**3.1. Polarity of topical issues**

A typical approach to sentiment analysis is to start with a lexicon of positive and negative words and phrases [4]. Polarity describes whether a word seems to evoke something positive

or something negative. For example, *beautiful* has a positive polarity and *horrid* has a negative polarity. Examples of tweets that represent a positive polarity include:

**Figure 2.** Sentiment polarity of tweets obtained on the decriminalization of marijuana in Jamaica.

Using Sentiment Analysis and Machine Learning Algorithms to Determine Citizens' Perceptions

http://dx.doi.org/10.5772/intechopen.72521

69

**Figure 3.** Sentiment polarity of no-retweets obtained on the decriminalization of marijuana in Jamaica.

*Eg. 1:* "Jamaica legalizes medical marijuana and decriminalizes recreational use."

*Eg. 2:* "the jamaican cabinet approves a bill to legalise use of small amounts of marijuana which will be examined in the senate this week."

Examples of tweets classified as having a negative polarity include:

*Eg. 1:* "what nbc didn't show kaci fennell miss jamaica"

*Eg. 2:* "miss jamaica says the miss universe pageant "went exactly as it should""


**2. Curiosity**

*"Around here, we don't look backwards for very long… We keep moving forward, opening up new doors and doing new things because we're curious… and curiosity keeps leading us down new paths"—Walt Disney.*

Curiosity has been described as being essential for human learning and achievement. As broadly defined by Kashdan et al. [19] curiosity is "the recognition, pursuit, and desire to explore novel, uncertain, complex, and ambiguous events" (p. 130). In order to help leaders and managers get curious about curiosity, recent research suggests there are five distinct types of curiosity [19]. Firstly there is the pleasurable experience of discovering something new and finding it intriguing. This is referred to as joyous exploration. This is where people have a love of learning and are generally fascinated about new things. While this aspect of curiosity is therefore associated with positive emotions, the next is more closely associated with negative emotions. This second type of curiosity is known as deprivation sensitivity. This is the sense of frustration caused by the awareness that there is something unknown that is desired to be known. Here people may be annoyed or anxious until they are able to resolve the information gap. The third aspect of curiosity is stress tolerance. This is the result of first noticing that an event is new in some way and worthy of attention, but then being able to cope with the stress associated with navigating the potential uncertainty. The fourth type of curiosity is the reverse of stress tolerance, where rather than just tolerate this stress people actively seek it. This is referred to as thrill seeking and is where the arousal from a novel situation is not something to be reduced but instead is amplified and what makes the situation desirable. The fifth type of curiosity is social curiosity. This is where we are seek information about other people and enables us to empathize with others. This comes about in two ways. Firstly through direct interactions with others we satisfy overt social curiosity to find out about others. And secondly, by indirect means we can have covert social curiosity which is most often used as a means of building self-esteem by comparison with others.

Research into curiosity in organizational settings has found that increased curiosity in an organization leads to greater levels of creativity and innovation [20–23]. But it also supports better decision making, reduced conflicts and allows more open communication [24]. However, while the benefits are well established, organizational culture still often gets in the way. One study found that while 83% of executives say they encourage curiosity, only 52% of employees agreed [25]. Gino [24] suggests that two key reasons for this is that leaders think allowing employees to follow their curiosity will make the organization harder to manage. And secondly, particularly established managers tend to focus on efficiency improvements rather than exploratory efforts. Similarly Kashdan [26] suggests that to encourage greater curiosity in organizations managers need to encourage rather than supress questions internally, emphasize user observations rather than relying on customer surveys, and actively seek different perspectives when making decisions.


**1. Introduction**

The genus *Fragaria* L. belongs to the family Rosaceae. The species of *Fragaria* are commonly known as strawberries. The fruit is technically known as accessory fruit (Achne) because the fleshy part is not derived from ovaries but from receptacles. The basic chromosome number is 7 (x = 7). There are around 20 species found in the genus of diploid, tetraploid, hexaploid and octoploid in nature*. Fragaria* is found in the temperate regions of the northern hemisphere as well as South America. Natural hybridization between *F*. *chiloensis* (octaploid) with *F*. *virginiana* (octaploid) gave rise to the present-day strawberry cultivars, *F.* × *ananassa* Duch. [1]. A large number of commercial varieties evolved later. *Fragaria* has *Duchesnea* and *Potentilla* as close relatives [2, 3]. Most extensively distributed species in the genus *F. vesca* L., is native to northern Eurasia, North and South America [4]. The commonly cultivated strawberry*, F.* x *ananassa* Duch., is grown in most of the arable regions of the world [5].

While strawberries are native to temperate climates, some varieties can be grown in subtropical climates. Many countries in Asia, North America, Europe and Africa produce strawberries. In 2018, the highest producer of strawberries was China (2.7 million tons) followed by US (1.2 million tons) and Mexico (0.59 million tons) [6]. Generally, strawberry is used for table and desert purposes; however various value-added products are also prepared like strawberry jam, jelly, candy and canned strawberry. A holistic approach is required to conserve such a valuable economically important species. Tissue culture technology has significantly contributed towards the propagation and conservation of *Fragaria* germplasm. The sections below will be useful for breeders, researchers, farmers, farm managers to have an overview of *Fragaria* genetic resource and its *ex situ* conservation.


*Article* **5** ′ **Untranslated Region Elements Show High Abundance and Great Variability in Homologous ABCA Subfamily Genes**

**Pavel Dvorak 1,2, \* , Viktor Hlavac 2,3 and Pavel Soucek 2,3**

Received: 7 October 2020; Accepted: 20 November 2020; Published: 23 November 2020

**Abstract:** The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is studied intensively. The regulation of translation initiation is implicated as the major mechanism in the processes of post-transcriptional modifications determining final protein levels. In the current bioinformatics study, we mapped the features of the 5 ′ untranslated regions (5 ′UTR) known to have the potential to regulate translation, such as the length of 5 ′UTRs, upstream ATG codons, upstream open-reading frames, introns, RNA G-quadruplex-forming sequences, stem loops, and Kozak consensus motifs, in the DNA sequences of all members of the subfamily. Subsequently, the conservation of the features, correlations among them, ribosome profiling data as well as protein levels in normal human tissues were examined. The 5 ′UTRs of ABCA genes contain above-average numbers of upstream ATGs, open-reading frames and introns, as well as conserved ones, and these elements probably play important biological roles in this subfamily, unlike RG4s. Although we found significant correlations among the features, we did not find any correlation between the numbers of 5 ′UTR features and protein tissue distribution and expression scores. We showed the existence of single nucleotide variants in relation to the 5 ′UTR features experimentally in a cohort of 105 breast cancer patients. 5 ′UTR features presumably prepare a complex playground, in which the other elements such as RNA binding proteins and non-coding RNAs play the major role in the fine-tuning of protein expression.

**Keywords:** 5 ′ untranslated region; cis-acting elements; ABC transporters; ABCA subfamily; bioinformatics


**8. Clinical trials on prevention strategies and therapeutic approaches for diabetic vasculopathy**

Growth of overweight and obese population due to diet and life-style changes worldwide correlates with the global T2DM epidemic [144]. However, majority of the studies focusing on diabetes prevention were not designed to assess CV outcomes [145]. There is a need for studies to explore the effect of exercise and diet on quality of life, morbidity, and mortality, with a special focus on CV outcomes.

Clinical trials examining the effect of *intensive glucose control* on CVD did not report consistency in beneficial effects of intensive glycemic control on CV events [146–149]. Although the risk of microvascular complications was reduced with strict glucose control in T2DM patients, its beneficial effects on CVD prevention or reduction remain ambiguous [150–152]. Data from UKPDS 34 (the United Kingdom Prospective Diabetes Study) suggested a protective effect of improved glucose control on CVD, CV mortality, and all-cause mortality [146]. However, a number of large randomized, controlled trials have reported conflicting results. ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [147], VADT (Veterans Affairs Diabetes Trial) [153], and NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) [154] showed no effect of intensive glucose control on major CV events. However, ACCORD (Action to Control Cardiovascular Disease in Diabetes) [149] demonstrated an increased risk of death from CV causes and total mortality associated with intensive glucose control. In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study [155], patients treated with pioglitazone had a significant 16% reduction in mortality, non-fatal myocardial infarction, and stroke. Further research is needed to examine effect of pharmacological approaches for the management of hyperglycemia on CVD.

