and are associated with a greater risk of CFRD, such as homozygous F508 patients [46].
\nCFRD generally occurs in patients with pancreatic insufficiency. There have been reports of CFRD in patients who are pancreatic sufficient, but the diagnostic criteria for exocrine pancreatic function do not appear to be robust [47]. Some of these patients were classified as pancreatic sufficient because they were not taking replacement enzymes, but had not undergone any formal diagnostic testing such as faecal elastase or 3-day fat stool sampling. More recent studies have demonstrated that the degree of pancreatic exocrine function appears to correlate with the development of CFRD. Soave et al. demonstrated a causal relationship between the level of serum trypsinogen on the newborn screen (a marker of exocrine pancreatic function used to diagnose CF) and the development of CFRD over time [15]. Trypsinogen is an inactive pancreatic enzyme precursor required for protein digestion and absorption. It is converted to trypsin when secreted into the small intestine, but this process is inhibited in CF and results in an elevated serum trypsinogen. A significant elevation in the blood levels of immunoreactive trypsinogen (IRT) on newborn screening is used to identify neonates with CF. The IRT level is known to decline rapidly over Time with ongoing pancreatic destruction. Soave et al. postulated that patients with CF who had more significant pancreatic disease at birth would have IRT levels that had already started to decline and would be relatively lower than the rest of the CF cohort [15]. They also demonstrated that those children with relatively low IRT amongst the CF cohort had an increased risk of CFRD, thus confirming the relationship between exocrine pancreatic function and endocrine disease.
\nThe presence of CF liver disease appears to be a significant risk factor in the development of CFRD. Leung et al. examined over 700 liver ultrasounds of patients with CF and found that patients with the features of heterogenous or cirrhotic liver disease on ultrasound were more likely to have abnormalities of glucose tolerance, including CFRD, than those with normal liver ultrasounds [56]. The relationship between liver disease and CFRD remains unclear. It could be a result of the more severe genotypes causing CFRD also increasing the risk of liver disease, or it could be the result of a non-CFTR genetic modifier.
\nAbnormal glucose tolerance is a known risk factor for progression to CFRD. CF patients with glucose abnormalities are up to 11 times more likely to develop early CFRD than other 6–9-year-old patients [48].
\nGlucose abnormalities in CF are associated with significantly increased morbidity and mortality [2]. Prior to the introduction of routine screening for CFRD, less than 25% of CFRD patients survived to age 30, compared with 60% of patients without diabetes [57]. When Moran et al. examined female CF cohorts with and without CFRD in the 1990s and compared them with cohorts after the introduction of routine CFRD screening, mortality rates had halved: 6.9 per 100 patients years in patients with CFRD versus 3.2 per 100 patient years in CF without diabetes, with similar results seen in men were reported [58]. Although mortality rates for patients with CFRD have seen a marked improvement, a significant difference between CF patients with and without diabetes persists [59].
\nCFRD leads to a significant increase in respiratory exacerbations, increased infection with CF pathogens [60] (including
Blood glucose levels >8 mmol/L correlate with increased airway glucose levels in patients with CF [62]. In non-CF patients, elevated airway glucose has been demonstrated to be a risk factor for respiratory infections, including MRSA (based on studies in patients intubated due to critical illness in the intensive care unit [63]). When Brennan et al. examined the airway glucose of patients with CF, they demonstrated that even patients with normal glucose tolerance on OGTT had glucose in their airway for longer periods of time than the control population. The duration of time spent with airway glucose levels >8 mmol/L correlated with the degree of glucose abnormality [62]. The level at which glucose appears in the airway is much lower than the 2-h OGTT glycaemic threshold for CFRD and also appears to be very close to the level of blood glucose level (BGL) which correlates with significant nutritional and respiratory decline [64].
\nRespiratory tract infections may not entirely account for the deterioration in lung function seen in patients with CF. Patients with diabetes mellitus from other causes have also been demonstrated to have poorer lung function than matched controls, even in the absence of respiratory disease [65, 66]. It is unclear whether this is a direct result of glucose in the airways or an indirect result of inflammation from relative insulin deficiency.
\nNutrition in CF has a direct correlation with survival [67], and insulin, an anabolic hormone, plays an integral role in maintaining weight and building muscle [18]. When CF patients are insulin deficient, this manifests as poorer nutritional status. Multiple studies have demonstrated the impact of CFRD and insulin deficiency on nutrition and growth [37]. The data of over 8000 CF patients on the epidemiologic study of cystic fibrosis (ESCF) was analysed in 2005 and confirmed a greater impairment in nutrition in the CFRD group when compared with the nondiabetic group [47]. The CFRD cohort had statistically lower height for age percentiles, weight for age percentiles and BMI (p < 0.001 for all three parameters). A statistically significant difference in body weight and BMI has also been demonstrated in the “prediabetic” CF patients when compared with CF patients with normal glucose tolerance [61]. This decline was detected by Lanng et al. in some patients 4 years prior to the diagnosis of CFRD being. Given the insidious nature of glycaemic abnormalities and the inherent difficulties with nutrition in patients with CF, particularly those with exocrine pancreatic insufficiency, the impact of insulin deficiency is often not recognised until CFRD is diagnosed on routine screening.
\nInsulin deficiency is progressive and results in a deterioration of glucose tolerance over time. CFRD lies at the end of a spectrum of glucose abnormalities. Glycaemic categories in CF are determined based on the results of the oral glucose tolerance test (OGTT) [51]. To perform an OGTT, a glucose load of 1.75 g/kg (maximum 75 g) is consumed after fasting. Classically the blood glucose level (BGL) is measured at 0 and 120 min [68]. Additional information about glucose tolerance is gained by also checking the BGL at 30 min, 60 min and 90 min, i.e. a 30-min sampled OGTT [64].
\nThe diagnosis of CFRD is made based on the American Diabetic Association (ADA) criteria [51] (see \nTable 1\n). CFRD is diagnosed when the 2-h OGTT level is ≥ 11.1 mmol/L and can occur with or without fasting hyperglycaemia (fasting BGL ≥ 7.0 mmol/L is defined as fasting hyperglycaemia). Fasting hyperglycaemia can also be considered diagnostic of CFRD, if still abnormal when repeated. One fasting BGL ≥ 7.0 mmol/L and another non-fasting level ≥ 11.1 mmol/L can also make a diagnosis of CFRD. If a patient is sick and glycaemic abnormalities persist for two days, then the diagnosis can also be made. Most guidelines recommend the OGTT/BGL is repeated before the diagnosis is confirmed. Some guidelines subclassify CFRD based on the fasting BGL, but this distinction does not alter management, as insulin treatment is recommended for those with and without fasting hyperglycaemia.
