More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
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Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
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IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\n
Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n
\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"818",leadTitle:null,fullTitle:"Tandem Mass Spectrometry - Applications and Principles",title:"Tandem Mass Spectrometry",subtitle:"Applications and Principles",reviewType:"peer-reviewed",abstract:"Tandem Mass Spectrometry - Applications and Principles presents comprehensive coverage of theory, instrumentation and major applications of tandem mass spectrometry. 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Prasain received his Ph.D. in 1998 from the Toyama Medical & Pharmaceutical University, Japan. He was a visiting fellow at the Biotechnology Research Institute, Montreal, Canada and then joined the Institute of Physical and Chemical Research (RIKEN), Japan in 2000 as a postdoctoral fellow where he worked on the use of tandem mass spectrometry in dereplication of natural products. He moved to the USA in 2001 and joined Dr. Stephen Barnes’ group at the University of Alabama at Birmingham (UAB). 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1. Introduction
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“It is a truism that each solution brings its own problems. Diabetic retinopathy in survivors of longstanding diabetes…represents the price paid for conquests that are not quite complete. The prolongation of life without corresponding prolongation of health, is loaded with intractable problems.” commented Arnold Sorsby on the “striking increase” of blindness from diabetes for both men and women between 1948 and 1962. [1]
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The next six decades saw intensive research in the pathogenesis and epidemiology of diabetic eye disease and the introduction of laser photocoagulation in the early treatment of diabetic retinopathy, pars plana vitrectomy for traction, and rhegmatogenous retinal detachment and intravitreal pharmacotherapy in the management of diabetic macular edema (DME), all addressing prevention of vision loss in these patients.
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2. Magnitude of blindness due to diabetic eye disease
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Reports on the vision loss attributable to diabetes in the 1980s and 1990s vary greatly in their methodology—some have derived clinical information from hospital series, and others have reviewed the registry forms of certified disabled persons from the records of societies of the blind; there are reviews on patients referred to low vision rehabilitation centers and finally some present data from population-based observational studies. Each source has its shortcomings. Definitions in registry databases depend on the national disability legislation and often differ from the categories for blindness and low vision in the International Classification of Diseases (ICD)—Ninth and Tenth Revisions—that were in use at that time. Many authors stress on the difficult task of identifying the onset and the main cause of vision loss in diabetic patients with multiple ophthalmic comorbidities, especially in their final stages. For a long period, well into the 1980s, non-ophthalmic professionals were allowed to certify blind persons for registration that raises reservations regarding the accuracy of the cause. A common concern is the inability to determine the number of underreported and unregistered diabetic persons with vision loss as registration is voluntary, and it depends on clinical, social, and cultural factors; many authors have noted a rise in the incidence rates of DR with the arrival of more consultants in the area, after upgrade in the financial benefits and social support for legally blind or following campaigns to improve public awareness and reduce stigmatization.
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Hospital series analyze clinical data collected in specialized diabetic units over long periods in a consistent manner and provide reliable estimate on the severity and progression of vision loss; however, extrapolations of their findings for the population beyond their urban region are seldom possible.
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Publications from the UK, Denmark, and Sweden demonstrate a decrease in the incidence of new blindness from DR in the 1980s and 1990s [2, 3, 4, 5]; however it remained unchanged between 1967 and 1991 in Italy and Avon, UK [6, 7]. In their review on the trends in blindness in Singapore, See et al. [8] present a sharp increase in the prevalence of diabetes in the age between 15 and 69 from 1.99% in 1975 to 8.6% in 1992 and a rise in the proportion of blindness from diabetic complications from 5% in the 1950s to 47.3% in the 1980s.
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Global data on blindness [9, 10], a review report of the WHO programme for prevention of blindness, summarized available information from population-based assessment of visual loss and its causes. DR was not among the four major causes for blindness and low vision globally and ranked between the first and fourth only in Western Europe, the former socialist economies of Europe, North America, Latin America, and Oceania. The authors note the lack of relevant epidemiological data for some specific causes of blindness; however they emphasize that this disease is “generally recognized to be the leading cause of blindness among those in working age in developed countries and rapidly emerging in urban areas of the developing world.”
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An update on the estimates of global and regional blindness and low vision was published in 2004 presenting results of new population-based studies and other sources of information. The proportion of DR rose to 4.8% globally, and it was ranked fifth as a cause of blindness, with significant regional variations reaching 17% for North America and Australia, 17–15% in Europe, and 3–7% in the rest of the world where the majority of vision loss was due to cataract, glaucoma, and corneal opacities as complications of trachoma [11].
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A meta-analysis of all available population-based studies performed worldwide from 1990 to 2010 [12] estimated that 833,690 people were blind and 3.7 million were visually impaired globally in 2010 due to DR. The highest number of blind diabetic patients was in South Asia, 295,000; North Africa/Middle East, 108,000; Eastern sub-Saharan Africa, 50,000; and Western sub-Saharan Africa, 66,000. The age-standardized prevalence of blindness from diabetic retinopathy in people over the age of 50 years was 0.05% globally, reaching 0.19% in Western sub-Saharan Africa, 0.16% in North Africa/Middle East, 0.14% in Eastern sub-Saharan Africa, and 0.12% in Southeast and East Asia. Moderate and severe vision impairment due to DR affected 3174 million, and the largest number of them were in South Asia, 1450 million, followed by North Africa/Middle East, 336,000; Eastern Asia, 279,000; Western Europe, 225,000; Western sub-Saharan Africa, 193,000; Eastern Europe, 166,000; Eastern sub-Saharan Africa, 128,000; and Central Latin America, 109,000. The age-standardized prevalence of moderate and severe vision impairment due to DR in people over the age of 50 years was 1.9% globally and was highest—0.51%—in South Asia, 0.50% in Western sub-Saharan Africa, 0.44% in North Africa/Middle East, 0.36% in Southern Latin America, 0.33% in Central sub-Saharan Africa, 0.32% in Andean Latin America, 0.31% in Eastern sub-Saharan Africa, and 0.26% in Oceania [13]. From 1990 to 2010, the number of blind diabetics had increased by 27% and those with visual impairment by 64% globally. Globally, age-standardized prevalence of blindness and vision impairment of diabetics over the age of 50 years was relatively unchanged in the course of these 20 years. It reduced by half in high-income Pacific Asia, Europe, Australasia, and North America; however it remained high in large, densely populated regions of Africa and Asia with rapidly increasing prevalence of diabetes.
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A continuation of this systematic review and meta-analysis of data from 261 population-based studies published till 2014 [14] observed that while blindness to all causes reduced between 1990 and 2015, DR was the only one with prevalence that increased by 7.7% for blindness and by 28.6% for impairment. The proportion of vision loss attributable to diabetes ranked seventh in 2015 at 1.06% (0.15–2.38) globally and was highest in Eastern Europe, 4.91%, followed by Australasia, high-income North America, high-income Pacific Asia, and Central Asia. The contribution of DR to moderate and severe vision impairment was 1.30% (0.20–2.93) and reached 5.06% in Eastern Europe, followed by Australasia, high-income North America, high-income Pacific Asia, and Central Asia. The same regions were leading in the percentage of blindness and low vision due to DR for people over the age of 50 years. The age-standardized prevalence of blindness from DR across all ages was relatively low, in the range of 0.00–0.01 (0.00–0.02), and was considerably higher for vision impairment, 0.03% (0.00–0.13), with Eastern Europe ranking first at 0.11%, Central Asia, 0.09%; Southern Latin America, 0.08%; and North Africa/Middle East and Australasia, 0.07%. The age-standardized prevalence of blindness of diabetics over the age of 50 was 0.02% (0.00–0.07) and was highest in North Africa/Middle East, Eastern Europe, and Central Asia. The age-standardized prevalence of low vision in the same age group was 0.13% (0.01–0.48), and the same regions were most affected. For the first time, this report presented data on the gender differences in the cause and magnitude of vision loss and demonstrated that the relative risk of blindness and vision impairment in diabetic women as compared to men was 2.52. The number of people with blindness due to diabetic retinopathy was estimated at 400,000 (0–1.5 million) and low vision 2.6 million (0.2 million—9.9 million), both almost doubled since 1990. The projections for diabetic complications for 2020 are for further increase, and the largest number of people are expected to reside in North Africa/Middle East, 73,000 blind and 4,480,000 with low vision; Eastern Europe, 47,000 blind and 362,000 with low vision; Western Europe, 46,000 blind and 422,000 with low vision; East Asia, 41,000 blind and 400,000 with low vision; and Southeast Asia, 30,000 blind and 216,000 with low vision. The authors point out that the prevalence of any DR and sight-threatening DR was similar in men and women, whereas their analysis suggested female preponderance for vision-impairing DR. They attribute this discrepancy to the use of aggregated data for both genders combined in some of the studies and highlight the need for further research into the gender differences. There are considerable regional variations in the blindness and low vision due to DR, and they are related to the prevalence of diabetes in the population and the life expectancy of the diabetic patients. In the Middle East, Kuwait, for example, the prevalence of diabetes has reached 20–25% of the whole population and over 50% after the age of 60 years. In some regions, in particular in South Asia, the life expectancy of diabetic individuals is reduced, they do not have the chance to develop retinopathy as sequela of the disease, and the prevalence of debilitating retinopathy is low despite the high proportion of diabetes.