Diabetic vasculopathy can be improved by *lowering blood pressure* with antihypertensive drugs which have antiatherogenic effects, e.g., ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and calcium channel blockers. Randomized controlled trials like UKPDS [33, 127], HOT (Hypertension Optimal Treatment) [156], SHEP (the Systolic Hypertension in the Elderly Program) [157–159], Syst-EUR (Systolic Hypertension in Europe) [158–161], HOPE (Heart Outcomes Prevention Evaluation) [162], LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) [163], and ALLHAT (the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [164] have found beneficial effects of adequately controlling blood pressure in improving CV outcomes, specifically, for stroke, when aggressive blood pressure targets are met [33, 156, 165, 166].

*Dyslipidemia* plays a significant role in CV complications in T2DM. Dyslipidemia comprises elevated total cholesterol and LDL cholesterol, decreased HDL cholesterol, and high triglyceride levels [74, 75]. Lowering LDL cholesterol reduces the risk of major vascular events in T2DM patients [167]. Randomized clinical trials in T2DM have consistently shown that statins significantly reduce the risk of major primary and secondary CVD endpoints. Clinical trials of fibrate therapy have shown mixed results.

Clinical trials e.g. CARDS (the Collaborative Atorvastatin Diabetes Study) [168], LIPID (Longterm Intervention with Pravastatin in Ischemic Disease) [169], 4S (Scandinavian Simvastatin Survival Study) [170] and HPS (the Heart Protection Study) [171], demonstrated that statin significantly reduced the incidence of stroke in diabetic patients.

Subgroup analysis of the Helsinki Heart Study [136], and VA-HIT (Veterans Affairs Highdensity lipoprotein Intervention Trial) [172, 173] provided evidence for the potential benefit of fibrate therapy in reducing CVD in T2DM. However, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study [174] failed to show similar benefits. The lipid arm of the ACCORD study examined combination therapy of statin and fibrate and failed to support the effectiveness to reduce CV risk as compared with statin alone [175].

*Antiplatelet drugs* reduce the risk of CV events in T2DM patients. Currently, aspirin is widely recommended for primary prevention of CV events in T2DM patients and is the main drug under investigation to reduce the risk of CVD [176]. Aspirin reduces the risk of serious vascular events in high risk patients by about 25% and also prevents the recurrence of angina, heart attack and stroke. Aspirin is routinely given for primary prevention of CV events in T2DM patients as all major guidelines recommend such preventive use that is based on evidence gathered from clinical trials of high-risk patients [177, 178]. However, the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial [179] demonstrated that aspirin failed to prevent a first CV event or death in T2DM patients, which contradicts the recommendations by many guidelines. The POPADAD trial recommended that aspirin should be used for secondary prevention of CVD in patients with T2DM. The JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) trial examined the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in T2DM patients and found that low-dose aspirin when used for primary prevention did not reduce the risk of CV events [180].

In a subgroup analysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study, patients with T2DM taking clopidogrel seem to derive enhanced benefit from clopidogrel compared with aspirin [181, 182]. The subgroup analysis of PRISMPLUS (Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) trial showed that triple therapy (aspirin, heparin, tirofiban) significantly reduced the incidence of myocardial infarction or death as compared with aspirin plus heparin [183].

### **9. Conclusion and recommendations**

increases cAMP concentration in platelets by inhibiting phosphodiesterase enzyme, and the increased cAMP levels inhibit activation of cytoplasmic second messengers. Dipyridamole also promotes prostacyclin release and inhibits thromboxane A2 synthesis. Glycoprotein IIb/

**8. Clinical trials on prevention strategies and therapeutic approaches for**

Growth of overweight and obese population due to diet and life-style changes worldwide correlates with the global T2DM epidemic [144]. However, majority of the studies focusing on diabetes prevention were not designed to assess CV outcomes [145]. There is a need for studies to explore the effect of exercise and diet on quality of life, morbidity, and mortality, with

Clinical trials examining the effect of *intensive glucose control* on CVD did not report consistency in beneficial effects of intensive glycemic control on CV events [146–149]. Although the risk of microvascular complications was reduced with strict glucose control in T2DM patients, its beneficial effects on CVD prevention or reduction remain ambiguous [150–152]. Data from UKPDS 34 (the United Kingdom Prospective Diabetes Study) suggested a protective effect of improved glucose control on CVD, CV mortality, and all-cause mortality [146]. However, a number of large randomized, controlled trials have reported conflicting results. ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [147], VADT (Veterans Affairs Diabetes Trial) [153], and NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) [154] showed no effect of intensive glucose control on major CV events. However, ACCORD (Action to Control Cardiovascular Disease in Diabetes) [149] demonstrated an increased risk of death from CV causes and total mortality associated with intensive glucose control. In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study [155], patients treated with pioglitazone had a significant 16% reduction in mortality, non-fatal myocardial infarction, and stroke. Further research is needed to examine effect of pharmacological approaches for the management of hyperglycemia on CVD.

Diabetic vasculopathy can be improved by *lowering blood pressure* with antihypertensive drugs which have antiatherogenic effects, e.g., ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and calcium channel blockers. Randomized controlled trials like UKPDS [33, 127], HOT (Hypertension Optimal Treatment) [156], SHEP (the Systolic Hypertension in the Elderly Program) [157–159], Syst-EUR (Systolic Hypertension in Europe) [158–161], HOPE (Heart Outcomes Prevention Evaluation) [162], LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) [163], and ALLHAT (the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [164] have found beneficial effects of adequately controlling blood pressure in improving CV outcomes, specifically, for stroke, when

*Dyslipidemia* plays a significant role in CV complications in T2DM. Dyslipidemia comprises elevated total cholesterol and LDL cholesterol, decreased HDL cholesterol, and high

aggressive blood pressure targets are met [33, 156, 165, 166].

IIIa receptor antagonists inhibit the final common pathway for platelet aggregation.

**diabetic vasculopathy**

80 Recent Trends in Cardiovascular Risks

a special focus on CV outcomes.

CV complications are the major causes of morbidity and mortality in patients with T2DM. Macrovascular complications are more common, and most diabetic patients develop or die of macrovascular diseases, predominantly by developing CVD.

The initiators of vasculopathy that ultimately develop into long-term complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Studies have shown that lifestyle interventions help in prevention and reduction of CV risk factors; however, there is a lack of studies investigating effects of lifestyle modifications on long-term CV outcomes that need to be addressed. Similarly, because the intensive glycemic control in T2DM patients did not show consistent beneficial effects on CV events, such a strict glycemic control needs to be revisited. Contrary to the disappointing results of intensive glucose control in prevention of CVD, intensive control of blood pressure using anti-hypertensive drugs, normalization of lipid profiles using lipid-lowering agents, and prevention of atherosclerosis and vascular thrombosis with antiplatelet therapy have been found to be beneficial.

Health promotion and patient education should be given priority to combat CV complications in T2DM patients. A multidisciplinary approach involving patients, health professionals, and researchers should be undertaken to reduce the incidence and prevalence of T2DM and CVD, and improve the quality of life and well-being of patients.