\nCategory | \nFasting level | \nMidpoint peak (1 h) | \n2-h plasma level | \n
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Normal glucose tolerance | \n<7 mmol/L | \n<11.1 mmol/L | \n<7.8 mmol/L | \n
Indeterminate glycaemia (INDET) | \n<7 mmol/L | \n≥11.1 mmol/L | \n<7.8 mmol/L | \n
Impaired glucose tolerance (IGT) | \n<7 mmol/L | \n\n | ≥7.8 and < 11.1 mmol/L | \n
CFRD without fasting hyperglycaemia | \n<7 mmol/L | \n\n | ≥11.1 mmol/L | \n
CFRD with fasting hyperglycaemia | \n≥7 mmol/L | \n\n | ≥11.1 mmol/L | \n
Classification of abnormalities of glucose tolerance in cystic fibrosis on OGTT.
Additional criteria have been published to subclassify the patients into glycaemic categories based on 30-min samples (see \nTable 1\n) [1]. Patients with normal glucose tolerance have fasting BGL <7.0 mmol/L and 2-h level <7.8 mmol/L. Indeterminate glycaemia (INDET) is defined as normal fasting and 2-h levels with a midpoint level ≥ 11.1 mmol/L. Impaired glucose tolerance (IGT) is defined by a 2-h level <11.1 mmol/L but ≥7.8 mmol/L.
\nChildren with abnormal glucose tolerance and CF may fluctuate between glycaemic categories because of increasing insulin requirements at times of illness or because of variable levels of resistance. In one study 18% of CF patients with abnormal glucose tolerance had glycaemic abnormalities that improved over time. Twenty-two percent of patients had a deterioration in their glucose tolerance [27]. This variability was replicated by Lanng et al. who saw a normalisation of the patient OGTT in 58% of adult patients with CF when followed up after 5 years [69]. Yi et al. examined glucose tolerance in young children (<6 years) and found that some of these children with abnormal glucose tolerance that normalised, including those that met CFRD criteria [45]. This variability adds to the difficulty seen in managing patients with CFRD, particularly younger children.
\nThe OGTT was not designed to diagnose diabetes in the CF population. The test was designed to determine the treatment threshold for Pima Native American population with Type 2 diabetes based on their risk of developing microvascular complications [70]. Although microvascular diabetes complications can occur in CF, the major concern for CFRD is its impact on nutrition and lung function. Complications from chronic intermediate hyperglycaemia may also result in microvascular disease prior to the patient meeting the criteria for CFRD [71]. More practical goals would include an initiation of treatment at a time that would alleviate significant respiratory morbidity such as recurrent infections and respiratory function decline. The drop in nutritional status and weight, or poor growth in younger children because of insulin deficiency catabolism, would be a more relevant CF-specific outcome to guide diagnostic targets.
\nThe decrease in lung function and nutrition seen in CFRD actually precedes the diagnosis by several years and is often insidious. Lanng et al. noted that a decline was present up to four years prior to the OGTT 2-h criteria being met [61]. Furthermore, insulin therapy has been demonstrated to reverse some of the nutritional decline seen in patients with abnormal glycaemia [72, 73]. However, once patients meet the criteria for CFRD, recovery of lung function is not always possible. Widger et al. postulate that by waiting until the patient meets the CFRD criteria to start insulin, the conceded progression from abnormal glucose tolerance to CFRD allows irreversible structural remodelling of the lungs that cannot be corrected with insulin therapy [74].
\nFurther evidence for insulin therapy at an earlier stage of the glycaemic spectrum is warranted, and initial data has highlighted which patients may benefit most. Schmid et al. demonstrated that in 1000 patients with CF, patients with midpoint level ≥11.1 mmol/L (INDET) were predictive for later development of CFRD [75]. Brodsky et al. were able to establish that the 1-h level on the OGTT correlated with poorer lung function [76]. They examined 101 patients with CF and these patients with higher 1-h levels had poorer respiratory status even when corrected for nutritional status. The 2-h “diagnostic” level in this group did not correlate with BMI or lung function. The findings of Coriati et al. [77] confirm that waiting for the 2-h BGL to be diagnostic of CFRD may be too late. Their cohort of patients with indeterminate glycaemia already had significant loss of lung function, equivalent to the lung function of patients with newly diagnosed CFRD. The criteria to start insulin in the future may be determined by the patient’s own risk of developing CFRD or by early clinical signals in lung function and intermediate glucose abnormalities.
\nHameed et al. used a 30-min sampled OGTT and found that a peak BGL ≥ 8.2 mmol/L was reliably predictive of a decline in lung function and nutrition in the preceding year [64]. Based on these results, this group proposed a new staging criteria to identify insulin deficiency and early glucose abnormalities in patients with CF (see \nTable 2\n) [78]. Cystic fibrosis insulin deficiencies (CFID) 4 and 3 correspond to existing CFRD categories with and without fasting hyperglycaemia, respectively. CFID 1 and 2 are earlier stages of insulin deficiency that are distinct from impaired glucose tolerance (IGT) because they are based on the peak glucose level and have 2-h levels < 11.1. CFID 1 is defined by a midpoint peak glucose level ≥8.2 mmol/L, and CFID2 has a midpoint glucose peak ≥11.1 mmol/L.
\nProposed new criteria | \nPeak blood glucose (BGmax) mmol/L | \nBlood glucose at 120 min mmol/L | \n
---|---|---|
CFID1 | \n≥8.2 | \n<11.1 | \n
CFID2 | \n≥11.1 | \n<11.1 | \n
CFID3 | \n\n | ≥11.1 Without fasting hyperglycaemia | \n
CFID4 | \n\n | ≥11.1 With fasting hyperglycaemia | \n
Proposed new staging criteria for insulin deficiency and early glucose abnormalities in CF, based on the OGTT with samples every 30 min.
CFID = cystic fibrosis insulin deficiency.