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A detailed meta-analysis of the trends in vision loss in high-income countries in Pacific Asia, Australasia, North and Latin America and Western Europe, as well as Central and Eastern Europe from 1990 to 2015 [15] presented a relatively low and stable prevalence of blindness due to DR for all ages in the range of 0.01–0.02% in the whole super-region; however the rates for moderate and severe visual impairment varied in the range from 0.6–0.7% in most of the high-income countries to 1.6% in Eastern Europe and Australasia. The crude prevalence of blindness among diabetics over 50 years was in the range of 0.02–0.03% in the high-income countries, 0.04% in Central Europe, and 0.06–0.07% in Eastern Europe, and visual impairment was lowest in Western and Central Europe and Pacific Asia, followed by North America and Australasia and highest in Eastern Europe. The projections for 2020 were for stable or slightly reduced prevalence of blindness and gradual increase of patients with visual impairment in the super-region.
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Vision loss in the multiethnic population of Singapore over the age of 40 years was investigated in a series of population-based studies that demonstrated relatively high prevalence of diabetes in the sample—29.5%; DR was the second leading cause of vision impairment and blindness, and Indians and Malays were more affected than the Chinese. The authors point out that DR-related blindness in these three ethnicities in Singapore was less than the mainland Southern Indians, mainland Han Chinese, and peninsula Malays, and they attribute this to better access to qualified eye screening and care in Singapore. Diabetes was a significant contributing factor for visual impairment generally and increased the risk by 2.96 for people below the age of 60 years and 12.70 times for those over 60, particularly for females and patients with cognitive impairment and deafness, a tendency that was consistently observed across Malays, Indians, and Chinese. Diabetes in combination with other comorbidities, hypertension, hyperlipidemia, cardiovascular, or renal disease, was associated with higher risk of vision loss, up to 9.51 for people younger than 60 years and 26.56 for those older than 60, particularly for Indians, and an interaction effect for concomitant diabetes and renal diseases [16].
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Vision-threatening DR (VTDR) is a compound term used in the literature for the presence of proliferative disease grading over level 60 by EDTRS scale and its modification and/or macular edema in its various stages [17, 18], and its magnitude is essential for planning the life-long management of these patients and prevention of blindness. The prevalence and risk factors of VTDR were estimated in a large meta-analysis of 38 population-based studies from Australia, the USA, Europe, and Asia involving 42,091 participants from 20 to 79 years with diabetes. There was no discernible sex difference in the age-standardized prevalence of VTDR, 11.7%; it was highest among African Americans, 16.89%; followed by Caucasians, 15.45%; and Hispanics, 10.35, and was lowest in South Asians—5.2%. Duration of diabetes (DM) was associated with rapidly increasing prevalence from 3.53% for DM less than 10 years to 17.78% for 10–20 years and up to 87% for more than 20 years. Metabolic control, estimated by the levels of HbA1c, directly affected the extent of VTDR—the disease doubled in patients with levels between 7.1 and 8.0% and tripled among those with more than 9.0%. Elevated blood pressure over 140/90 and hypercholesterolemia over 4.0 mMol/L elevated the risk of VTDR twice, particularly for macular edema. Individuals with type 1 diabetes for more than 20 years were 15 times more likely to have proliferative diabetic retinopathy (PDR) (15.3 [11.3–20.8]), 5 times more likely to have DME (4.83 [3.71–6.30]), and 8.7 times more likely to have VTDR (8.69 [7.10–10.63]) than those with type 2 diabetes for less than 10 years. On a positive note, the prevalence of VTDR reduced from 15.62% in studies where the fundus photographs were taken before the year 2000 to 7.86% in the studies with assessment of the patients after 2000.
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This pivotal work highlighted the importance and cutoff levels of the systemic factors associated with progression of DR to sight-threatening stage and the need for close collaboration with the treating diabetology team. It outlined the profile of the patients at risk of vision loss with their features—type and duration of diabetes, levels of metabolic control, hypertension, and hypercholesterolemia. The role of ethnicity was limited to the populations studied, and the authors note the absence of studies from Middle East, Africa, and South America that could affect the accuracy of their global estimates. The differences in the rates of VTDR in the various populations could be due to both genetic factors and access to health care. Ethnicity itself is multidimensional, and it may not be possible to differentiate its effect from the risk associated with remoteness, urbanization, lifestyle, education, health awareness, and individual income.
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3. Social and economic risk factors
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Social and economic factors have a fundamental impact on the visual prognosis of diabetic eye disease. A number of studies have investigated the negative influence of deprivation on the prevalence of diabetes, access to evaluation and care, level of metabolic control, and rate of complications and were reported in systematic reviews for type 1 [19] and type 2 diabetes [20]. Remoteness [odds ratio (OR) 2.02] and diabetes in combination with never having had an eye examination (OR 14.47) were among the main risk factors for vision loss in indigenous Australians, and blindness prevalence was 2.8 times higher among them than in non-indigenous Australians after age and gender adjustment [21]. The presence of PDR was associated with low income (OR = 3.6 for developing PDR if income was less than $20000) in the Proyecto VER Study in the USA involving 4774 Hispanics over the age of 40, after controlling for other factors [22]. Deprivation, as a comprehensive measure of income, employment, health and disability, education, crime, barriers to housing, services, and living environment at the level of small geographic areas, was developed in the UK as a numerical index per residential code and used in a large national database study of 79,775 diabetic patients to highlight its effect on visual acuity and need for early treatment at first hospital presentation [23]. The OR of presenting with “sight impairment” at first visit to the hospital eye service was gradually decreasing from 1.29 in the most deprived group to 0.77 in the least deprived one, and OR for “severely sight impaired” was 1.17 in the most deprived decile versus 0.88 in the least deprived one. The risk of sight-threatening maculopathy and vitreous hemorrhages showed little variations across the deprivation range, and tractional retinal detachment was less likely in the two least deprived deciles. The large scale of the study and use of “real-world” multicenter in-hospital dataset provided statistical strength to the conclusion that the impact of deprivation extends to late presentation of retinopathy, significant loss of vision at presentation, and a pattern of advanced retinal complications that affect the treatment these patients receive. Financial factors are often self-reported by diabetic patients who are missing screening appointments and treatment sessions. However a study in Tanzania revealed that the reasons for poor compliance are more complicated. The clarity of referral process and ease of navigation through the unfamiliar hospital environment are essential, particularly for the elderly and less educated patients from remote areas [24]. Another formidable obstacle is the widespread complacency and fatalistic resignation with the notion that retinopathy will inevitably end up with blindness. Constant assurance and encouragement that diabetic eye disease is a treatable condition with good prognosis is a practical strategy to prevent delays in diagnosis of sight-threatening complications. Lack of education greatly affects the health awareness and adherence with retinopathy management. In Kuwait, 16% of the men and 46% of the women over 65 years are illiterate, and 20% of the men and 24% of the women in the same age group can only read and write [25]. This is a significant barrier to in-depth understanding and compliance with recommended treatment and lifestyle and eventually compromises the visual outcome despite the high economic standard of the Kuwaiti nationals and availability of services in the country. Family support greatly improves the continuum of care and is essential for the regular attendance of the patients, especially females from a more conservative background.
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Progression of nonproliferative to proliferative disease was investigated in several large cohort studies [26, 27]. Disease severity was estimated by the EDTRS classification and taken separately for each eye or concatenated as the bilateral grade, and progression was defined as the increase of two or more steps in severity. The rate of progression to PDR varied greatly—it was from 4 to 9.9% in the first 4–5 years and 8–12% in the next 5 years and reached a cumulative level of 31% after 16 years and 42% after 25 years in type 1 and type 2 diabetics. There are differences between the populations and methodology applied in the hospital-based and community-based studies as more patients with severe disease that required active management were probably referred to tertiary care centers [28, 29, 30, 31, 32].