### **Author details**

Sayeeda Rahman1 , Md. Anwarul Azim Majumder2 \*, Russell Kabir3 , Mainul Haque4 , Subir Gupta2 , Sana Mohammad Yasir Arafat5 , Nkemcho Ojeh2 and Prasad Dalvi6

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Clinical Sciences, Faculty of Life Sciences, School of Medical Sciences, University of Bradford, UK

2 Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados, West Indies

3 Department for Allied and Public Health, Faculty of Medical Sciences, Anglia Ruskin University, Chelmsford, Essex, UK

4 Faculty of Medicine and Defense Health, National Defense University of Malaysia, Kuala Lumpur, Malaysia

5 Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

6 Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA

### **References**

[1] Stemmer EA. Diabetes mellitus and vascular disease. In: Aronow WS, Stemmer EA, Wilson SE, editors. Vascular Disease in the Elderly. Armonk: Futura; 1997. pp. 199-220

The initiators of vasculopathy that ultimately develop into long-term complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Studies have shown that lifestyle interventions help in prevention and reduction of CV risk factors; however, there is a lack of studies investigating effects of lifestyle modifications on long-term CV outcomes that need to be addressed. Similarly, because the intensive glycemic control in T2DM patients did not show consistent beneficial effects on CV events, such a strict glycemic control needs to be revisited. Contrary to the disappointing results of intensive glucose control in prevention of CVD, intensive control of blood pressure using anti-hypertensive drugs, normalization of lipid profiles using lipid-lowering agents, and prevention of atherosclerosis

and vascular thrombosis with antiplatelet therapy have been found to be beneficial.

and CVD, and improve the quality of life and well-being of patients.

, Md. Anwarul Azim Majumder2

\*Address all correspondence to<EMAIL_ADDRESS>
6 Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA

, Sana Mohammad Yasir Arafat5

**Author details**

82 Recent Trends in Cardiovascular Risks

Sayeeda Rahman1

versity of Bradford, UK

versity, Chelmsford, Essex, UK

Gupta2

West Indies

Lumpur, Malaysia

**References**

Health promotion and patient education should be given priority to combat CV complications in T2DM patients. A multidisciplinary approach involving patients, health professionals, and researchers should be undertaken to reduce the incidence and prevalence of T2DM

, Nkemcho Ojeh2

1 Department of Clinical Sciences, Faculty of Life Sciences, School of Medical Sciences, Uni-

2 Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados,

3 Department for Allied and Public Health, Faculty of Medical Sciences, Anglia Ruskin Uni-

4 Faculty of Medicine and Defense Health, National Defense University of Malaysia, Kuala

5 Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

[1] Stemmer EA. Diabetes mellitus and vascular disease. In: Aronow WS, Stemmer EA, Wilson SE, editors. Vascular Disease in the Elderly. Armonk: Futura; 1997. pp. 199-220

\*, Russell Kabir3

and Prasad Dalvi6

, Mainul Haque4

, Subir

[33] UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ. 1998;**317**:703-713

[17] Li H, Oldenburg B, Chamberlain C, O'Neil A, Xue B, Jolley D, Hall R, Dong Z, Guo Y. Diabetes prevalence and determinants in adults in China mainland from 2000 to 2010: A systematic review. Diabetes Research and Clinical Practice. 2012 Nov;**98**(2):226-235 [18] Rahman S, Rahman T, Ismail AA, Rashid AR. Diabetes-associated macrovasculopathy: Pathophysiology and pathogenesis. Diabetes, Obesity & Metabolism 2007;**9**:767-780 [19] Virsaladze D, Kipiani V. Endothelial dysfunction in diabetic vasculopathy. Annals of

[20] Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vascu-

[21] Clark CM Jr, Lee DA. Prevention and treatment of the complications of diabetes mel-

[22] Rahman S, Majumder MAA. Diabetes and macrovasculopthy: Double trouble. South

[23] Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatintreated patients with coronary heart disease and diabetes or impaired fasting glucose levels: Subgroup analyses in the Scandinavian Simvastatin Survival Study. Archives of

[24] Rahman S, Majumder MAA. Links between Vitamin D deficiency and macrovascular

[25] Sowers JR. Diabetes mellitus and cardiovascular disease in women. Archives of Internal

[26] Singer DE, Moulton AW, Nathan, DM. Diabetic myocardial infarction: Interaction of

[27] Smith JW, Marcus FI, Serokman R. Prognosis of patients with diabetes mellitus after acute myocardial infarction. American Journal of Cardiology. 1984;**54**:718-721

[28] Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New England Journal of Medicine.

[29] Wingard DL, Barrett-Connor EL, Scheidt-Nave C et al. Prevalence of cardiovascular and renal complications in older adults with normal or impaired glucose tolerance or

[30] UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors.

[31] Balkau B, Pyörälä M, Shipley M, Forhan A, Jarrett J, Eschwège E, Pyörälä K. Noncardiovascular disease mortality and diabetes mellitus. Lancet. 1997;**350**:1680

[32] King's Fund. Counting the Cost. The Real Impact of Non-Insulin Dependent Diabetes.

diabetes with other preinfarction risk factors. Diabetes. 1989;**38**:350-357

NIDDM: a population-based study. Diabetes Care. 1993;**16**:1022-1025

lopathy: An overview. American Journal of Hypertension. 2001;**14**:475-486

Biochemical Research and Education. 2001;**1**:44-48

East Asia Journal of Public Health. 2013:**3**(2):1-3

Internal Medicine. 1999;**159**:2661-2667

Diabetes Research. 1990 Jan;**13**(1):1-11

British Diabetic Association; London. 1996

Medicine. 1998;**158**:617-621

84 Recent Trends in Cardiovascular Risks

2005;**353**:2643-2653

litus. New England Journal of Medicine. 1995;**332**:1210-1217

diseases. South East Asia Journal of Public Health. 2015:**5**(2):3-6

[64] The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine. 1993;**329**:977-986

[49] Stein B, Weintraub WS, Gebhart S. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation. 1995:**91**:979-989

[50] Winocour PD, Bryszewska M, Watula C. Reduced membrane fluidity in platelets from

[51] Davi G, Catalons I, Averna M. Thromboxane biosynthesis and platelet function in type II

[52] Vlassara H. Recent progress in advanced glycation end products and diabetic complica-

[53] Parving HH, Nielsen FS, Bang LE et al. Macromicroangiopathy and endothelium dysfunction in NIDDM patients with and without diabetic nephropathy. Diabetologia.

[54] Chaturvedi N, Fuller JH, Pokras F, Rottiers R, Papazoglou N, Aiello LP. Circulating plasma vascular endothelial growth factor and microvascular complications of type I diabetes mellitus: The influence of ACE inhibition. Diabetic Medicine. 2001;**18**:288-294

[55] García Frade LJ, de la Calle H, Alava I, Navarro JL, Creight LJ, Gaffney LJ. Diabetes mellitus as an hypercoagulable state: Its relationship with fibrin fragments and vascular

[56] Ford I, Singh TP, Kitchen S, Makris M, Ward JD, Preston FE. Activation of coagulation in diabetes mellitus in relation to the presence of vascular complications. Diabetic

[57] Carmassi F, Morale M, Puccetti R. Coagulation and fibrinolytic system impairment in

[58] Sowers JR, Tuck ML, Sowers DK. Plasma antithrombin III and thrombin generation time: Correlation with hemoglobin A1 and fasting serum glucose in young diabetic women.

[59] Ramirez LC, Arauz-Pacheco C, Lackner C. Lipoprotein (a) levels in diabetes mellitus: Relationship to metabolic control. Annals of Internal Medicine. 1992;**117**:42-47

[60] Ceriello A, Quatraro A, Dello Russo P. Protein C deficiency in insulin dependent diabetes: A hyperglycemia related phenomenon. Thrombosis & Haemostasis. 1990;**64**:104-107

[61] Vukovich TC, Proidl S, Knobl P, Teufelsbauer H, Schnack C, Schernthaner G. The effect of insulin treatment on the balance between tissue plasminogen activator and plasminogen activator inhibitor-1 in type 2 diabetic patients. Thrombosis & Haemostasis.

[62] Laakso M. Hyperglycaemia and cardiovascular disease in type 2 diabetes. Diabetes.