Continuous glucose monitoring (CGM) has been used for several years in the management of Type 1 diabetes although it is not licenced for use as a diagnostic device. CGM uses a small probe inserted into the subcutaneous space where it measures interstitial glucose levels. Inserting the device is a relatively simple procedure that can be done within a few minutes in a clinic environment. It is easy to remove at home by the patient or carer, without any specific medical training. The device averages the glucose readings every five minutes and can be worn for several days whilst the patient continues to participate in normal activities and consumes their normal diet. The CGM device has been validated in CF and non-CF populations and shown to correlate with plasma glucose measurements [79, 80]. When compared with OGTT, CGM appears to be reproducible and a reliable assessment of glycaemic abnormalities. When used in Type 1 diabetes, Bergenstal was able to demonstrate that children and adults on insulin pumps had improved glycaemic control, as measured by HbA1c than those who did not use CGM [81].
\nCGM may be particularly useful in managing cystic fibrosis. CF patients frequently demonstrate early postprandial hyperglycaemia [79, 82, 83], reflected by elevations in readings on a 30-min sampled OGTT in the setting of a normal 2-h level. This intermittent postprandial hyperglycaemia may be reflected in the poor correlation of HbA1c (glycated haemoglobin) with early glycaemic abnormalities in CF. HbA1c represents an index of the average of blood glucose concentrations in the preceding 2–3-month period, and the result is influenced by the half-life of the red cells [84]. When measured in CF, it is a poor indicator of glycaemic abnormalities as it is often still normal by the time a diagnosis of CFRD has been made. The poor sensitivity of the test may result from the intermittent nature of hyperglycaemia in patients with CF, which is not revealed in the HbA1c level when the glucose levels are “averaged”, as well as increased red cell turnover in CF.
\nCGM provides a useful tool to guide insulin treatment once the diagnosis of CFRD has been made [79], but it may also offer a potential opportunity to capture the moments of postprandial hyperglycaemia in CF in the screening and diagnostic phase. In CF patients with normal glucose tolerance on OGTT, abnormalities on CGM have been detected [79, 82, 83]. This could reflect the fact that patients with CF undergo a period of fasting prior to their glucose load in the OGTT which will only measure two values. When a CGM is worn, patients can be at home and may consume their normal CF diet including a carbohydrate load that may exceed the glucose level consumed during an OGTT. In the same way that HbA1c may not reflect a true picture of glycaemic abnormalities in CF, so too may the OGTT underestimate the hyperglycaemia in these patients, particularly in the early phase of glucose abnormalities.
\nCGM may be a useful device in predicting which children with CF will develop glycaemic abnormalities. Schiaffini et al. performed OGTT and CGM on children with CF and then repeated the OGTT after 2 years. Children who had diabetic excursions on CGM at baseline, even those with normal glucose tolerance on OGTT, developed impaired glucose tolerance or CFRD when the OGTT was repeated 2 years later [83]. Initial data on CGM does appear to suggest that this tool may be useful in identifying clinically significant glucose abnormalities in CF. Leclercq et al. demonstrated, in a CF population with normal OGTT, that patients who recorded glucose levels in the diabetic range (≥11.1 mmol/L) on CGM had poorer lung function and greater colonisation with CF respiratory pathogens such as
Glycaemic abnormalities are known to have a significant impact on nutrition in patients with CF. CGM may provide an opportunity to highlight which children are at risk of nutritional decline secondary to abnormities of glucose tolerance as described in the study by Hameed et al. [64]. In this study of 25 children with CF undergoing CGM, if ≥ 4.5% of the study duration was spent with an interstitial glucose reading >7.8 mmol/L, this was predictive of a decline in weight standard deviation score. This CGM criterion had a sensitivity of 89% and a specificity of 86% in detecting this nutritional decline. CGM abnormalities do appear to be clinically significant, but there are not studies as yet demonstrating a benefit from treatment based on CGM recordings in CF, and the device is not yet licenced to make a diagnosis of diabetes.
\nThe main aim of CFRD treatment is to correct the hyperglycaemia and its downstream effects on respiratory function and infections, in addition to reversing significant protein catabolism secondary to insulin deficiency. Optimal management has been shown to improve lung function and morbidity [72]. Although a drop in mortality from late CFRD diagnosis has been seen, the risk of early mortality is still higher in this population. The mainstay of treatment is exogenous insulin therapy, but studies are underway examining the benefits of dietary changes and the use of oral hypoglycaemic agents in CF.
\nInsulin plays a major role in the management of CFRD. Insulin replacement by subcutaneous injection in CFRD has been shown to improve lung function and reduce pulmonary exacerbation frequency [86]. It has also been shown to benefit the nutritional status of the patient, with an improvement in growth seen in children with CF [73]. Recent studies have also demonstrated that insulin therapy in the prediabetic phase may also play a valuable role in the management of patients with CF. Hameed et al. were able to replicate previous studies demonstrating a benefit of insulin therapy on lung function and nutrition in patients with CF and revealed an improvement in weight standard deviation score (p = 0.003) and lung function (FEV1 improvement p = 0.004) with once daily insulin injections (detemir, Levemir™) [73].
\nInsulin is given via subcutaneous injection. Unlike Type 1 diabetes, a once daily dose of long-acting insulin may be all that is required to demonstrate a benefit for this population [73]. Insulin doses vary with each patient, but because of the important anabolic role insulin plays in growth and nutrition, the highest tolerated dose without hypoglycaemia or other side effects is generally recommended [52] (taking into account patient-specific factors such as ability to recognise hypoglycaemic symptoms). The dose prescribed may vary over time with increasing requirements during times of relative increase in insulin resistance such as with glucocorticoid use or during periods of growth and pregnancy. Given the progressive nature of insulin deficiency in CF, increasing requirements may be seen over time, particularly in the paediatric population with CF that have age- and weight-based doses.
\nInsulin pumps that continuously deliver a small amount of insulin into the subcutaneous space have been used in patients with CFRD [87] although the uptake in CF has been poor when compared with other forms of diabetes. When wearing a pump, patients are currently required to undertake much more intensive finger-prick blood glucose testing than that required with a once daily insulin injection. This may prove to be too onerous for patients with CFRD who already have a significant treatment burden with multiple oral and nebulised medications and physiotherapy. Future insulin pump devices may include closed loop systems, in which interstitial glucose levels measured by CGM calibrate the rate and amount of insulin secreted by the pump [88]. These devices are currently under investigation for Type 1 DM, but there are no data published about their use in CFRD to date.