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The diagnosis of diabetic macular edema has evolved with the introduction of stereoscopic photography of the posterior pole and optical coherence tomography (OCT). The presence of any edema and clinically significant edema (CSME) by the modified EDTRS classification has been investigated in multiple hospital series and population-based studies. Detection of DME in non-stereoscopic fundus photographs is less sensitive to milder forms with recent onset, and probably the reported prevalence covers the more severe chronic stage. The prevalence of CSME in type 1 patients was from 5.73% in Spain to 9.4% in Brazil [33, 34]. Among patients with type 2 diabetes, it was in the range from 1.4% in Portugal to 12.8% in Denmark [35, 36]. There are reports indicating that the prevalence of DME in Central and Eastern Europe [37], North Africa, and Middle East [38] is considerably higher, and further research on the magnitude of CSME and risk factors for its progression will contribute to the estimates of sight-threatening retinopathy globally.
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4. Diabetic nephropathy
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Diabetic nephropathy (DN), the primary cause of chronic kidney disease, is significantly associated with incidence and progression of diabetic retinopathy as demonstrated in Brazilian [39], Spanish [40], Korean [41], Taiwanese Chinese [42], and Australian [43] patients. The presence of chronic kidney impairment had adjusted a hazard ratio of 5.01 for nonproliferative and 9.7 for proliferative disease as compared to patients without nephropathy. At 5-year follow-up, the hazard ratio of progression to PDR was 2.26 in patients with DN, and it was related to the levels of microalbuminuria and estimated glomerular filtration rate with cutoff below 60 mL/min/1.73 m2 [44]. Hypertension and DN in patients with chronic kidney disease increased the risk of progression to proliferative disease; however diabetic nephropathy did not significantly affect the development or progression of DME. Among the Taiwanese Chinese patients, diabetic macular edema had high crude hazard ratio association with cerebrovascular accidents and lesser one for hypertension and use of statins; however the significance was lost after controlling for age, sex, comorbidities, and medications.
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5. Pregnancy in diabetic patients
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Diabetes affects 17% of pregnancies worldwide and can be pre-existing type 1, gestational, or type 2, in some of the patients—previously undiagnosed. The highest rate of diabetes in pregnancy is recorded in Southeast Asia, 25%, and the prevalence of pre-existing diabetes is highest among women from the Middle East and North Africa—3.1%. Australian mothers who were born in high diabetes risk areas such as Polynesia, Asia, and the Middle East are 1.4 times more likely to have type 2 diabetes during pregnancy [45]. Similarly, in the USA and UK, patients belonging to Black, Asian, Hispanic, and Pacific Island ethnic minorities had higher proportion of pre-existing diabetes and pre-existing type 2 DM. Progression of retinopathy during pregnancy is related to the level of diabetic retinopathy prior to conception and was noted in 58% of the patients with moderate or more severe DR at baseline. Duration of diabetes type 1 greater than 15 years and type 2 more than 6 years was significantly associated with higher rate of progression of retinopathy in patients with pre-existing proliferative disease. Poor glycemic control prior and during pregnancy was an independent risk factor for retinopathy progression; however tight control and rapid optimization of metabolic control in such patients were associated with worsening of retinopathy. As the long-term benefits of proper glycemic management outweigh the short-term risk of deteriorating retinopathy, optimal control is currently recommended prior to and as soon as possible after conception for the health of the mother and fetus. Progression of retinopathy during pregnancy was significantly higher in diabetic patients with preeclampsia, with sight-threatening complications in 50% of the diabetic women with preeclampsia compared to 8% without it [46]. Other risk factors for deteriorated retinopathy during pregnancy include young age of type 1 onset, insulin treatment in type 2 prior to pregnancy, low vision at baseline, and pre-existing macular edema at baseline [47].
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6. Diabetic foot syndrome
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Diabetic foot syndrome is one of the important consequences of long-term uncontrolled diabetes, which occurs due to a combination of peripheral neuropathy and microvasculopathy in the lower extremities. It may vary from a minor ulceration to necrosis of tissues, sometimes warranting amputation [48]. Several hospital series demonstrated the presence of retinopathy in 90–95% and proliferative disease and severe nonproliferative changes in 39–55% in such patients independent of the ulcer severity [49]. Diabetic foot syndrome in type 1 and type 2 diabetic patients with retinopathy was associated with higher levels of HbA1c, serum creatinine, older age, and lower hematocrit, particularly elevated in the subgroup with proliferative disease—all characteristics of concomitant chronic kidney disease and neuropathy in poorly controlled, long-lasting diabetes. Despite the lack of data on macular edema, the presence of any stage of diabetic foot ulcer is emerging as a predictor for retinopathy deterioration [50, 51].
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7. Depression and anxiety
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The overall prevalence of depressive symptoms in diabetic patients with retinopathy is estimated in the range of 35% in China to 50% in African Americans and is more prevalent in type 2 [52, 53]. The association between depressive symptoms, diabetes, and diabetic retinopathy is likely to be bidirectional: the impairment and burden of diabetes and its complications can precipitate depression and vice versa, and depression can impair diabetes control through various biological and behavioral pathways [54, 55]. Depression aggregates negative attitudes toward treatment and often leads to poorer glycemic control, less adherence to treatment, higher risk for PDR, greater morbidity and mortality, and higher costs [56]. Low income has been implicated in some research from the USA; however it was not found significant in a large cross-sectional study from Australia. Patients with longer duration of diabetes, worse glycemic control, lower educational level, and severe vision impairment below 20/63 were associated with greater depression symptoms. Symptoms of anxiety were associated with type 1 diabetes, presence of myocardial infarction/angina, arrhythmia, stroke, asthma, anemia, arthritis or osteoporosis, younger age, and female gender [57]. Severe NPDR and PDR, but not macular edema, were independently associated with depressive symptoms, and the authors suggest that severity of retinopathy could be an indicator to prompt monitoring of depression in at-risk diabetic individuals. Antidepressant medications have been associated with slowing the progression of retinopathy in diabetic patients. However the outcome was limited to subjects with elevated C-reactive protein over 0.3 mg/dL. Selective serotonin reuptake inhibitor users had significantly lower risk of developing severe retinopathy than non-SSRI users [58]. The results of longitudinal studies show that the speed of cognitive decline in type 2 diabetic patients is up to twice as fast as that of normal aging individuals and diabetic patients have an increased risk of mild cognitive impairment (MCI). In addition, type 2 diabetic patients had an almost twofold higher risk of developing Alzheimer’s disease than age-matched nondiabetic subjects. This increased risk was maintained even after adjusting for vascular risk factors. The annual conversion rate from MCI to dementia ranges between 10 and 30% in the general population, but this is much higher in the type 2 diabetic population. The impact of cognitive impairment on the compliance with lifelong retinopathy treatment and its outcome needs further evaluation; however clinical practice indicates the need for personalized multidisciplinary approach.
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8. Progression to vision-threatening retinopathy
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The variability in the rate of progression to vision-threatening retinopathy and particularly in the response to treatment was noted from the onset of clinical and epidemiological studies in diabetic patients and has been attributed to the effect of genetic predisposition together with systemic and socioeconomic factors. Single-nucleotide polymorphisms [58, 59, 60] and genome-wide associations [61, 62, 63] have been investigated in patients with proliferative disease and macular edema, and the results so far are inconclusive mainly due to the size of the samples and the inclusion of cases with coexisting proliferations and edema in the cohorts. Detailed assessment in the polymorphisms of the VEGF gene revealed that some of them are related to higher susceptibility to severe retinopathy, but not to the outcome of ranibizumab intravitreal injections [64] in contrast to an earlier report on the response to bevacizumab [65]. In order to confirm the association of several novel genetic loci with severe retinopathy, replication studies and extension in additional cohorts and ethnic groups have been recommended [66]. Research of systemic and retinal inflammation as risk factors for DR and DME [67, 68], upregulated leptin [69, 70] and adiponectin [71], oxidative stress [72], and vitamin D deficiency [73] has provided significant associations. Reliable and accessible markers of these factors can be important predictors of the disease severity and progression and thus provide early guidance in personalizing the monitoring and treatment of the patients at risk of vision loss.