[63] Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circulation.

insulin dependent diabetes mellitus. Thrombosis Research. 1992;**67**:643-654

diabetes mellitus. New England Journal of Medicine. 1990;**322**:1768-1774

diabetic patients. Diabetes. 1990;**39**:241-244

tions. Diabetes. 1997;**46**(Suppl. 2):S19-S25

damage. Thrombosis Research. 1987;**47**:533-540

1996;**39**:1590-1597

86 Recent Trends in Cardiovascular Risks

Medicine. 1991;**8**:322-329

Diabetes Care. 1980;**3**:655-658

1992;**68**:253-256

1999;**48**:937-942

1999;**100**:1134-1146

[95] Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987;**257**:2318-2324

[80] Hunter SJ, Garvey T. Insulin action and insulin resistance: Diseases involving defects in insulin receptors, signal transduction and glucose transport effector system. American

[81] Sowers JR, Sowers PS, Peuler JD. Role of insulin resistance and hyper-insulinemia in development of hypertension and atherosclerosis. Journal of Laboratory and Clinical

[82] Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: The role of insulin resistance and sympathetic adrenal system. New England

[83] Gilbert RE, Rumble JR, Cao ZM et al. Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in exper-

[84] Myllärniemi M, Calderon L, Lemström K, Buchdunger E, Häyry P. Inhibition of plateletderived growth factors receptor kinase inhibits smooth muscle cell migration and prolif-

[85] Feener EP, King GL. Vascular dysfunction in diabetes mellitus. Lancet. 1997;**350**(Suppl. 1):

[86] Koya D, King GL. Protein kinase C activation and the development of diabetic complica-

[87] Storey AM, Perry CJ, Petrie JR. Endothelial dysfunction in type 2 diabetes. The British

[88] Brodsky S, Chen J, Lee A, Akassoglou K, Norman J, Goligorsky MS. Plasmin dependent and independent effects of plasminogen activators and inhibitor-1 on ex-vivo angiogen-

[89] Nishikawa T, Edelstein D, Du XL et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;**404**:787-790 [90] Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: A new perspec-

[91] Baynes JW. Role of oxidative stress in development of complications in diabetes.

[92] Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA. High WBC count is associated with a worsening of insulin sensitivity and predicts the development

[93] Tuttle HA, Davis-Gorman G, Goldman S, Copeland JG, McDonagh PF. Platelet neutrophil conjugate formation is increased in diabetic women with cardiovascular disease.

[94] Sower JR, Lester MA. Diabetes and cardiovascular disease. Diabetes Care. 1998;**22**(Suppl. 3):

Journal of Medicine. 1998;**5**:331-346

Journal of Medicine. 1996;**334**:374-381

eration. FASEB Journal. 1997;**11**:1111-1126

tions. Diabetes. 1998;**47**:859-866

Diabetes. 1991;**40**:405-412

c.14-c.20

imental diabetes. Circulation Research. 2000;**86**:158-165

Journal of Diabetes & Vascular Disease. 2001;**1**:22-27

tive on an old paradigm. Diabetes. 1999;**48**:1-9

of type 2 diabetes. Diabetes. 2002;**51**:455-461

Cardiovascular Diabetology. 2003;**2**:1-16

esis. American Journal of Physiology. 2001;**281**:H1784-H1792

Medicine. 1994;**123**:647-652

88 Recent Trends in Cardiovascular Risks

S9-S13

[125] Kolterman OG, Gra RS, Shapiro G, Scarlett JA, Griffin J, Olesfsky JM. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984;**33**:346-354

[111] Cameron JD, McGrath BP, Dart AM. Use of radial applanation tonometry and a generalized transfer function to determine aortic augmentation in subjects with treated

hypertension. Journal of the American College of Cardiology 1998;**32**:1214-1220 [112] Wilkinson IB, MacCallum H, Flint L, Cockcroft JR et al. The influence of heart rate on augmentation index and central arterial pressure. Journal of Physiology 2000;**525**:263-270

[113] Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H. et al. Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. Journal of the

[114] Rehman A, Rahman ARA, Rasool AHG. Effect of angiotensin II on pulse wave velocity

[115] Chowienczyk PJ, Kelly RP, MacCallum H, Millasseau SC, et al. Photoplethysmographic assessment of pulse wave reflection. Journal of the American College of Cardiology.

[116] Resnick LM, Militianu D, Cunnings AJ, Pipe JG, et al. Direct magnetic resonance determination of aortic distensibility in essential hypertension: Relation to age, abdominal visceral fat and in situ intracellular free magnesium. Hypertension. 1997;**30**:654-659

[117] Mohiaddin RH, Underwood SR, Bogren HG, Firmin DN, et al. Regional aortic compliance studied by magnetic resonance imaging: The effects of age, training and coronary

[118] Rahman S, Majumder MAA, Rahman ARA. Treatment of diabetic vasculopathy: An

[119] Emoto M, Nishizawa Y, Kawagishi T, Maekawa K, Hiura Y, et al. Stiffness indexes ß of the common carotid and femoral arteries are associated with insulin resistance in

[120] Ngim CA, Rahman ARA, Ibrahim A. Pulse wave velocity as an index of arterial stiffness: A comparison between newly diagnosed (untreated) hypertensive and normotensive middle-aged Malay men and its relationship with fasting insulin. Acta Cardiologica.

[121] Rahman S, Ismail AA, Rahman AR. Treatment of diabetic vasculopathy with rosiglitazone and ramipril: Hype or hope? International Journal of Diabetes in Developing

[122] American Diabetes Association. Position statement: Diabetes mellitus and exercise.

[123] Dela F, Ploug T, Handberg A, et al. Physical training increases muscle GLUT 4 protein

[124] Lebovitz HE, Feinglos MN. Mechanism of action of the second generation sulfonylurea

and mRNA in patients with NIDDM. Diabetes. 1994;**7**:862-865

glipizide. American Journal of Medicine. 1983;**75**:46-54

overview. Research and Reports in Endocrine Disorders. 2011;**1**:21-36

) receptors. Journal of Human

American College of Cardiology. 2002;**39**:1005-1011

artery disease. British Heart Journal. 1989:**62**:90-96

NIDDM. Diabetes Care. 1998;**21**:1178-1182

Hypertension. 2002;**16**:261-266

1999;**34**:2007-2014

90 Recent Trends in Cardiovascular Risks

1999;**54**:277-282

Countries. 2009;**29**:110-117

Diabetes Care. 1990;**13**:804-805

in humans is mediated through angiotensin II type 1 (AT1

and Recurrent Events Trial investigators. New England Journal of Medicine. 1996;**335**: 1001-1009

[152] Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 2008;**359**:1577-1589

and Recurrent Events Trial investigators. New England Journal of Medicine. 1996;**335**:

[139] The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. New England

[140] Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care.

[141] Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol.

[142] Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: The Diabetes Atherosclerosis

[143] Hankey GJ, Eikelboom JW. Antiplatelet drugs. Medical Journal of Australia. 2003;**178**:

[144] Gillies CL, Abrams KR, Lambert PC, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance:

[145] Stiegler RS, Zimmet PZ, Cameron AJ, et al. Lifestyle management: Preventing type 2

[146] UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes

[147] Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with Type 2 diabetes. New England Journal of Medicine.