\nNutritional education and support are of utmost importance for patients with a diagnosis of CFRD. Children with CF require a higher caloric intake (may need up to 200% of usual recommendations [89]) to achieve optimal nutritional and growth targets. If nutritional targets are not met, there may be significant consequences as a lower BMI has been associated with increased mortality in CF [67]. These additional calories are best taken from fat and protein-based meals, but a significant proportion is taken from carbohydrates [90]. Patients with abnormalities of glucose tolerance and CFRD will be required to recognise carbohydrates in their diet, as the carbohydrate load will affect the glucose level and the resulting insulin requirements. This is usually done by educating the family and patient about carbohydrate-insulin ratios.
\nThere are very limited data regarding the dietary management of CFRD. This is of particular significance given that hyperglycaemia has been demonstrated to worsen glycaemic abnormalities in CF, possibly by potentiating beta-cell apoptosis. As such, glycaemic control in CFRD needs to be tight, and diets that perpetuate postprandial hyperglycaemia may have a negative impact on glycaemic abnormalities in CF and increase insulin requirements. A low glycaemic diet is often recommended in Type 1 and Type 2 diabetes to optimise control of hyperglycaemia and has been shown to decrease insulin requirements and improve glucose homeostasis, without having a significant impact on quality of life for these patients. Whereas weight loss due to change in diet may be beneficial in Type 2 DM, this may have serious negative consequence in CF. There is not enough information in the literature to recommend any dietary changes that might improve glycaemic control or prevent or delay progression to CFRD if instituted at an earlier stage.
\nOral agents do not play a role in the management of patients with CFRD. Many agents target insulin resistance (e.g. metformin), which is not a major feature in the early glycaemic abnormalities of CF where insulin deficiency plays the key role and as such will not be of significant benefit to CF patients. Significant side effects from oral hypoglycaemic agents such as hepatotoxicity are a serious complication for the CF population where a significant proportion may develop CF liver disease [91]. Insulin therapy in states of insulin deficiency such as Type 1 diabetes has been shown to preserve insulin secretion and “rest” the residual beta cells. Conversely, agents that stimulate insulin secretion may potentially hasten beta-cell loss. For example, agents such as repaglinide may be useful in the short term but ultimately have a negative long-term impact.
\nEvidence for the use of potentiators in CFRD is limited, but a few pilot studies have been published that suggest a benefit on glucose homeostasis in CF. In a single pair of CF siblings with abnormal glucose tolerance (one with CFRD) and gating mutations, a reduction in the glucose AUC and an improvement in the insulin secretion profile was demonstrated after the introduction of ivacaftor (Kalydeco™). Bellin et al. also demonstrated improvements in glucose homeostasis after the introduction of ivacaftor. In this group of five CF patients with glucose abnormalities, four of five demonstrated improvements in insulin secretion. The patient whose insulin secretion did not improve had long-standing CFRD, whereas the others had earlier glycaemic abnormalities. Theoretically, the patient with long-standing CFRD could already have undergone such significant pancreatic destruction that the abnormalities of glucose tolerance could not be corrected at the level of the CFTR.
\nLong-standing hyperglycaemia and insulin deficiency will result in an increase in respiratory exacerbations and morbidity and poorer nutrition. It will also result in complications from chronic hyperglycaemia seen in other forms of diabetes. Historically the life-limiting nature of CF and in particularly those with CFRD meant that CF patients were unlikely to live long enough to develop end-organ dysfunction from the macrovascular and microvascular complications seen in other forms of diabetes. With an improvement in life expectancy, these long-term issues need to be addressed, and routine screening needs to be a part of CF clinical care. This will include examination for neuropathy and retinopathy and urine screening for microalbuminuria. In one study, 10 years after the diagnosis of CFRD has been made, subjects with fasting glycaemia demonstrated rates of microalbuminuria of approximately 14%, retinopathy 16%, neuropathy 55% and autonomic gastropathy 50% [51]. Gilchrist et al. reported retinopathy in three patients with abnormal glucose tolerance but not meeting criteria for CFRD [71] which further supports the proposition that the OGTT may not be the ideal test for significant glycaemic abnormalities in patients with CF.
\nCystic fibrosis–related diabetes continues to pose a significant risk of increased morbidity and mortality to the CF population. However, CFRD lies at the endpoint of spectrum of glucose abnormalities, and increasing evidence implies that earlier glycaemic abnormalities may also be clinically significant. The standard OGTT does not appear to be sensitive enough to pick up early, clinically significant abnormalities of glucose tolerance secondary to insulin deficiency and the dysregulation of insulin secretion detected in CF patients. Hyperglycaemia in CF affects lung function, risk of respiratory pathogens, nutrition and growth in young children, and treating teams need to be proactive in the screening and diagnosis of glycaemic abnormalities that may be insidious and potentially irreversible if recognised late. Early recognition of hyperglycaemia in CF is required to prevent significant morbidity. Novel techniques such as continuous glucose monitoring may play a role in screening and early identification of at risk patients, as they have been shown to be predictive of significant glucose abnormalities in the future such as CFRD, but there is not enough evidence as yet to recommend their routine use in diagnosis. Future directions may include the use of potentiators and correctors in CF which appear to have potential to correct abnormalities of glucose tolerance but may be limited if instituted late and once significant pancreatic destruction has occurred.
\nSH and CFV are grateful for funding assistance from the National Health and Medical Research Council of Australia, Australasian Cystic Fibrosis Research Trust, Regional Diabetes Support Scheme, Sydney Children’s Hospital Foundation and Australasian Paediatric Endocrine Care Grant from Pfizer and for industry support from Novo Nordisk, Medtronic and Abbott Diagnostics. BP has been awarded a scholarship from the Thoracic Society of Australia and New Zealand and Vertex.
\nAs an important component of the transportation infrastructure, asphalt pavement is composed of multi-layer complex system of different materials subjected to various combinations of traffic as well as environmental loadings. During their lifetime asphalt pavements experience various forms of distresses as they undergo oxidative aging, freeze-thaw cycles, and traffic repetitions. One of the most widespread type of deterioration in asphalt roads which shortens the pavement life and results in premature failure of the pavement structure is cracking. An accurate and realistic assessment of cracking performance of asphalt pavements has remained as a challenging task for civil engineers.