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9. Management of DME
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The introduction of intravitreal anti-VEGF drugs and corticosteroid implants revolutionized the management of DME. Prospective randomized clinical trials have addressed the efficacy and safety of different types of agents and administration regimens and have shown wide variations in terms of visual acuity gain. In the DRCR.net trial, after 2 years of treatment, approximately 98% of the patients maintained their visual acuity and attained visual gain in 37% of the patients on ranibizumab, 35% of those on bevacizumab, and 39% of those on aflibercept [74]. Stratified analysis of RESTORE in DME, RETAIN, and Protocol I demonstrated that the most significant gain in number of EDTRS letters after 12–36 months was in patients with baseline BCVA 60 and less letters in the range of 8.6–10.36 letters, versus the gain for patients with baseline BCVA 61–71 letters who achieved 7.96–4.36 letters, and the least gain of 5.42–4.2 letters was in the group with baseline BCVA better that 73 letters [75]. Thus, the patients with most severe vision deterioration and baseline BCVA in the range of 20/320–20/63 who responded favorably to 2 years of intensive therapy improved to BCVA from 20/160 to 20/40. High visual acuity in the range of 20/40–20/32 was achieved only in patients with baseline BCVA over 20/30 despite the small number of gained EDTRS letters. The range and stability of this visual improvement depended on increasing age, level of glycemic control, and previous panretinal photocoagulation [76]. OCT markers of better functional outcome after anti-VEGF treatment were the presence of intact ellipsoid zone and lack of hyperreflective spots or disruption of the inner retinal layers, which are seen in patients with more recent onset of the edema and no previous macular grid laser [77]. Patients with chronic macular edema had considerably better functional and structural results after treatment with steroid implants. Visual gain of more than 15 letters was achieved in 22% after 3 years on intravitreal dexamethasone [78] and in 34% after 3 years on fluocinolone acetonide [79]. Eyes with submacular fluid, no hyperreflective foci, and a continuous IS-OS layer responded better to dexamethasone implants with gain of 10 or more letters after 2 and 4 months [80]. The adverse effects of both implants included the formation of cataract, 13–50% after 1 year on dexamethasone and 82% after 3 years on fluocinolone acetonide, and intraocular pressure rise over 25 mmHg in 42% of the eyes with dexamethasone and 38% with fluocinolone acetonide; however a small percentage required glaucoma surgery—0.5% of the eyes with dexamethasone and 4.8% with fluocinolone acetonide. Patients with poorly controlled diabetes and DME, severe nonproliferative or proliferative disease, epimacular membranes, myopia, glaucoma, and various degrees of cataract are excluded from the randomized clinical trials; however such cases are predominant in real-world practice and add new dimensions to the challenge of visual rehabilitation. Analysis of large electronic medical record databases from the USA [81] and Korea [82] demonstrated visual outcomes that are meaningfully inferior to those in the clinical trials and were attributed to undertreatment and lack of close monitoring. A sizable group of DME patients were lost to follow-up in the initial stages of anti-VEGF treatment—25% were reported from a single retina practice in the USA and the main risk factors were being Hispanic, Black, or a Pacific islander; low income, AGI less than $50,000; and decreasing baseline visual acuity [83]. In a study of European DME patients, 46% had at least one break-off in their anti-VEGF treatment for more than 100 days, and the most common reason for poor compliance was comorbidity. In 60% of these cases, the visual acuity deteriorated significantly after the break [84]. Prevention of vision loss from diabetic macular edema is achievable with the current therapeutic modalities; however it requires very early identification at stages with relatively high visual acuity and needs the introduction of best-corrected visual acuity and OCT in the screening protocol. As shown in the Protocol G—Subclinical DME study of the DRCR.net that involved a longitudinal assessment of eyes that had retinal thickening on OCT without thickening on clinical exam, a progression to clinically apparent DME was seen in 23–58% of eyes within 2 years.
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10. Management of proliferative disease
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Vision loss in approximately 25% of patient with diabetic retinopathy is associated with complications of proliferative disease. An estimated 17 million diabetic people worldwide have PDR [17], and without treatment more than half of the patients with high-risk PDR will be blind within 5 years. Panretinal photocoagulation was established as an effective treatment to reduce by 50% the incidence of severe vision loss, if performed prior to the development of vitreous hemorrhages and tractional retinal detachment [85]. Still, the EDTRS has shown that 5% of patients with PDR will require vitreous surgery despite having received adequate PRP [86]. The Diabetic Retinopathy Vitrectomy Study validated the superiority of vitrectomy over observation; however despite the fact that the trial did not include patients with macula, involving traction, the visual outcome was low. Subsequent studies on vitrectomy for PDR reported that between 10 and 20% of the patients did not improve their visual acuity above hand motion or less [87]. Favorable factors for visual rehabilitation after vitrectomy for macula-involving tractional retinal detachment included short duration of detachment, previous panretinal photocoagulation, and lack of severe neovascularization and vitreous hemorrhage. Predictors of poor visual results were iris neovascularization and neovascular glaucoma, papillo-vitreal traction, baseline visual acuity below 20/200, initial macular detachment, intraoperative iatrogenic break, or use of heavy silicone oil [88, 89, 90]. Functional outcome was significantly affected in patients with postoperative macular ischemia, recurrent vitreous hemorrhage, optic atrophy, epiretinal membranes, and recurrent retinal detachment [91, 92]. The introduction of small-gauge vitrectomy instruments and trans-scleral cannulas enabled the fast and effective removal of most fibrovascular membranes with the vitrectomy probe applying the lift and shave technique [93]. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula and eyes with extensive membranes and with silicone oil as tamponade; however both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative and postoperative complications [94]. The integration of swept-source optical coherence tomography and digital displays can provide important guidance during surgery for PDR complications and facilitate decision-making [95]; however further research will show whether these technological advances will translate into better postoperative visual outcome.
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Medical treatment for PDR has had minimal advancement over the past 40 years since the wide acceptance of panretinal photocoagulation in the early management of the disease. Regression of proliferative activity was noted in eyes treated with anti-VEGF for concomitant macular edema [96] and that lead to a series of trials on aflibercept and ranibizumab versus panretinal photocoagulation in the management of PDR. Both drugs were superior to PRP in 1 [97] and 2 years [98] in terms of visual acuity and visual field sensitivity. Assessment of the peripapillary retinal nerve fiver layer thickness in patients treated with ranibizumab revealed reduction that was due to decreased edema rather than loss of axons [99]. Patients with mild and moderate vitreous hemorrhages treated with ranibizumab had significantly less need for vitrectomy, less recurrences of hemorrhage, and better visual acuity on all follow-up visits than the patient under observation or operated for non-resolving or aggravated hemorrhages [100]. However, despite the improvement in retinopathy severity on color photographs, the retinal perfusion did not improve on wide-field fluorescein angiography that revealed no reperfusion of small vessels in areas of previous capillary non-perfusion [101]. Diabetic patients are prone to significant loss to follow up due to illness, financial hardship, and lack of compliance. The rate of complications and loss of vision after unintentional interruptions for more than 6 months in PDR patients treated only on anti-VEGF was considerably higher than the eyes that received PRP, with a significantly higher number of eyes with tractional retinal detachment and neovascularization of the iris [102]. In a retrospective review of 13 eyes treated exclusively with anti-VEGF for PDR with or without macular edema or severe NPDR with macular edema, with hiatus of 12 months, 9 presented with vitreous hemorrhage, 5 with neovascular glaucoma, and 4 with tractional retinal detachment. Despite the aggressive treatment of the complications, 10 eyes lost more than 3 lines of vision, and 2 had final vision hand motions [103]. So, while anti-VEGF proved to be effective for PDR in the clinical trials, in real-world the unclear long-term advantages of pharmacological monotherapy over PRP, the increased cost, and treatment burden are not optimal for many diabetic patients.
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Neovascular glaucoma is a late complication of proliferative disease with chronic ischemia in the posterior segment and development of a fibrovascular membrane on the anterior surface of the iris and iridocorneal angle of anterior chamber, and usually its onset correlates with poor glycemic control. In the early stages, iris neovascularization can be found without elevated IOP. Panretinal photocoagulation remains the mainstay in controlling the neovascular drive and should be considered in all cases of neovascularization of the anterior segment when retinal ischemia is present. After panretinal photocoagulation, complete regression of retinal neovascularization can be reached in 67–77% of cases, visual loss can be prevented in 59–73%, and IOP reduction can be achieved in 42% [104]. Anti-VEGF injections can lead to regression of both iris and angle neovascularization and improve intraocular pressure control when the angle remains open. However, the effects of anti-VEGF agents seemed to induce only a temporary regression of new vessels in the anterior chamber angle and IOP reduction, generally lasting between 4 and 6 weeks [105]. Glaucoma drainage devices are usually considered the first treatment option for refractory glaucoma. Neovascular glaucoma patients are at greater risk for surgical failure after glaucoma valve surgery compared with non-neovascular glaucoma controls. A recent retrospective, comparative, case series of 163 eyes of 151 patients with neovascular glaucoma included 99 treated without and 64 treated with intravitreal bevacizumab. IOP decreased to 18.3 ± 13.8 mmHg in the non-bevacizumab group and 15.3 ± 8.0 mmHg in the bevacizumab group. Panretinal photocoagulation substantially reduced the need for glaucoma surgery (P < 0.001) in bevacizumab-treated eyes. Therefore, although bevacizumab delayed the need for glaucoma surgery, panretinal photocoagulation was the most important factor that reduced the need for surgery. Vision and IOP in eyes with neovascular glaucoma treated with bevacizumab showed no long-term differences when compared with eyes that were not treated with bevacizumab. Thus, intravitreal anti-VEGF drugs serve as an effective temporizing treatment but are not a replacement for close monitoring and definitive treatment of neovascular glaucoma [106, 107].