[148] Schor S. The University Group Diabetes Program. A statistician looks at the mortality

[149] Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. New England Journal of Medicine. 2008;**358**:2545-2559

[150] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complica-

[151] Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;**23**

tions in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;**352**:837-853

Intervention Study, a randomised study. Lancet. 2001;**357**:905-910

diabetes and cardiovascular complications. Therapy. 2009;**6**:489-496

1001-1009

92 Recent Trends in Cardiovascular Risks

1998;**21**:641-648

568-574

Journal of Medicine. 1998;**339**:1349-1357

New England Journal of Medicine. 1999;**341**:410-418

Systematic review and meta-analysis. BMJ. 2007;**334**:299

(UKPDS 34). Lancet. 1998;**352**:854-865

results. JAMA. 1971;**217**:1671-1675

2008;**358**:2560-2572

Suppl 2:B21-B29

[177] Buse JB, Ginsberg HN, Bakris GL, et al, American Heart Association, American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;**115**:114-126

[165] Chobanian AV, Bakris GL, Black HR, et al. The seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood

[166] Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective

[167] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised

[168] Colhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-

[169] Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose:

[170] Pederson TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischaemic signs and symptoms in the Scandinavian simvastatin survival study (4S). American Journal of

[171] Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised

[172] Rubins HB, Robins SJ, Collins D, et al. VA-HIT Study Group. Diabetes, plasma insulin, and cardiovascular disease subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Archives of Internal Medicine.

[173] Robins SJ, Collins D, Wittes JT, et al, VA-HIT Study Group. Veterans Affairs highdensity lipoprotein intervention trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: A randomized controlled trial. JAMA.

[174] Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study):

[175] The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes

[176] Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. Journal of the American College of Cardiology

Results from the LIPID trial. Diabetes Care. 2003;**26**:2713-2721

placebo-controlled trial. Lancet. 2003;**361**:2005-2016

Randomised controlled trial. Lancet 2005;**366**:1849-1861

mellitus. New England Journal of Medicine. 2010;**362**:1563-1574

Pressure: The JNC 7 report. JAMA. 2003;**289**:2560-2572

observational study. BMJ. 2000;**321**:412-419

94 Recent Trends in Cardiovascular Risks

placebo-controlled trial. Lancet. 2002;**360**:7-22

controlled trial. Lancet. 2004;**364**:685-696

Cardiology 1998;**81**:333-335

2002;**162**:2597-2604

2001;**285**:1585-1591

2010;**55**:2878-2886


I.Self-Monitoring of Blood Glucose (SMBG)

People who are on insulin using SMBG should be inspired to test when appropriate based on their insulin regimen. This may include testing when fasting, preceding meals and snacks, at bedtime, before exercise, when low blood glucose is suspected, after treating low blood glucose until they are normoglycemic, and earlier and while performing critical tasks.

When suggesting SMBG, ensure that patients gather ongoing instruction and regular evaluation of technique, results, and their ability to use data, including uploading/sharing data (if applicable), from SMBG devices to adjust therapy. SMBG is especially significant for insulin-treated patients to monitor for and avoid hypoglycemia and hyperglycemia. A database study on children and adolescents with type 1 diabetes presented that, after adjustment for multiple confounders, increased daily frequency of SMBG was significantly associated with lower A1 [11].


Chapter 2

*Mass Spectrometry - Future Perceptions and Applications*

approach to identify food markers to support discrimination between organic and conventional tomato crops. Journal of Chromatography. A. 2018;**1546**:66-76. DOI: 10.1016/j.chroma.2018.03.002

[41] Cichon MJ, Riedl KM, Schwartz SJ. A metabolomic evaluation of the phytochemical composition of tomato juices being used in human clinical trials. Food Chemistry. 2017;**228**:270-278. DOI: 10.1016/j.

[42] Sidwick KL, Johnson AE, Adam CD, Pereira L, Thompson DF. Use of liquid chromatography quadrupole time-of-flight mass spectrometry and metabonomic profiling to differentiate between normally slaughtered and dead on arrival poultry meat. Analytical Chemistry. 2017;**89**(22):12131-12136. DOI: 10.1021/acs.analchem.7b02749

[43] Gallart-Ayala H, Kamleh MA, Hernández-Cassou S, Saurina J, Checa A. Ultra-high-performance liquid chromatography–high-resolution mass spectrometry based metabolomics as a strategy for beer characterization. Journal of the Institute of Brewing. 2016;**122**(3):430-436. DOI: 10.1002/

[44] Subbaraj AK, Kim YHB, Fraser K, Farouk MM. A hydrophilic interaction liquid chromatographymass spectrometry (HILIC-MS) based metabolomics study on colour stability of ovine meat. Meat Science. 2016;**117**:163-172. DOI: 10.1016/j.

meatsci.2016.02.028

jib.340

foodchem.2017.01.118

[34] Molina-Calle M, Sanchez de Medina V, Priego-Capote F, Luque de Castro MD. Establishing compositional differences between fresh and black garlic by a metabolomics approach based on LC-QTOF MS/MS analysis. Journal of Food Composition and Analysis. 2017;**62**:155-163. DOI: 10.1016/j.jfca.2017.05.004

[35] Popping B, De Dominicis E, Dante M, Nocetti M. Identification of the geographic origin of Parmigiano Reggiano (P.D.O.) cheeses deploying non-targeted mass spectrometry and chemometrics. Food. 2017;**6**(2):13. DOI:

[36] Le Boucher C, Courant F, Royer AL, Jeanson S, Lortal S, Dervilly-Pinel G, et al. LC-HRMS fingerprinting as an efficient approach to highlight fine differences in cheese metabolome during ripening. Metabolomics. 2015;**11**(5):1117-1130. DOI: 10.1007/

[37] D'Urso G, Sarais G, Lai C, Pizza C, Montoro P. LC-MS based metabolomics study of different parts of myrtle berry from Sardinia (Italy). Journal of Berry Research. 2017;**7**(3):217-229. DOI:

Analytical and Bioanalytical Chemistry. 2015;**407**(23):7197-7213. DOI: 10.1007/

[39] Black C, Haughey SA, Chevallier OP, Galvin-King P, Elliott CT. A comprehensive strategy to detect the fraudulent adulteration of herbs: The oregano approach. Food Chemistry. 2016;**210**:551-557. DOI: 10.1016/j.

[40] Martínez Bueno MJ, Díaz-Galiano FJ, Rajski L, Cutillas V, Fernández-Alba AR. A non-targeted metabolomic

10.3390/foods6020013

s11306-014-0769-0

10.3233/JBR-170158

s00216-015-8882-0

foodchem.2016.05.004

[38] Guijarro-Díez M, Nozal L, Marina ML, Crego AL. Metabolomic fingerprinting of saffron by LC/ MS: Novel authenticity markers.

**24**


**7. IEC 61850 GOOSE Based HIL testing**

IEC 61850 GOOSE is one of the enabling communication protocol of the standard. Its concept to replace the legacy interlocking hard-wired signal. According to GOOSE implementation, it publishes number of fast GOOSE messages from the original message in case of event occur to increase the reliability that one copy of these messages reach its destination. GOOSE assigned with the high priority (4). On the other hand, IEDs within the SAS need to be configured based on the publisher GOOSE messages parameters in order to successfully subscriber to the GOOSE messages.

GOOSE supports wide range of possible common data that can be integrated within the GOOSE dataset (binary and analog measured values). IEC 61850–7-1 part defines the GOOSE protocol where several parameters control the publishing process as follows;

DataSet: Contains ObjectReferences that the values of the members shall be transmitted by GOOSE Control Block (GoCB).

GoEna: To remotely enable/disable the publishing of the GOOSE messages.

AppID: Associated in the GOOSE messages to be used as identifier of the LOGICAL-DEVICE and a handler for subscription to different GOOSE messages from different IEDs in the same time.

ConRev: Contains the configuration revision indicate the changing updating in the data set within the GoCB.

T (time stamp): Contains the time when the attribute StNum was incremented.

StNum: State number containing a counter that is incremented each time when data set member value change is detected and the GOOSE message has been published.

SqNum: Sequence number contains counter that each time increments when GOOSE message has been published.

GoRef: The reference for the GOOSE control block.

Test: Indicates the implementing of the values of the message based on TRUE (testing purpose) or FALSE (operation purpose).

NdsCom: Needs commissioning, indicates that the GoCB requires further configuration [15].