The AE technique has become very popular in recent decades due to its unique ability in detecting and locating microstructural failures in different types of materials. This method has been successfully used for damage detection of various materials such as steel, concrete, wood, and rock. However, for the case of asphalt roads, there has been only a limited application of this technology in damage assessment of asphalt pavements. In one of the studies Khosla and Goetz [1] used the acoustic emission approach at low temperatures to locate crack initiation and propagation in indirect tensile (IDT) asphalt concrete specimens. They found that the material failure due to fracture was accompanied by a sudden increase in total AE counts where a big portion of AE counts occurred at about 80% of the peak load. In another study conducted by Valkering and Jongeneel [2], AE technique was implemented to carefully monitor the thermally-induced cracking in asphalt concrete materials subjected to low temperature cooling cycles (−10°C to −40°C). Results showed that the AE activity of the material such as number of events were strongly correlated with the extent of thermal fracture in the specimens. Results also demonstrated that at low temperatures the source of AE activities in restrained specimens were crack initiation originated from defects exists in the material. In the research study performed by Hesp et al. [3] the AE method was employed for restrained asphalt concrete specimens at low temperatures (−32°C to −20°C) to measure and to detect crack initiation and propagation in the restrained samples. They compared the total amount of AE activities in different mixtures and found that the styrene-butadiene-styrene (SBS)-modified asphalt concrete materials exhibited less AE activities as compared to that of for the unmodified asphalt concrete mixes. The AE approach was implemented by Li et al. [4, 5, 6, 7, 8] to evaluate and to quantify fracture in semi-circular bending (SCB) asphalt specimens at −20°C. They concluded that most of the AE activities in the material happens at about 70% of the material strength. Their results also showed that the maximum intensity of AE amplitudes correlated well with the extent of macrocracking damage in the specimen. They also found that the location of AE events is the good indicator of approximate size of the fracture process zone (FPZ). Nesvijski and Marasteanu [9, 10] in another research study, used the AE spectral analysis approach at low temperatures in order to investigate and assess fracture in semi-circular bending (SCB) asphalt samples. They were able to successfully demonstrate that the AE approach could be applied for accurate characterization of cracking in asphalt concrete materials.
This chapter will focus on various applications of the acoustic emission technique in asphalt pavements including: (1) assessing the low-temperature cracking performance of asphalt binders and asphalt pavement materials (2) use of acoustic emission technique for quantitative evaluation of restoring aged asphalt pavements with rejuvenators.
Low temperature cracking, a.k.a. thermal cracking, is a very common type of damage occurring in asphalt pavements located either in regions with cold climates or in milder climate regions with large daily temperature fluctuations. In asphalt pavements built in cold climates with severe winters, thermal cracking usually happens as a result of fast cooling rates (single-event thermal cracking). On the other hand, in asphalt roads located in regions with milder climate, thermal cracks develop at a slower rate, and it usually takes several cooling cycles for cracks to initiate and propagate through the pavement thickness (thermal fatigue cracking) [11]. When the temperature drops, surface of the pavement has the lowest temperature, and the temperature changes are highest there. Thermal tensile stresses develop in the restrained pavement layer due to the change in pavement temperature. The thermally-induced stresses are greatest in the longitudinal direction of the road which will lead to formation of transversely-oriented surface-initiated thermal cracks of various lengths and widths along the road.
Numerous research studies have demonstrated that the low temperature characteristics of asphalt pavements are closely related to that of the asphalt binder used in pavement construction. The AE method is implemented to evaluate the thermal cracking in asphalt binders. The AE binder sample consists of a 6 mm thick layer of asphalt binder bonded to an aluminum plate. To conduct the test, prepared specimens are placed inside the freezer and exposed to decreasing temperatures, ranging from 20°C to −40°C, or even to −50°C, if necessary for some polymer modified binders. To continuously monitor and record the sample temperature, a K-type thermocouple is placed on the specimens’ surface. Due to the relatively small size of the AE sample, there is a thermal lag at the beginning of the test, which becomes negligible at temperature lower than −10°C. Differential thermal contraction between aluminum and asphalt binder induces progressively higher thermal stresses in the binder leading to formation of thermal cracks in the material. Thermal cracks formation in the sample is accompanied by a release of elastic energy in the form of transient waves which could be picked up using the AE piezoelectric sensor(s) mounted on aluminum plate. The critical cracking temperature, a.k.a. the embrittlement temperature, of the asphalt binders tested are determined by processing and analyzing the emitted elastic waves captured during the tests using the AE technique. Figure 1a schematically illustrates an AE testing sample of asphalt binder with an aluminum substrate [12, 13, 14, 15, 16, 17, 18, 19, 20, 21].
AE testing samples used for (a) asphalt binders (b) asphalt concrete materials.
To conduct the AE test for asphalt concrete materials, a semicircular-shaped asphalt concrete sample with a 50°mm thickness and a 150°mm diameter is used as the testing specimen, see Figure 1b. The testing sample for asphalt concrete can be fabricated from either field cores or from gyratory compacted samples. To conduct the AE test, similar to the binder test, the prepared AE sample is subjected to decreasing temperatures ranging from 20°C to -40°C and the acoustic activities and temperature of asphalt material test sample is continuously monitored and recorded using piezoelectric AE sensors and a K-type thermocouple, respectively. The source of acoustic emission activities in asphalt concrete materials is formation of thermally-induced microdamages within the asphalt mastic. As a heterogeneous viscoelastic material, the thermally induced stresses develop in asphalt concrete due to the thermal contraction mismatch between aggregates and surrounding asphalt mastic [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].
The acoustic emission testing set up used for assessing asphalt materials consists of several wideband piezoelectric AE sensors along with pre-amplifiers and data acquisition system with processing and analysis software. The Digital Wave-Model B1025 wideband AE sensors with nominal frequency range of 20 kHz to 1.5 MHz used in this study in order to record and continuously monitor AE activities of the material while conducting the experiment. To reduce extraneous noise, the AE signals picked up by AE sensors are first pre-amplified 20 dB using broad-band preamplifiers. Then AE signals are amplified again 21 dB for a total of 41 dB. At the end signals are filtered using a 20 kHz high-pass double-pole filter through using the signal conditioning unit. A 16-bit analog to digital converter (ICS 645B-8) with 2 MHz sampling frequency and a length of 2048 points per channel per acquisition trigger are used to digitize the signals and outputs are stored for the post-processing.