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Impairment of vision in diabetic patients is not limited to retinopathy—the leading causes of deteriorated vision and progression of vision loss in a cohort from South India were cataracts and uncorrected refractive errors [108]. The introduction of phacoemulsification significantly reduced the surgical trauma and leads to a growing tendency toward earlier cataract surgery in diabetic patients [109]. This approach facilitates panretinal photocoagulation and allows for the identification and adequate treatment of diabetic macular edema before and after cataract surgery. Preexisting macular edema can increase the risk of edema progression by 20–50%, and intravitreal anti-VEGF agents are recommended perioperatively [110]. Steroids, on the other hand, have been shown to be effective for persistent or refractory diabetic macular edema prior to and after cataract procedures. Dexamethasone implants and fluocinolone implants resulted in significant improvement in clinically significant macular edema and visual outcomes [111]. Despite the advancement in phacoemulsification technology, poor visual acuity following cataract extraction is still common in patients with diabetes. Posterior capsule opacification, postoperative cystoid macular edema, diabetic macular edema [112], and worsening of the DR are the main complications seen in diabetic patients. According to the Early Treatment of Diabetic Retinopathy Study, the presence of clinically significant diabetic macular edema at the time of cataract surgery was significantly associated with poor visual acuity and was a predictor of final visual acuity worse than 20/200 following uncomplicated phacoemulsification [113]. The severity of DR at the time of cataract surgery is also a significant determinant of postoperative VA; more severe retinopathy seems to be associated with an increased prevalence of macular ischemia or edema and a reduced tendency for spontaneous resolution of postoperative macular edema with associated poor postoperative VA. Treatment-naïve PDR before cataract surgery may progress to vitreous hemorrhage and tractional retinal detachment following phacoemulsification, thus threatening good visual outcome [114].
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In conclusion, vision loss due to diabetic complications in the eye is growing worldwide despite availability of screening programs, advanced diagnostic tools, pharmacotherapy, and rapidly evolving surgical technology. Prevention requires:
Identification of the social groups and individuals at high risk of vision-threatening diabetic complications
Coverage with diabetic retinopathy screening with introduction of AI tools, wide-field retinal assessment, telemedicine, and OCT of the posterior segment
Outreach of qualified management closer to the diabetic patients’ communities
Early, intensive management before significant vision loss
Lifetime, highly qualified monitoring and early management of complications
Close, continuous collaboration with the treating diabetology team
Involvement of the family, community, diabetic patients’ organizations, and social media in patient care, adherence to treatment, prevention of physical and mental disability, and improvement of quality of life
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\n\n',keywords:"diabetic retinopathy, trends, blindness, risk factors, treatment, visual outcome",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68627.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68627.xml",downloadPdfUrl:"/chapter/pdf-download/68627",previewPdfUrl:"/chapter/pdf-preview/68627",totalDownloads:907,totalViews:0,totalCrossrefCites:1,dateSubmitted:"April 5th 2019",dateReviewed:"July 22nd 2019",datePrePublished:"August 19th 2019",datePublished:"September 9th 2020",dateFinished:"August 19th 2019",readingETA:"0",abstract:"Prevalence of diabetes is rising worldwide. In the course of the last 20 years, blindness and low vision due to diabetic eye complications have increased in large regions in Eastern Europe, North Africa/Middle East, Asia, Latin America, and Oceania. The magnitude and trends of vision-threatening disease are presented. Systemic risk factors for progression to sight-threatening disease are reviewed. The impact of economic and cultural background on early diagnosis and adherence to treatment is highlighted. Current management of diabetic macular edema, proliferative diabetic retinopathy, neovascular glaucoma, and cataract surgery of diabetic patients is outlined, and its contribution to preventing vision loss is reviewed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68627",risUrl:"/chapter/ris/68627",signatures:"Maya Georgieva Pandova",book:{id:"7176",type:"book",title:"Visual Impairment and Blindness",subtitle:"What We Know and What We Have to Know",fullTitle:"Visual Impairment and Blindness - What We Know and What We Have to Know",slug:"visual-impairment-and-blindness-what-we-know-and-what-we-have-to-know",publishedDate:"September 9th 2020",bookSignature:"Giuseppe Lo Giudice and Angel Catalá",coverURL:"https://cdn.intechopen.com/books/images_new/7176.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-258-5",printIsbn:"978-1-83880-257-8",pdfIsbn:"978-1-83962-953-2",isAvailableForWebshopOrdering:!0,editors:[{id:"87607",title:"M.D.",name:"Giuseppe",middleName:null,surname:"Lo Giudice",slug:"giuseppe-lo-giudice",fullName:"Giuseppe Lo Giudice"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"300935",title:"Ph.D.",name:"Maya G.",middleName:null,surname:"Pandova",fullName:"Maya G. Pandova",slug:"maya-g.-pandova",email:"mayapandova@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Magnitude of blindness due to diabetic eye disease",level:"1"},{id:"sec_3",title:"3. Social and economic risk factors",level:"1"},{id:"sec_4",title:"4. Diabetic nephropathy",level:"1"},{id:"sec_5",title:"5. Pregnancy in diabetic patients",level:"1"},{id:"sec_6",title:"6. Diabetic foot syndrome",level:"1"},{id:"sec_7",title:"7. Depression and anxiety",level:"1"},{id:"sec_8",title:"8. Progression to vision-threatening retinopathy",level:"1"},{id:"sec_9",title:"9. Management of DME",level:"1"},{id:"sec_10",title:"10. Management of proliferative disease",level:"1"}],chapterReferences:[{id:"B1",body:'\nSorsby A. The Incidence and Causes of Blindness in England and Wales. London: Her Majesty’s Stationary Office; 1966. p. 6\n'},{id:"B2",body:'\nHovind P, Tarnow L, Rossing K, Rossing P, Eising S, Larsen N, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care. 2003;26(4):1258-1264\n'},{id:"B3",body:'\nAclimandos WA, Galloway NR. Blindness in the city of Nottingham (1980-1985). Eye (London, England). 1988;2(Pt 4):431-434\n'},{id:"B4",body:'\nThompson JR, Du L, Rosenthal AR. Recent trends in the registration of blindness and partial sight in Leicestershire. The British Journal of Ophthalmology. 1989;73(2):95-99\n'},{id:"B5",body:'\nBäcklund LB, Algvere PV, Rosenqvist U. New blindness in diabetes reduced by more than one-third in Stockholm County. Diabetic Medicine. 1997;14(9):732-740\n'},{id:"B6",body:'\nPorta M, Tomalino MG, Santoro F, Ghigo LD, Cairo M, Aimone M, et al. Diabetic retinopathy as a cause of blindness in the province of Turin, north-west Italy, in 1967-1991. Diabetic Medicine. 1995;12(4):355-361\n'},{id:"B7",body:'\nGrey RH, Burns-Cox CJ, Hughes A. Blind and partial sight registration in Avon. The British Journal of Ophthalmology. 