As the GOOSE protocol is flexible and reliable based on serving different parameters that support different applications in which that compatible with the different application requirements and different data types [16]. At this point, and based on the IEC 61850 GOOSE high reliability and flexibility it is common natural to pursue *Advanced Communication and Control Methods for Future Smart Grid DOI: http://dx.doi.org/10.5772/intechopen.96596*

smart energy system application based on IEC 61850 communication protocols e.g. LoM smart application. Therefore, along with testing steps for the proposed LoM smart protection application based GOOSE, different IEC 61850 IEDs need to be designed and configured for implementing the publishing and subscription role. At the IED GOOSE different subscribers the execution of the final smart LoM protection decision making functions are done and the new status need to be publish with other GOOSE message back to the real time simulator. More details about the smart LoM protection distributed decision making algorithm was published in our previous work.

### **8. The round trip GOOSE latency**

The flexible GOOSE model is used by all of the state-of-the-art IEC 61850 IEDs and systems. From the GOOSE implementation point view, the publisher write the GOOSE parameter value in the local buffer, while the subscriber read the value from the local buffer. The subscriber local buffer is continuously updated via the communication system, were within the publisher side in order to control the procedure the GSE control class is used.

GOOSE round trip latency is calculated for different designed IEDs in different tests. One of the main objective of this test is to verify the GOOSE performance that the messages was compliant with the IEC 61850 requirement (not exceed 4 ms), as well as, to verify and ensuring the interoperability that the designed IEDs had the ability to operate within the multi-vendor environment.

In order to compare the GOOSE round trip latency for different designed IEDs, as well as for the commercial IEDs instantaneous GOOSE round trip latency is measured. From (1) GOOSE overall round trip latency time includes seven individual times that may affect the connection channel performance. The first individual time is the real-time model running in the target that publish GOOSE messages to the communication network, next is the communication network latency which is the needed time to deliver the message to the DUTs. Then every DUT that subscribe to the GOOSE message need to extract and computes the new status and then periodically publishes a GOOSE message to the communication network back to the real time simulator. This process was monitored by using a network protocol analyzer, Wireshark.

$$
\overline{t}\_{\text{RTT}} = \overline{t}\_{\text{out},} \ + \overline{t}\_{\text{net}} + \overline{t}\_{\text{in},} \ + \overline{t}\_{\text{app}} + \overline{t}\_{\text{out},} \ + \overline{t}\_{\text{net}} + \overline{t}\_{\text{in}}, \tag{1}
$$

where

*RTT t* : round trip time average,

, : *out Target t* out from the target time average,

*net t* : communication network time average,

*in DUT* , *t* : DUT time average,

*app t* : DUT internal application average time,

*out DUT* , *t* : DUT, out time average,

*out Target* , *t* : target out time average.

In our proposed LoM case study GOOSE round-trip time between Opal-rt simulator as a publisher and different IEDs as a subscribers and publishers had been recorded by IEDScout GOOSE recording feature as illustrated in **Figure 4**. Recording file is opened by the Siemens SIGRA fault analyzer tool as illustrated in **Figure 5**. From **Figure 5** GOOSE round trip time can be measured based on the difference between IED1 GOOSE and IED2 and IED3 responses. This GOOSE roundtrip time includes all the seven individual times included in the equations above.

**Figure 4.** *GOOSE recording application.*

**Figure 5.** *Recorded signal in Sigra fault analyzer tool.*

*Advanced Communication and Control Methods for Future Smart Grid DOI: http://dx.doi.org/10.5772/intechopen.96596*


**6. Conclusion**

Glycation stress is a potential factor that reduces physical functions, which has become attention in recent years as well as oxidative stress. Glycation stress is mainly caused by intracellular AGEs formation and accumulation in the body, and also by ingestion from food products. Exposure to AGEs on skeletal muscle cells leads to skeletal muscle dysfunctions including reductions of mass, contractile function, insulin sensitivity. These dysfunctions seem to be attributed to RAGEinduced inflammatory responses and deteriorations of cellular signaling transduction, including insulin/IGF-1 signaling. However, some therapeutic strategies, such as treatment with RAGE antagonists, AGEs inhibitors, phytochemicals can overcome the aggravating effects. Glycation research on skeletal muscle has not been sufficiently carried out, and further studies in the future, especially the elucidation of the effect of glycation stress on skeletal muscle and its underlying molecular mechanism, and the development of strategies on preventing the accumulation of AGEs in skeletal muscle, are desired.


4. Device activation

It is our practice to provide two initial programs. The first is a standard, default program recommended by the manufacturer's specifications, and the second has frequency-to-electrode allocation, as indicated above, based on the surgical outcome indicated by X-ray findings for the particular patient. We ask the new user to switch between the two programs in order to experience whether one is more pleasing and/or effective than the other. We speculate that postlinguistically deafened adults will have difficulty adjusting to the sound quality for the standard program and choose the second that was derived from the intraoperative findings and one that avoids a "boomy" sound indicative of a mixing up of low-frequency sensations produced by apical cross-turn stimulation.

The second program will usually take into consideration the possible frequencyplace mismatches relative to insertion depth, that is, the physical position of the electrode contacts. The default frequency allocations provided in the programs of the sound processor may need adaptation [1], as discussed above.

All new users are sent home for a month after receiving counseling about ways in which they can direct their own rehabilitation through practice at home and in different environments in which they commonly find themselves. They are also reminded of expectations, and family members and/or significant others are provided counseling in ways to support the new CI user. It is an option to test the subject for sentence understanding in quiet during the first days of activation. We have found that if a new user scores >60% at day 1, they will obtain scores >80% by the 1-month follow-up (Figure 2). These CI users will likely need little active rehabilitation and already appear to be on a good course. Thus, early performance is indicative of later, long-term performance.

Figure 2 Sentences in quiet evaluated at 1 day and at 1 month, post-implant.

Prognostics Factors of Cochlear Implant in Adults: How Can We Improve Poorer Performers? DOI: http://dx.doi.org/10.5772/intechopen.89577

In fact, the development of speech understanding with a CI does not follow a linear function with time. High sentence recognition scores can be obtained at only 1 day after activation, and the first 2 weeks are as important as the next 6 months and the following 2–3 years. It is not fully understood why CI user's individual performance progress at different rates. In James et al. [1], they observed different patterns of growth in scores, both in quiet and in noise, from the first month, but always following a logarithmic growth curve, such that each additional increment in performance took twice as long as the preceding increase.

### 5. Optimizing maps and initial evaluations: 1-month follow-up

Significant improvement will usually take place from activation to 1 month; thereafter increases continue but at a much slower pace. Increases in understanding will be about the same after 6 months of experience for sentences in quiet. Adapting to any new sensation requires time; an auditory signal presented through a CI will always first be perceived as very different. It is unclear why some new users immediately accept the new input and others reject it as sounding too foreign. In any case, we believe a month of exposure to the new signals is the minimum time to allow all patients for the initial accommodation to the input. Thus, all CI users are re-evaluated at 1 month.

By the first month, there already is access to data logging to confirm speech processor program usage, the users are usually aware of which program they might prefer, and the speech recognition scores in quiet will have been tested. The outcome of sentence recognition testing and CI user reports may indicate a need for alternative device programming. Looking at Tables 1 and 2, approximately 40–50% of the variance is not explained by the patient-related and surgical factors. There are dynamics in play that may never be known such as the impact of certain disadvantages (insertion depth, dislocation, cochlear condition at surgery) and others. Alternative programs (differing mapping parameters) may also take into consideration speed of stimulation (refractory period) as demonstrated through different stimulation rates or spread of excitation via channel selectivity (perhaps deactivating particular electrodes). These more advanced aspects of programing, however, are taken into consideration at every programming session, as indicated. Optimizing sound processor programs is the most direct way to compensate for the degraded speech signals delivered through a cochlear implant.