In general there are two methods normally used to analyze AE signals: (1) the “classic” or “parameter-based” method; (2) the “quantitative” or “signal-based” approach. In the first approach, the AE signals are not recorded, instead only some AE parameters are recorded and analyzed. Whereas in the signal-based approach, the actual AE signals are recorded and used to analyze the materials microstructure. The failure and microdamage occurring in the material could generate significant number of AE signals within a very short time generating big amount of AE data. In the parameter-based method only some rudimentary analysis can be performed on AE data however it is faster than the quantitative method. On the other hand, while the signal-based approach is slower, it is capable of more sophisticated analysis of performance of the material.
For evaluation of thermal cracking in asphalt materials, both parameter-based and signal-based techniques were implemented on recorded AE signals and associated test temperature. AE event is an individual waveform with the threshold of 0.1 V and the energy level equal to or greater than 4 V2 μs. The emitted energy associated with each event is one of the important characteristics of an AE signal and can be calculated using Eq. (1), where EAE is the AE energy of an event (V2 μsec) with duration of time t (μsec) and recorded voltage of V(t) [1].
Figure 2 shows a typical plot of AE events counts versus temperature for typical asphalt binder and asphalt concrete AE tests which consists of four distinct regions, namely: (1) pre-cracking, (2) transition, (3) stable cracking, and (4) fully cracked regions. In the “pre-cracking region”, thermally-induced stresses in the sample are building up and they are still below the strength of the material. As a result no damage and consequently no AE events are observed within this region. In the “transition” region, as soon as the thermal stresses reach the strength of the material, microdamages form in the material which manifests itself as a cluster of high amplitude AE events. The temperature corresponding to the AE event with the first peak energy within the transition region has been termed the “embrittlement temperature,” as shown in Figure 3. The embrittlement temperature is the onset of damage in asphalt material. Results has demonstrated that the embrittlement temperature is a fundamental material state which is independent of material constraint, sample size (as long as a statistically representative volume or larger is used), and sample shape [15]. In the “transition region”, material behavior gradually changes from a quasi-brittle to a brittle state where resistance to fracture is generally very low, allowing microdamages to propagate readily.
Typical AE event counts vs. temperature plot regions.
Typical plot of event count and AE energy vs. temperature [
The third region is the “stable cracking region” which normally initiates at a very low temperatures when the material is brittle. Significant amount of AE activities are observed during this region. The last region, is the “fully cracked region” where the rate of AE activities of the sample begins to reduce until it reaches almost zero at the end of this region. The AE activities originate from formation of new microdamage inside the sample. Thus reduction in the rate of AE activity can be linked to the presence of plenty of microdamage in the sample. This region is usually observed when the sample is cooled down to very cold temperatures allowing all microdamage to develop within the sample [15].
Figure 4 illustrates the typical envelope locus of AE event energies of asphalt samples and demonstrates the intensity of the released energies of AE events. In the pre-cracking region, the envelope locus is zero and suddenly at the beginning of the transition region it jumps to its maximum magnitude. The magnitude of AE event energies gradually tapers off in stable cracking region until it reaches almost zero in the fully cracked region.
Typical envelope locus of AE events energy during thermal cooling [
The histogram presented in Figure 5 shows the graphical representation of the distribution of AE events energies for asphalt materials. Results suggest that only a small portion of AE events are high energy events while the rest of the events are in fact low energy. Generally, the energy content of an event is proportional with the size of the microdamage causing that event. The high energy events result from the formation of large microcracks while the low energy AE events could be linked to formation of hairline microcracks in the material.
Typical histogram of AE events energies for asphalt binder material [
The AE test results for 24 different types of asphalt materials (eight different binders, each at three aging levels) including: AAA-1 (PG 58-28), AAB-1 (PG 58-22), AAC-1 (PG 58-16), AAD-1 (PG 58-28), AAF-1 (PG 64-10), AAG-1 (PG 58-10), AAK-1 (PG 64-22), AAM-1 (PG 64-16) are presented in Figure 6. In this experiment each binder was tested at three aging levels: (1) unaged (TANK) (2) short-term aged (RTFO), and (3) long-term aged (PAV). The ASTM D2872-04 (ASTM 2004) and ASTM D6521-05 (ASTM 2008) were used to perform the oxidative aging process of RTFO and PAV binders, respectively. It should be mentioned that in PG XX-YY used for expressing the Performance Grade of asphalt materials, XX corresponds to the expected average high temperature of asphalt pavement over a 7 days, and YY is the lowest expected temperature of the pavement.
Correlation between AE embrittlement temperature and BBR-based cracking temperature illustrating the conservative nature of the BBR-based cracking temperatures [
Results show that the AE embrittlement temperatures correlated well with the bending beam rheometer (BBR-based) critical cracking temperatures with R2 = 0.85. Results suggest that AE-based embrittlement temperatures are lower than the corresponding BBR-based critical cracking temperatures. This could be attributed to the fact that the AE-based embrittlement temperatures are directly related to the cracking performance of the material while the BBR- base critical temperatures are based upon the binder’s rheological material properties and include an inherent factor of safety to avoid low-temperature pavement cracking. In addition, numerous studies have demonstrated that AE approach is sensitive to aging level of the material and could successfully evaluate asphalt materials at different oxidative aging levels. Finding of different studies show that the embrittlement temperature of asphalt materials is sensitive to aging levels, where TEMB-TANK < TEMB-FTFO < TEMB-PAV.
Oxidative aging is a common problem in asphalt pavements which leads to an increase in stiffness and loss of ductility and cohesion of binders. It negatively affects the fracture resistance of pavements. Certain chemical properties of the asphalt binders such as asphaltenes to maltenes ratio changes in the oxidation process. The oxidation rate of asphalt materials is accelerated at high temperatures and/or high exposure to ultraviolet light and air [21, 22, 23, 24, 25, 26]. Different methods such as pavement surface milling and the application of rejuvenators are employed to restore asphalt pavements to their crack-resistant state. Application of rejuvenators is one of the popular techniques to restore the physical and chemical properties of aged asphalt materials. Rejuvenators change the asphaltenes to maltenes ratio to its original state leading to softening the aged asphalt materials [21, 22, 23, 24, 25, 26]. Rejuvenators are generally sprayed on the surface of aged pavements. It is very important that rejuvenator could penetrate the surface via capillary action and gravity and diffuse through the aged asphalt.