1989;73(2):88-94\n'},{id:"B8",body:'\nSee JL, Wong TY, Yeo KT. Trends in the pattern of blindness and major ocular diseases in Singapore and Asia. Annals of the Academy of Medicine, Singapore. 1998;27(4):540-546\n'},{id:"B9",body:'\nThylefors B, Négrel AD, Pararajasegaram R, Dadzie KY. Global data on blindness. Bulletin of the World Health Organization. 1995;73(1):115-121\n'},{id:"B10",body:'\nThylefors B, Négrel AD, Pararajasegaram R, Dadzie KY. Available data on blindness (update 1994). Ophthalmic Epidemiology. 1995;2(1):5-39\n'},{id:"B11",body:'\nResnikoff S, Pascolini D, Etya\'ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bulletin of the World Health Organization. 2004;82(11):844-851 [Epub Dec 14, 2004]\n'},{id:"B12",body:'\nLeasher JL, Bourne RR, Flaxman SR, Jonas JB, Keeffe J, Naidoo K, et al., Vision Loss Expert Group of the Global Burden of Disease Study. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 1990 to 2010. Diabetes Care. 2016;39(9):1643-1649\n'},{id:"B13",body:'\nFlaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al., Vision Loss Expert Group of the Global Burden of Disease Study. Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis. The Lancet Global Health. 2017;5(12):e1221-e1234. DOI: 10.1016/S2214-109X(17)30393-5 [Epub Oct 11, 2017]\n'},{id:"B14",body:'\nGBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. DOI: 10.1016/S0140-6736(18)32279-7 [Epub Nov 8, 2018]\n'},{id:"B15",body:'\nRRA B, Jonas JB, Bron AM, Cicinelli MV, Das A, Flaxman SR, et al., Vision Loss Expert Group of the Global Burden of Disease Study. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe in 2015: magnitude, temporal trends and projections. The British Journal of Ophthalmology. 2018;102(5):575-585. DOI: 10.1136/bjophthalmol-2017-311258 [Epub Mar 15, 2018]\n'},{id:"B16",body:'\nWong TY, Tham YC, Sabanayagam C, Cheng CY. Patterns and risk factor profiles of visual loss in a multi-ethnic asian population: The Singapore epidemiology of eye diseases study. American Journal of Ophthalmology. 2019. DOI: 10.1016/j.ajo.2019.05.006. pii: S0002-9394(19)30226-0 [Epub ahead of print]\n'},{id:"B17",body:'\nYau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al., Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564. DOI: 10.2337/dc11-1909 [Epub Feb 1, 2012]\n'},{id:"B18",body:'\nWu L, Fernandez-Loaiza P, Sauma J, Hernandez-Bogantes E, Masis M. Classification of diabetic retinopathy and diabetic macular edema. World Journal of Diabetes. 2013;4(6):290-294. DOI: 10.4239/wjd.v4.i6.290\n'},{id:"B19",body:'\nLindner LME, Rathmann W, Rosenbauer J. Inequalities in glycaemic control, hypoglycaemia and diabetic ketoacidosis according to socio-economic status and area-level deprivation in Type 1 diabetes mellitus: a systematic review. Diabetic Medicine. 2018;35(1):12-32. DOI: 10.1111/dme.13519 [Epub Nov 3, 2017]\n'},{id:"B20",body:'\nGrintsova O, Maier W, Mielck A. Inequalities in health care among patients with type 2 diabetes by individual socio-economic status (SES) and regional deprivation: A systematic literature review. International Journal for Equity in Health. 2014;13:43. DOI: 10.1186/1475-9276-13-43\n'},{id:"B21",body:'\nForeman J, Xie J, Keel S, van Wijngaarden P, Sandhu SS, Ang GS, et al. The prevalence and causes of vision loss in indigenous and non-indigenous Australians: The National Eye Health Survey. Ophthalmology. 2017;124(12):1743-1752. DOI: 10.1016/j.ophtha.2017.06.001 [Epub Jul 6, 2017]\n'},{id:"B22",body:'\nWest SK, Munoz B, Klein R, Broman AT, Sanchez R, Rodriguez J, et al. Risk factors for Type II diabetes and diabetic retinopathy in a mexican-american population: Proyecto VER. American Journal of Ophthalmology. 2002;134(3):390-398\n'},{id:"B23",body:'\nDenniston AK, Lee AY, Lee CS, Crabb DP, Bailey C, Lip PL, et al., UK DR EMR Users Group. United Kingdom Diabetic Retinopathy Electronic Medical Record (UK DR EMR) Users Group: Report 4, real-world data on the impact of deprivation on the presentation of diabetic eye disease at hospital services. The British Journal of Ophthalmology. 2019;103(6):837-843. DOI: 10.1136/bjophthalmol-2018-312568 [Epub Sep 29, 2018]\n'},{id:"B24",body:'\nMtuya C, Cleland CR, Philippin H, Paulo K, Njau B, Makupa WU, et al. Reasons for poor follow-up of diabetic retinopathy patients after screening in Tanzania: A cross-sectional study. BMC Ophthalmology. 2016;16:115. DOI: 10.1186/s12886-016-0288-z\n'},{id:"B25",body:'\nPandova MG, Al-Merjan JI, Sadeq NA. Registered blindness in Kuwait—15 Years of dynamic changes. Ophthalmic Epidemiology. 2019;26(2):75-83. DOI: 10.1080/09286586.2018.1521981 Epub 2018 Oct 4\n'},{id:"B26",body:'\nTam VH, Lam EP, Chu BC, Tse KK, Fung LM. Incidence and progression of diabetic retinopathy in Hong Kong Chinese with type 2 diabetes mellitus. Journal of Diabetes and its Complications. 2009;23(3):185-193. DOI: 10.1016/j.jdiacomp.2008.03.001\n'},{id:"B27",body:'\nJones CD, Greenwood RH, Misra A, Bachmann MO. Incidence and progression of diabetic retinopathy during 17 years of a population-based screening program in England. Diabetes Care. 2012;35(3):592-596. DOI: 10.2337/dc11-0943\n'},{id:"B28",body:'\nBroe R, Rasmussen ML, Frydkjaer-Olsen U, Olsen BS, Mortensen HB, Peto T, et al. The 16-year incidence, progression and regression of diabetic retinopathy in a young population-based Danish cohort with type 1 diabetes mellitus: The Danish cohort of pediatric diabetes 1987 (DCPD1987). Acta Diabetologica. 2014;51(3):413-420. DOI: 10.1007/s00592-013-0527-1\n'},{id:"B29",body:'\nVarma R, Choudhury F, Klein R, Chung J, Torres M, Azen SP. Four-year incidence and progression of diabetic retinopathy and macular edema: the Los Angeles Latino Eye Study. American Journal of Ophthalmology. 2010;149(5):752-761. DOI: 10.1016/j.ajo.2009.11.014\n'},{id:"B30",body:'\nKlein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008;115(11):1859-1868. DOI: 10.1016/j.ophtha.2008.08.023\n'},{id:"B31",body:'\nCikamatana L, Mitchell P, Rochtchina E, Foran S, Wang JJ. Five-year incidence and progression of diabetic retinopathy in a defined older population: The Blue Mountains Eye Study. Eye (London, England). 2007;21(4):465-471\n'},{id:"B32",body:'\nLeske MC, Wu SY, Hennis A, Nemesure B, Schachat AP, Hyman L, et al. Nine-year incidence of diabetic retinopathy in the Barbados eye studies. Archives of Ophthalmology. 2006;124(2):250-255. DOI: 10.1001/archopht.124.2.250\n'},{id:"B33",body:'\nPedro RA, Ramon SA, Marc BB, Juan FB, Isabel MM. Prevalence and relationship between diabetic retinopathy and nephropathy, and its risk factors in the North-East of Spain: A population-based study. Ophthalmic Epidemiology. 2010;17(4):251-265. DOI: 10.3109/09286586.2010.498661\n'},{id:"B34",body:'\nEsteves JF, Kramer CK, Azevedo MJ, Stolz AP, Roggia MF, Larangeira A, et al. Prevalence of diabetic retinopathy in patients with type 1 diabetes mellitus. Revista da Associação Médica Brasileira. 2009;55(3):268-273. DOI: 10.1590/S0104-42302009000300017\n'},{id:"B35",body:'\nDutra Medeiros M, Mesquita E, Papoila AL, Genro V, Raposo JF. First diabetic retinopathy prevalence study in Portugal: RETINODIAB Study-Evaluation of the screening programme for Lisbon and Tagus Valley region. The British Journal of Ophthalmology. Oct 2015;99(10):1328-1333. DOI: 10.1136/bjophthalmol-2015-306727. [Epub 2 Apr 2015]\n'},{id:"B36",body:'\nKnudsen LL, Lervang HH, Lundbye-Christensen S, Gorst-Rasmussen A. The north Jutland county diabetic retinopathy study: Population characteristics. The British Journal of Ophthalmology. 