The one aspect to be evaluated may be behavioral responses to changes in stimulation rate. Postoperative NRT testing may be indicated to assess neural recovery functions to gain information about beneficial stimulation rates. From their studies on the temporal characteristics of auditory nerve stimulation via CIs, [16] suggest that the programmed stimulation rate relates to the refractory period of the nerve. CI user performance may be addressed, in some cases, by reducing the stimulation rate. It is not possible to define when the so-called aging process begins, but it is clear that neural transmission times slow as one ages [17, 18]. Older CI users may be more susceptible to stimulation rate effects. Any means of enhancing auditory signals that occur in the presence of poor temporal processing will provide a better foundation for learning to overcome perceptual difficulties.

#### 5.1 Initial performance evaluations

During this test interval, it is possible to identify, with more clarity, the individuals who might be classified as potentially having poor performance. By definition, on average, approximately 50% of recipients will demonstrate "normal" performance, i.e., 70% or greater scores for sentence understanding in quiet. However, if

close enough to activate auditory nerves. Those outside, mislocated into the scala

It is our practice to provide two initial programs. The first is a standard, default program recommended by the manufacturer's specifications, and the second has frequency-to-electrode allocation, as indicated above, based on the surgical outcome indicated by X-ray findings for the particular patient. We ask the new user to switch between the two programs in order to experience whether one is more pleasing and/or effective than the other. We speculate that postlinguistically deafened adults will have difficulty adjusting to the sound quality for the standard program and choose the second that was derived from the intraoperative findings and one that avoids a "boomy" sound indicative of a mixing up of low-frequency

The second program will usually take into consideration the possible frequencyplace mismatches relative to insertion depth, that is, the physical position of the electrode contacts. The default frequency allocations provided in the programs of

All new users are sent home for a month after receiving counseling about ways in which they can direct their own rehabilitation through practice at home and in different environments in which they commonly find themselves. They are also reminded of expectations, and family members and/or significant others are provided counseling in ways to support the new CI user. It is an option to test the subject for sentence understanding in quiet during the first days of activation. We have found that if a new user scores >60% at day 1, they will obtain scores >80% by the 1-month follow-up (Figure 2). These CI users will likely need little active rehabilitation and already appear to be on a good course. Thus, early performance is

vestibuli, may yield no NRT response [13].

Advances in Rehabilitation of Hearing Loss

sensations produced by apical cross-turn stimulation.

indicative of later, long-term performance.

Sentences in quiet evaluated at 1 day and at 1 month, post-implant.

Figure 2

146

the sound processor may need adaptation [1], as discussed above.

4. Device activation

we consider individuals who present with no negative patient-related factors, they should perform better than 70% and on average around 90%. This is, then, the second use of the model. The prediction of the model is compared with the actual score at 1-month post-activation; if the actual score is lower than the prediction, it points to a need for remedial action. Thus, two groups are identified who will undergo further evaluation: those individuals who are overall "poor" performers and achieve less than 70% and those whose actual scores are below their predicted scores from the model. The others with satisfactory performance will be advised to continue their own patient-directed practices (passive rehabilitation). Complete remediation of the effects of duration of deafness and congenital hearing loss would result in a "corrected" distribution as shown in Figure 1, with an overall average (median) performance at about 90% and only 25% of cases performing less than 70%. Such an improvement is the aim of the remedial actions described in the following sections.

Figure 3 illustrates the further needs of the less-than-satisfactory poor user or overall poor performer. The results of intraoperative NRT findings are compared, and mapping considerations are applied to create alternative programs, as described above. This is considered part of the bottom-up approach. Other, more specific analytic psychophysics may also be included in a rehabilitation program, if indicated [5].

demonstrating poor working memory lead to applying auditory cognitive training; however, if the results of the evaluations point to an abnormal working memory

Prognostics Factors of Cochlear Implant in Adults: How Can We Improve Poorer Performers?

It is beyond the scope of this chapter to supply specific evaluation and training materials. Methods should be consistent with culture and the available materials in a particular language and according to the consensus within the country. A review of rehabilitation methods that can be applied to cochlear implant users can be found in [19] and in [20]. In common, however, is that counseling will focus on the CI user gaining confidence in associating the digitally coded sounds that are presented through a CI with meaningful speech. It is advisable to remember that a CI user needs adequate time to experience modifications; even poorer users do not require constant reprogramming. In general, poorer users are seen at the clinic in 3-month intervals, and better performers are seen in 6-month to annual intervals. Interactions with local speech-language therapists are the main support for poorer performers with frequent liaison between the therapist and specialists within our clinic.

Harris et al. [2] point out that no standardized rehabilitation approach exists despite decades of CI use in individuals of all ages. Agreement is found in the concept of tailoring post-implant rehabilitation to the needs of the individual user [21, 22]. The challenge is that long-term rehabilitation may be indicated but that limitations in funding through reimbursement are available mainly due to a lack of evidence for demonstrable effects [2, 18]. Our experience, and that of [21], indicates that rehabilitation may be required for as long as 2 years to reach a so-called

Conceptually, rehabilitation can be divided into two approaches, top-down or bottom-up [23]. Methods that focus on bottom-up procedures utilize materials relating specifically to the input signals possible via a CI, that is, how a signal is processed. The elements of sound serve as building blocks, starting with the smallest unit (i.e., a phoneme). Relative to a CI, acquiring responses to the psychophysical tasks (temporal, spectral, and amplitude cues) during the mapping process entails a bottom-up approach, which is an analytic method. Some of these tasks may

Top-down methods represent a synthetic approach and have the aim of enhanc-

ing communication strategies through cognitive processing. As mentioned,

and phonological sensitivity, neurocognitive evaluations are pursued.

Indications for rehabilitation training in poorer performers.

DOI: http://dx.doi.org/10.5772/intechopen.89577

5.2 Rehabilitation approach

Figure 4.

performance plateau.

149

be adapted for auditory training purposes [5].

5.2.1 Synthetic-cognitive training (top-down)

A poor performer will require thorough auditory evaluations and cognitive testing. Given that the predictive model accounts for approximately 63% of the variance in performance, the contribution of cognitive factors must be considered. If poor performance is identified or suspected, steps are taken to investigate the factors that may be affecting the user's ability to process the sound information they are receiving through the CI including the central aspects of linguistic and neurocognitive skills influencing communication strategies as outlined in Figure 4.

Evaluations that yield scores within normal limits for phonological sensitivity and working memory point to motivation issues and, therefore, intense counseling are provided without the need for active rehabilitation support. If poor linguistic skills are revealed, training in phonological aspects is indicated. Evaluations

Figure 3. Flow diagram illustrating the development of patient-specific rehabilitation strategies.

Prognostics Factors of Cochlear Implant in Adults: How Can We Improve Poorer Performers? DOI: http://dx.doi.org/10.5772/intechopen.89577

Figure 4.

we consider individuals who present with no negative patient-related factors, they should perform better than 70% and on average around 90%. This is, then, the second use of the model. The prediction of the model is compared with the actual score at 1-month post-activation; if the actual score is lower than the prediction, it points to a need for remedial action. Thus, two groups are identified who will undergo further evaluation: those individuals who are overall "poor" performers and achieve less than 70% and those whose actual scores are below their predicted scores from the model. The others with satisfactory performance will be advised to continue their own patient-directed practices (passive rehabilitation). Complete remediation of the effects of duration of deafness and congenital hearing loss would result in a "corrected" distribution as shown in Figure 1, with an overall average (median) performance at about 90% and only 25% of cases performing less than 70%. Such an improvement is the aim of the remedial actions described in the

Figure 3 illustrates the further needs of the less-than-satisfactory poor user or overall poor performer. The results of intraoperative NRT findings are compared, and mapping considerations are applied to create alternative programs, as described above. This is considered part of the bottom-up approach. Other, more specific analytic psychophysics may also be included in a rehabilitation program, if indi-

A poor performer will require thorough auditory evaluations and cognitive testing. Given that the predictive model accounts for approximately 63% of the variance in performance, the contribution of cognitive factors must be considered. If poor performance is identified or suspected, steps are taken to investigate the factors that may be affecting the user's ability to process the sound information they

neurocognitive skills influencing communication strategies as outlined in Figure 4. Evaluations that yield scores within normal limits for phonological sensitivity and working memory point to motivation issues and, therefore, intense counseling are provided without the need for active rehabilitation support. If poor linguistic skills are revealed, training in phonological aspects is indicated. Evaluations

are receiving through the CI including the central aspects of linguistic and

Flow diagram illustrating the development of patient-specific rehabilitation strategies.

following sections.