Currently there is no standardized method to assess the performance of rejuvenators when applied in the field. The efficiency of rejuvenators is evaluated by the following three methods which are cumbersome and time consuming and they are not often used.: (1) estimating the penetration of rejuvenator in the pavement by comparing the penetration value of the binder at 25°C in the asphalt binder extracted from untreated and treated sample; (2) comparing the asphalt binders’ viscosity at 60°C obtained from untreated and treated cores; and (3) comparing the amount of loss in aggregates in the abrasion test in untreated vs. treated samples [26].
The AE source location approach has recently been employed to assess the efficiency of rejuvenators in restoring aged asphalt materials to their original crack resistant condition. The Geiger’s iterative source location method was used to accurately detect the source of AE activities in the material [26, 27]. This iterative technique is based on the Gauss-Newton algorithm. To build the arrival time function of the ith sensor, see Eq. (2), data from at least four sensors is required for the Geiger’s method:
where
where
In this chapter results from one of the studies on evaluation of rejuvenators on aged asphalt materials are presented where PG64-22 was used as the based binder. The asphalt content of the mixture was 5.6% by weight and the gyratory compacted specimens were made using a maximum aggregate size of 19 mm. Some specimens were aged in the oven for 2 h at 155°C to simulate the aging level during plant production. Part of the specimens were aged in the oven for 36 h at 155°C (in addition to the short term aging) to mimic the long term aged asphalt pavement materials. The oxidative aging process was done on loose mixtures in order to obtain uniformly-aged compacted samples. Figure 7 shows one of specimens with eight AE sensors mounted on the top and bottom surfaces of the specimen, four sensors on each side. To avoid numerical instability, AE sensors pattern at the bottom of the specimen has a 45° offset angle with respect to the pattern of sensors coupled on the top surface.
(a) Oxidative aged AE testing sample with eight piezoelectric sensors, four sensors on each side. (b) AE testing setup used for source location [
Some aged specimens were treated by spraying a thin layer of rejuvenator on the top surface of the sample. The amount of rejuvenator used was 10% by weight of the asphalt binder. The rejuvenator-treated specimens were then stored for a prescribed dwell time of 2, 4, 6, and 8 weeks before performing the AE tests. After each dwell time, specimens were tested using the same AE source location procedure used to test the 36 h and 2 h aged specimens, allowing the estimation of the embrittlement temperatures throughout the sample thickness.
To characterize the efficiency of rejuvenator on the aged asphalt materials, the embrittlement temperatures of the material were determined throughout the thickness of asphalt concrete samples by implementing the AE source location method. Figure 8 illustrates the embrittlement temperatures results vs. sample thickness for different aged asphalt concrete materials. The effect of oxidative aging on the embrittlement temperature is clearly noticeable as the embrittlement temperature of the short-term aged sample (−22°C) is lower than that of the 36 h aged samples (−13°C). It is also observed that for all specimens the embrittlement temperatures of oxidative aged materials after 2 weeks of dwell time of rejuvenator have been recuperated. The test results obtained from samples after 6 and 8 weeks of dwell time were quite surprising as the embrittlement temperatures of the aforementioned samples far exceeded the embrittlement temperatures of the virgin materials. Moreover, the method was also able to successfully capture the embrittlement temperature gradation throughout the sample thickness for the dwell times of 2 and 4 weeks. This could be attributed to the fact that the rejuvenator has had enough time to penetrate and act on the top material layers. Results suggest that the AE method can be employed to accurately evaluate the graded embrittlement temperature properties of oxidative aged asphalt pavements. One important outcome of this study is that the AE approach can be used to intelligently select the best maintenance strategies for oxidative aged asphalt roads through optimizing the amounts of rejuvenators required to restore pavement to the original crack-resistant condition, or by optimizing the relative amount of milling and surface replacement of asphalt roads. In addition, the AE results obtained from source location approach were found to be consistent with those of obtained from non-collinear ultrasonic wave mixing method [28, 29, 30, 31].
Average measured embrittlement temperatures of rejuvenator-treated oven-aged asphalt concrete samples (for 36 h at 135°C) after dwell times of 2, 4, 6 and 8 weeks [
The acoustic emission approach has been successfully implemented to address the shortage for accurate and reliable techniques to evaluate cracking performance of asphalt pavements. In addition, the AE method has been applied for assessing the efficiency of rejuvenator-treated pavements and to evaluate and characterize virgin, short-term, and long-term asphalt binders and asphalt concrete materials. The AE technique has also been employed in different areas such as evaluating asphalt pavements containing recycled materials such as RAP or RAS, assessing the effect of cooling cycles upon the structural integrity of pavements, and characterizing the thermal cracking performance of graded, i.e., aged asphalt pavements. The promising results from aforementioned studies suggest that the AE technique can be considered as a viable approach for the assessment of asphalt pavements. Moreover, when used for preventive maintenance and rehabilitation, AE method can serve as a powerful tool in enhancing pavement sustainability. Both up-stream and down-stream suppliers and producers of asphalt concrete binders could benefit from AE technique. The up-stream supplies of polymer, chemical, and other additives (warm-mix additives, antistrip agents) could use AE for rapid assessment of low-temperature characteristics of trial formulations, and could quickly evaluate the compatibility of blended additive systems. Asphalt mixture designers could take advantage of the AE technology in order to verify binder grade selection and to optimize the amount of recycled materials used in the pavement. Finally, the pavement owners could implement AE for quality assurance of asphalt binders and asphalt mixtures, for periodic pavement condition assessments, and for the scheduling of preventive maintenance and rehabilitation, where pavement cracking is of concern.