2006;90(11):1404-1409. DOI: 10.1136/bjo.2006.093393\n'},{id:"B37",body:'\nJaki Mekjavić P, Jūratė Balčiūnienė V, Ćeklić L, Ernest J, Jamrichova Z, Zsolt Nagy Z, et al. The burden of macular diseases in Central and Eastern Europe-implications for healthcare systems. Value in Health Regional Issues. 2019;19:1-6. DOI: 10.1016/j.vhri.2018.11.002\n'},{id:"B38",body:'\nAl Ghamdi AH, Rabiu M, Hajar S, Yorston D, Kuper H, Polack S. Rapid assessment of avoidable blindness and diabetic retinopathy in Taif, Saudi Arabia. The British Journal of Ophthalmology. 2012;96(9):1168-1172. DOI: 10.1136/bjophthalmol-2012-301874\n'},{id:"B39",body:'\nBoelter MC, Gross JL, Canani LH, Costa LA, Lisboa HR, Três GS, et al. Proliferative diabetic retinopathy is associated with microalbuminuria in patients with type 2 diabetes. Brazilian Journal of Medical and Biological Research. 2006;39(8):1033-1039\n'},{id:"B40",body:'\nLópez M, Cos FX, Álvarez-Guisasola F, Fuster E. Prevalence of diabetic retinopathy and its relationship with glomerular filtration rate and other risk factors in patients with type 2 diabetes mellitus in Spain. DM2 HOPE study. Journal of Clinical & Translational Endocrinology. 2017;9:61-65. DOI: 10.1016/j.jcte.2017.07.004. eCollection 2017 Sep\n'},{id:"B41",body:'\nPark YH, Shin JA, Han JH, Park YM, Yim HW. The association between chronic kidney disease and diabetic retinopathy: the Korea National Health and Nutrition Examination Survey 2008-2010. PLoS ONE. 2015;10(4):e0125338. DOI: 10.1371/journal.pone.0125338 (eCollection 2015)\n'},{id:"B42",body:'\nWat N, Wong RL, Wong IY. Associations between diabetic retinopathy and systemic risk factors. Hong Kong Medical Journal. 2016;22(6):589-599 [Epub Oct 24, 2016]\n'},{id:"B43",body:'\nJeng CJ, Hsieh YT, Yang CM, Yang CH, Lin CL, Wang IJ. Diabetic retinopathy in patients with diabetic nephropathy: Development and progression. PLoS ONE. 2016;11(8):e0161897. DOI: 10.1371/journal.pone.0161897 (eCollection 2016)\n'},{id:"B44",body:'\nMan RE, Sasongko MB, Wang JJ, MacIsaac R, Wong TY, Sabanayagam C, et al. The association of estimated glomerular filtration rate with diabetic retinopathy and macular edema. Investigative Ophthalmology & Visual Science. 2015;56(8):4810-4816. DOI: 10.1167/iovs.15-16987\n'},{id:"B45",body:'\nMorrison JL, Hodgson LA, Lim LL, Al-Qureshi S. Diabetic retinopathy in pregnancy: A review. Clinical & Experimental Ophthalmology. 2016;44(4):321-334. DOI: 10.1111/ceo.12760 [Epub May 17, 2016]\n'},{id:"B46",body:'\nLövestam-Adrian M, Agardh CD, Aberg A, Agardh E. Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in Type 1 diabetic patients. Diabetic Medicine. 1997;14(12):1059-1065\n'},{id:"B47",body:'\nVestgaard M, Ringholm L, Laugesen CS, Rasmussen KL, Damm P, Mathiesen ER. Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 diabetes. Diabetic Medicine. 2010;27(4):431-435. DOI: 10.1111/j.1464-5491.2010.02958.x\n'},{id:"B48",body:'\nAlavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: Part I. Pathophysiology and prevention. Journal of the American Academy of Dermatology. 2014;70(1):1.e1-1.e18; quiz 19-20\n'},{id:"B49",body:'\nHwang DJ, Lee KM, Park MS, Choi SH, Park JI, Cho JH, et al. Association between diabetic foot ulcer and diabetic retinopathy. PLoS ONE. 2017;12(4):e0175270. DOI: 10.1371/journal.pone.0175270 (eCollection 2017)\n'},{id:"B50",body:'\nKaram T, Kamath YS, Rao LG, Rao KA, Shenoy SB, Bhandary SV. Diabetic retinopathy in patients with diabetic foot syndrome in South India. Indian Journal of Ophthalmology. 2018;66(4):547-550. DOI: 10.4103/ijo.IJO_1000_17\n'},{id:"B51",body:'\nHarris Nwanyanwu K, Talwar N, Gardner TW, Wrobel JS, Herman WH. Stein JD Predicting development of proliferative diabetic retinopathy. Diabetes Care. 2013;36(6):1562-1568\n'},{id:"B52",body:'\nChen X, Lu L. Depression in diabetic retinopathy: A review and recommendation for psychiatric management. Psychosomatics. 2016;57(5):465-471. DOI: 10.1016/j.psym.2016.04.003 [Epub Apr 22, 2016]\n'},{id:"B53",body:'\nRees G, Xie J, Fenwick EK, Sturrock BA, Finger R, Rogers SL, et al. Association between diabetes-related eye complications and symptoms of anxiety and depression. JAMA Ophthalmology. 2016;134(9):1007-1014. DOI: 10.1001/jamaophthalmol.2016.2213\n'},{id:"B54",body:'\nYekta Z, Xie D, Bogner HR, Weber DR, Zhang X, Harhay M, et al. The association of antidepressant medications and diabetic retinopathy among people with diabetes. Journal of Diabetes and its Complications. 2015;29(8):1077-1084. DOI: 10.1016/j.jdiacomp.2015.06.009 [Epub Jun 26, 2015]\n'},{id:"B55",body:'\nNicolau J, Rivera R, Francés C, Chacártegui B, Masmiquel L. Treatment of depression in type 2 diabetic patients: effects on depressive symptoms, quality of life and metabolic control. Diabetes Research and Clinical Practice. 2013;101(2):148-152. DOI: 10.1016/j.diabres.2013.05.009 [Epub Jun 22, 2013]\n'},{id:"B56",body:'\nSimó-Servat O, Hernández C, Simó R. Diabetic retinopathy in the context of patients with diabetes. Ophthalmic Research. 2019;24:1-7. DOI: 10.1159/000499541 [Epub ahead of print]\n'},{id:"B57",body:'\nLiao JL, Xiong ZY, Yang ZK, Hao L, Liu GL, Ren YP, et al. An association of cognitive impairment with diabetes and retinopathy in end stage renal disease patients under peritoneal dialysis. PLoS ONE. 2017;12(8):e0183965. DOI: 10.1371/journal.pone.0183965 (eCollection 2017)\n'},{id:"B58",body:'\nDong L, Lv XY, Wang BJ, Wang YQ , Mu H, Feng ZL, et al. Association of monocyte chemoattractant protein-1 (MCP-1)2518A/G polymorphism with proliferative diabetic retinopathy in northern Chinese type 2 diabetes. Graef’s Archive for Clinical and Experimental Ophthalmology. 2014;252(12):1921-1926. DOI: 10.1007/s00417-014-2651-1 [Epub May 9, 2014]\n'},{id:"B59",body:'\nDong L, Bai J, Jiang X, Yang MM, Zheng Y, Zhang H, et al. The gene polymorphisms of IL-8(−251T/A) and IP-10(-1596C/T) are associated with susceptibility and progression of type 2 diabetic retinopathy in northern Chinese population. Eye (London, England). 2017;31(4):601-607. DOI: 10.1038/eye.2016.287 [Epub Dec 9, 2016]\n'},{id:"B60",body:'\nKaidonis G, Gillies MC, Abhary S, Liu E, Essex RW, Chang JH, et al. A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients. Acta Diabetologica. 2016;53(4):643-650. DOI: 10.1007/s00592-016-0850-4 [Epub Mar 21, 2016]\n'},{id:"B61",body:'\nKaidonis G, Burdon KP, Gillies MC, Abhary S, Essex RW, Chang JH, et al. Common sequence variation in the VEGFC gene is associated with diabetic retinopathy and diabetic macular edema. Ophthalmology. 2015;122(9):1828-1836. DOI: 10.1016/j.ophtha.2015.05.004 [Epub Jun 11, 2015]\n'},{id:"B62",body:'\nGrassi MA, Tikhomirov A, Ramalingam S, Below JE, Cox NJ, Nicolae DL. Genome-wide meta-analysis for severe diabetic retinopathy. Human Molecular Genetics. 2011;20(12):2472-2481. DOI: 10.1093/hmg/ddr121 [Epub Mar 26, 2011]\n'},{id:"B63",body:'\nGraham PS, Kaidonis G, Abhary S, Gillies MC, Daniell M, Essex RW, et al. Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy. BMC Medical Genetics. 2018;19(1):71. DOI: 10.1186/s12881-018-0587-8\n'},{id:"B64",body:'\nTetikoğlu M, Yüksel Z, Aktas S, Sağdik HM, Özcura F. VEGF-A gene polymorphisms and responses to intravitreal ranibizumab treatment in patients with diabetic macular edema. International Ophthalmology. 2018;38(6):2381-2388. DOI: 10.1007/s10792-017-0738-5 [Epub Oct 13, 2017]\n'},{id:"B65",body:'\nEl-Shazly SF, El-Bradey MH, Tameesh MK. Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular oedema and its correlation with anti-vascular endothelial growth factor treatment outcomes. Clinical & Experimental Ophthalmology. 