Advances in Rehabilitation of Hearing Loss

cated [5].

Figure 3.

148

Indications for rehabilitation training in poorer performers.

demonstrating poor working memory lead to applying auditory cognitive training; however, if the results of the evaluations point to an abnormal working memory and phonological sensitivity, neurocognitive evaluations are pursued.

It is beyond the scope of this chapter to supply specific evaluation and training materials. Methods should be consistent with culture and the available materials in a particular language and according to the consensus within the country. A review of rehabilitation methods that can be applied to cochlear implant users can be found in [19] and in [20]. In common, however, is that counseling will focus on the CI user gaining confidence in associating the digitally coded sounds that are presented through a CI with meaningful speech. It is advisable to remember that a CI user needs adequate time to experience modifications; even poorer users do not require constant reprogramming. In general, poorer users are seen at the clinic in 3-month intervals, and better performers are seen in 6-month to annual intervals. Interactions with local speech-language therapists are the main support for poorer performers with frequent liaison between the therapist and specialists within our clinic.

#### 5.2 Rehabilitation approach

Harris et al. [2] point out that no standardized rehabilitation approach exists despite decades of CI use in individuals of all ages. Agreement is found in the concept of tailoring post-implant rehabilitation to the needs of the individual user [21, 22]. The challenge is that long-term rehabilitation may be indicated but that limitations in funding through reimbursement are available mainly due to a lack of evidence for demonstrable effects [2, 18]. Our experience, and that of [21], indicates that rehabilitation may be required for as long as 2 years to reach a so-called performance plateau.

Conceptually, rehabilitation can be divided into two approaches, top-down or bottom-up [23]. Methods that focus on bottom-up procedures utilize materials relating specifically to the input signals possible via a CI, that is, how a signal is processed. The elements of sound serve as building blocks, starting with the smallest unit (i.e., a phoneme). Relative to a CI, acquiring responses to the psychophysical tasks (temporal, spectral, and amplitude cues) during the mapping process entails a bottom-up approach, which is an analytic method. Some of these tasks may be adapted for auditory training purposes [5].

#### 5.2.1 Synthetic-cognitive training (top-down)

Top-down methods represent a synthetic approach and have the aim of enhancing communication strategies through cognitive processing. As mentioned,

outcomes of the predictive model accounted for more than 60% of the variance in quiet and 50% of the variance in noise for sentence recognition scores obtained at 1 month after CI activation [1]. Thus, cognitive factors play a large role in the wide variance seen in performance scores obtained by the adult CI population. Optimizing a personalized rehabilitation strategy must take into consideration the cognitive dynamics of speed of processing, working memory, and attention and executive function [23].

Increases continue even up to 3 years, but the incremental gain is much less that

Prognostics Factors of Cochlear Implant in Adults: How Can We Improve Poorer Performers?

We summarize the complete rehabilitation process in Figure 5. Pre-implant counseling based on the results of the predictive modeling; surgical planning focusing on considerations to the size of cochlea and type of electrode; and intraoperative testing using X-ray findings to confirm placement and depth of insertion along with NRT to confirm neural interface via electrostimulation all take place before initial activation. This includes counseling that may need to modify expectations based on surgical outcomes and intraoperative evaluations. Two MAPs are developed at first fitting where one is based on intraoperative findings. At 1 month, observations gathered from data logging, along with comparing sentence scores in quiet to the predictive model, provide an indication as to whether a new CI user will need specialized rehabilitation. Again, counseling may need to guide and modify expectations. The type of rehabilitation is determined, usually a combination of both bottom-up and top-down approaches. At the 6-month interval, testing in noise is applied, and further adaptations to the MAPs are made. In the future, we hope to extend the predictive model to include factors for analysis of performance in noise for the long term. Continued appropriate rehabilitation after 6 months ensues, and continued counseling insures that the CI user understands the need to support

Providing viable rehabilitation to adult poor performers lies within the realm of

As CI specialists, we provide access to direct rehabilitation and rehabilitation support. Specialized rehabilitation, given the wide variability in patient outcomes,

detective work. In the early stages, it provides affirmative counseling based on predictive modeling and effective surgical planning and its implementation. Counseling patients with realistic expectations, however, takes place throughout the entire rehabilitation process. There will always be differences in outcomes, but having a full array of options based on objective measures and individual case history will guide the specialist to advise for optimal use of their hearing abilities. Motivation is a very important component of success, and this needs to be reinforced especially for this population who, often, have unrealistic expectations

what is usually seen during the first 6 months of use.

DOI: http://dx.doi.org/10.5772/intechopen.89577

hearing progress with ongoing rehabilitation, if needed.

(this includes the family and supporting individuals).

7. Summary

Figure 5.

151

Stages of the rehabilitation process.

The input from any CI is inherently degraded compared to that available in normal-hearing individuals or, indeed, to those able to utilize a hearing aid effectively. Aging may play a role, slowing the process of learning [18] to accommodate to speech sounds presented as a new, seemingly unusual, set of sounds. Cognitive training should take into consideration the age of the CI user. In fact, it has been suggested that older CI users (>80 years) may benefit more from rehabilitation than younger users. A top-down approach may be the most appropriate approach for the older population [18].

#### 5.3 Role of plasticity

It is unknown to what degree the brain reorganizes speech when confronted with hearing loss [24]. We studied the dynamics of reversed cross-modal plasticity by TEP brain imaging during speech tracking before and after CI at two time points [25]. Essentially, as a result of auditory sensory deprivation, regions in the brain associated with perceiving visual input are activated during speech communication. After implantation, neuroplasticity is demonstrated as the brain recruits more auditory networks during tests of speech recognition. Olds et al. [26] confirmed these findings using the functional near-infrared spectroscopy (fNIRS) imaging technique. They observed cortical reorganization and suggested that listening effort may be involved in the cortically activated regions.  This may account for the activated regions seen in our study, although neither of the test intervals utilized direct auditory input. We speculate that during hearing deprivation, sensitivity to voice progressively decreases. Anderson and Kraus [20] refer to this as "deprivation-induced changes in auditory mapping." Once sound is reintroduced, the more visually focused cortical regions reassert into the voice-sensitive regions. This cross-modal reactivation shows the cooperation between visual and auditory cortex. Thus, a profound aim of active rehabilitation is to take advantage, and encourage, reverse plasticity to aid in restoring cortical preference to meaningful auditory signals. This need is also recognized by other authors [27].

## 6. Ongoing post-implant support, evaluations of progress, and hearing training: 6-month follow-up

Testing speech in noise takes place at 6 months. We have seen that the relationship between performance in quiet and in noise is highly correlated. The early performance in quiet is manifested in the 6-month scores (see Figure 1). Testing at a signal-to-noise ratio (SNR) of 10 dB creates a reasonable challenge and serves as a further indicator of who requires continued rehabilitation. We have observed that it is possible to identify CI users who have demonstrated early success or a steep learning curve. The remaining patients continue as poor users needing support and ongoing counseling to maintain their motivation. With continued exposure to auditory stimulation, they can be advised that still more progress is possible for them.

Increases continue even up to 3 years, but the incremental gain is much less that what is usually seen during the first 6 months of use.


**Author details**

Paritosh C. Kulkarni Department of Chemical Engineering, Manipal Institute of Technology, MAHE, Manipal, India

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