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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. 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Many AST options exist, but proton pump inhibitors (PPIs) have developed popularity in symptomatic relief for refractory GERD patients. To help reduce persistent symptoms, the use of AST therapy optimization is imperative and involves timing doses appropriately and increasing the dose and dosing frequency. Recently, more data has become available regarding the safety profile of AST, specifically PPI use. This data has raised awareness about its potential for toxicity with long-term use. 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Chronic stress causes these physical symptoms and emotional symptoms. Due to the awareness created by the media and internet, patients are generally aware that they should seek help immediately for chest pain. Therefore, attention and studies on stress-induced heart dysfunction would help uncover the pathophysiological mechanisms of cardiac response to non-heart diseases and provide an insight of heart-protection drugs. At the same time, physicians should be aware of this new condition and how to diagnose and treat it, even though the causal mechanisms are not yet fully understood. This special chapter will discuss on the cardiac response to the stresses especially on our associated research in recent decades such as Trypanosoma cruzi (T. cruzi)-induced cardiomyopathy and burn injury–induced cardiomyopathy, and on some very popular stresses such as behavior, motion, mental, and smoking.",book:{id:"11739",title:"Cardiovascular Diseases",coverURL:"https://cdn.intechopen.com/books/images_new/11739.jpg"},signatures:"Jake J. Wen and Ravi S. Radhakrishnan"},{id:"83052",title:"Macrophages as a Target for Treating Diabetic Foot Ulcers",slug:"macrophages-as-a-target-for-treating-diabetic-foot-ulcers",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.106613",abstract:"In all stages of wound healing, macrophages play a pivotal role by coordinating the repair steps in a timely and accurate fashion. The successful completion of wound healing requires proper spatiotemporal presence and function of macrophages. Diabetes significantly alters the proliferation, polarization and functionality of macrophages, leading to a suboptimal but prolonged pro-inflammatory M1-like phenotype in wound macrophages and a failure of their late transition to a reparative M2-like phenotype. This defect in macrophage phenotype and the proper transition results in delayed or even failure of wound healing. Specifically in the diabetic foot ulcer (DFUs), this macrophage dysfunction results in chronic infection and potentially amputation. The abnormal macrophage phenotype in diabetes is not fully understood but is believed to mainly result from epigenetic changes in macrophages and altered interactions between macrophages and other cell types, such as fibroblasts, endothelial cells, neutrophils and T-cells. Recent research on DFUs has focused on developing strategies to improve diabetic wound repair through modulation of macrophage polarization. Treatment of DFUs will greatly benefit from a multi-modal therapy that includes controlling high blood glucose, topical support, prevention of secondary infection, resolution of sustained inflammation and application of cellular therapies targeting macrophages.",book:{id:"11855",title:"Diabetic Foot - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11855.jpg"},signatures:"Lingyan Zhu, Yu Xiao, Yao Xiao, Yinan Jiang, Maha Adama and George K. Gittes"},{id:"83031",title:"Oncological-Therapy-Associated Liver Injuries",slug:"oncological-therapy-associated-liver-injuries",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106214",abstract:"Drug-induced liver injury (DILI) represents a large group of hepatic disease caused by various treatments, including oncological agents. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated. The most common liver disease patterns induced by oncologic therapy are steatosis and steatohepatitis, focal nodular hyperplasia, pseudocirrhosis, acute hepatitis, hepatic necrosis, immune-mediated hepatitis, cholestasis, fibrosis and cirrhosis, sinusal obstructive syndrome. In rare cases, chemotherapy treatment is associated with a high-risk hepatic adenoma or hepatocellular carcinoma development. It was demonstrated that the majority of chemotherapy classes can induce these effects on the liver, for example, alkylating agents, antimetabolites, and antitumor antibiotics, but also immunotherapy agents can be involved. The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Imaging techniques may be helpful in the diagnosis of oncological-therapy-associated liver injuries, for example, focal nodular hyperplasia, pseudocirrhosis, and sinusal obstructive syndrome. If liver disease occurs as an adverse effect of these agents, the recommendation to stop or continue the administration of oncologic treatment with close monitoring relies upon the risk and benefits of this medication.",book:{id:"11265",title:"Hepatotoxicity",coverURL:"https://cdn.intechopen.com/books/images_new/11265.jpg"},signatures:"Victor-Mihai Sacerdoțianu, Costin-Teodor Streba, Ion Rogoveanu, Liliana Streba and Cristin Constantin Vere"},{id:"81663",title:"Cultural Competence and the Education of CSD Professionals in Times of COVID-19",slug:"cultural-competence-and-the-education-of-csd-professionals-in-times-of-covid-19",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.104649",abstract:"This manuscript aims to discuss the experiences and expectations regarding the cultural competence of Brazilian CSD students and the challenges brought by the COVID-19 pandemic. Cultural awareness has been one of the competencies focused on by CSD programs in Brazil. However, travel and face-to-face contact with persons from different cultures and environments is just one of the possible ways of experiencing cultural awareness. The interruption of these opportunities due to the COVID-19 pandemic did not reduce the interest in learning and improving cultural abilities. It is possible to think about alternatives for embedding discussions and experiences regarding cultural sensitivity in students’ routine studies and practice.",book:{id:"11592",title:"COVID-19 Pandemic, Mental Health and Neuroscience - New Scenarios for Understanding and Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11592.jpg"},signatures:"Fernanda Dreux M. Fernandes, Maria Vitoria do Amaral and Cibelle La Higuera Amato"},{id:"82671",title:"Atrial Fibrillation in Heart Failure: Rate or Rhythm Control Strategy",slug:"atrial-fibrillation-in-heart-failure-rate-or-rhythm-control-strategy",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105777",abstract:"Atrial fibrillation and heart failure are intimately related as they shared the same risk factors, unsurprisingly they commonly coexist and complicate each other. Management of atrial fibrillation in heart failure is usually simplified into rate or rhythm control strategy, as each offers its advantages and limitations. Pharmacological rate and rhythm control strategy has been compared for the last decades; however, as more nonpharmacological approach raised as viable option has driven the management strategy discussion even further. On the other hand, heart failure understanding is also evolving and more detailed classification has been made based on left ventricular function. Justification for rate or rhythm control strategy should be individualized predicated on clinical phenotype. 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She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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He is also Member of the Laboratory of genetic, animal and feed resource and member of Animal science Department of INAT. He graduated from Higher School of Agriculture of Mateur, University of Carthage, in 2002 and completed his masters in 2006. Dr. M’HAMDI completed his PhD thesis in Genetic welfare indicators of dairy cattle at Higher Institute of Agronomy of Chott-Meriem, University of Sousse, in 2011. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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