2014;42(4):369-378. DOI: 10.1111/ceo.12182 [Epub Sep 24, 2013]\n'},{id:"B66",body:'\nGrassi MA, Tikhomirov A, Ramalingam S, Lee KE, Hosseini SM, Klein BE, et al. Replication analysis for severe diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2012;53(4):2377-2381. DOI: 10.1167/iovs.11-8068\n'},{id:"B67",body:'\nTang J, Kern TS. Inflammation in diabetic retinopathy. Progress in Retinal and Eye Research. 2011;30(5):343-358. DOI: 10.1016/j.preteyeres.2011.05.002 [Epub May 25, 2011]\n'},{id:"B68",body:'\nSasongko MB, Wong TY, Jenkins AJ, Nguyen TT, Shaw JE, Wang JJ. Circulating markers of inflammation and endothelial function, and their relationship to diabetic retinopathy. Diabetic Medicine. 2015;32(5):686-691. DOI: 10.1111/dme.12640 [Epub Dec 9, 2014]\n'},{id:"B69",body:'\nDossarps D, Petit JM, Guiu B, Cercueil JP, Duvillard L, Bron AM, et al. Body fat distribution and adipokine secretion are not associated with diabetic retinopathy in patients with type 2 diabetes mellitus. Ophthalmic Research. 2014;51(1):42-45. DOI: 10.1159/000355323 [Epub Nov 2013]\n'},{id:"B70",body:'\nSari R, Balci MK, Apaydin C. The relationship between plasma leptin levels and chronic complication in patients with type 2 diabetes mellitus. Metabolic Syndrome and Related Disorders. 2010;8(6):499-503. DOI: 10.1089/met.2009.0127 [Epub Aug 17, 2010]\n'},{id:"B71",body:'\nYilmaz MI, Sonmez A, Acikel C, Celik T, Bingol N, Pinar M, et al. Adiponectin may play a part in the pathogenesis of diabetic retinopathy. European Journal of Endocrinology. 2004;151(1):135-140\n'},{id:"B72",body:'\nPeng JJ, Xiong SQ , Ding LX, Peng J, Xia XB. Diabetic retinopathy: Focus on NADPH oxidase and its potential as therapeutic target. European Journal of Pharmacology. 2019;853:381-387. DOI: 10.1016/j.ejphar.2019.04.038 [Epub Apr 19, 2019]\n'},{id:"B73",body:'\nZhang J, Upala S, Sanguankeo A Relationship between vitamin D deficiency and diabetic retinopathy: A meta-analysis Canadian Journal of Ophthalmology 2017;52 Suppl 1:S39-S44. doi: 10.1016/j.jcjo.2017.09.026\n'},{id:"B74",body:'\nCai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Current Opinion in Ophthalmology. 2017;28(6):636-643. DOI: 10.1097/ICU.0000000000000424\n'},{id:"B75",body:'\nDugel PU, Hillenkamp J, Sivaprasad S, Vögeler J, Mousseau MC, Wenzel A, et al. Baseline visual acuity strongly predicts visual acuity gain in patients with diabetic macular edema following anti-vascular endothelial growth factor treatment across trials. Clinical Ophthalmology. 2016;10:1103-1110. DOI: 10.2147/OPTH.S100764 (eCollection 2016)\n'},{id:"B76",body:'\nBressler SB, Odia I, Maguire MG, Dhoot DS, Glassman AR, Jampol LM, et al., Diabetic Retinopathy Clinical Research Network. Factors associated with visual acuity and central subfield thickness changes when treating diabetic macular edema with anti-vascular endothelial growth factor therapy: An exploratory analysis of the Protocol T randomized clinical trial. JAMA Ophthalmology. 1 Apr 2019;137(4):382-389. DOI: 10.1001/jamaophthalmol.2018.6786 [Epub ahead of print]\n'},{id:"B77",body:'\nCampos A, Campos EJ, do Carmo A, Caramelo F, Martins J, Sousa JP, et al. Evaluation of markers of outcome in real-world treatment of diabetic macular edema. Eye and Vision (Lond). 2018;5:27. DOI: 10.1186/s40662-018-0119-9 (eCollection 2018)\n'},{id:"B78",body:'\nBoyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, et al., Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914. DOI: 10.1016/j.ophtha.2014.04.024 [Epub Jun 4, 2014]\n'},{id:"B79",body:'\nChakravarthy U, Yang Y, Lotery A, Ghanchi F, Bailey C, Holz FG, et al. Clinical evidence of the multifactorial nature of diabetic macular edema. Retina. 2018;38(2):343-351. DOI: 10.1097/IAE.0000000000001555\n'},{id:"B80",body:'\nZur D, Iglicki M, Busch C, Invernizzi A, Mariussi M, Loewenstein A, et al., International Retina Group. OCT biomarkers as functional outcome predictors in diabetic macular edema treated with dexamethasone implant. Ophthalmology. 2018;125(2):267-275. DOI: 10.1016/j.ophtha.2017.08.031 [Epub Sep 19, 2017]\n'},{id:"B81",body:'\nCiulla TA, Bracha P, Pollack J, Williams DF. Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States. Ophthalmology Retina. 2018;2(12):1179-1187. DOI: 10.1016/j.oret.2018.06.004 [Epub Jul 29, 2018]\n'},{id:"B82",body:'\nPark KH, Kim YY, Jo YJ, Oh J, Lee JE, Lee JE, et al. Healthcare utilization and treatment patterns in diabetic macular edema in Korea: A retrospective chart review. Journal of Korean Medical Science. 2019;34(15):e118. DOI: 10.3346/jkms.2019.34.e118\n'},{id:"B83",body:'\nGao X, Obeid A, Aderman CM, Talcott KE, Ali FS, Adam MK, et al. Loss to follow-up after intravitreal anti-vascular endothelial growth factor injections in patients with diabetic macular edema. Ophthalmology Retina. 2019;3(3):230-236. DOI: 10.1016/j.oret.2018.11.002 [Epub Nov 10, 2018]\n'},{id:"B84",body:'\nWeiss M, Sim DA, Herold T, Schumann RG, Liegl R, Kern C, et al. Compliance and adherence of patients with diabetic macular edema to intravitreal anti-vascular endothelial growth factor therapy in daily practice. Retina. 2018;38(12):2293-2300. DOI: 10.1097/IAE.0000000000001892\n'},{id:"B85",body:'\nPhotocoagulation treatment of proliferative diabetic retinopathy: The second report of diabetic retinopathy study findings. The diabetic retinopathy study research group. Ophthalmology. 1978;85(1):82-106\n'},{id:"B86",body:'\nFlynn HW Jr, Chew EY, Simons BD, Barton FB, Remaley NA, Ferris FL 3rd. Pars plana vitrectomy in the early treatment diabetic retinopathy study. ETDRS report number 17. The Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1992;99(9):1351-1357\n'},{id:"B87",body:'\nYang CM. Surgical treatment for diabetic retinopathy: 5-Year experience. Journal of the Formosan Medical Association. 1998;97(7):477-484\n'},{id:"B88",body:'\nSakamoto M, Hashimoto R, Yoshida I, Ubuka M, Maeno T. Risk factors for neovascular glaucoma after vitrectomy in eyes with proliferative diabetic retinopathy. Clinical Ophthalmology. 2018;12:2323-2329. DOI: 10.2147/OPTH.S184959 (eCollection 2018)\n'},{id:"B89",body:'\nRamezani A, Ahmadieh H, Rozegar A, Soheilian M, Entezari M, Moradian S, et al. Predictors and outcomes of vitrectomy and silicone oil injection in advanced diabetic retinopathy. Korean Journal of Ophthalmology. 2017;31(3):217-229. DOI: 10.3341/kjo.2016.0018 [Epub May 12, 2017]\n'},{id:"B90",body:'\nYorston D, Wickham L, Benson S, Bunce C, Sheard R, Charteris D. Predictive clinical features and outcomes of vitrectomy for proliferative diabetic retinopathy. The British Journal of Ophthalmology. 2008;92(3):365-368. DOI: 10.1136/bjo.2007.124495\n'},{id:"B91",body:'\nFlaxel CJ, Dustin L, Kim J, Bekendam P, Row P. Outcome of diabetic vitrectomy in Latino population. Retina. 2007;27(9):1274-1278\n'},{id:"B92",body:'\nAbunajma MA, Al-Dhibi H, Abboud EB, Al Zahrani Y, Alharthi E, Alkharashi A, et al. The outcomes and prognostic factors of vitrectomy in chronic diabetic traction macular detachment. Clinical Ophthalmology. 2016;10:1653-1661. Published online Aug 26, 2016. DOI: 10.2147/OPTH.S98555\n'},{id:"B93",body:'\nBerrocal MH. All-probe vitrectomy dissection techniques for diabetic tractional retinal detachments: Lift and shave. Retina. 2018;38(Suppl 1):S2-S4. DOI: 10.1097/IAE.0000000000001884\n'},{id:"B94",body:'\nShroff CM, Gupta C, Shroff D, Atri N, Gupta P, Dutta R. Bimanual microincision vitreous surgery for severe proliferative diabetic retinopathy: Outcome in more than 300 eyes. Retina. 2018;38(Suppl 1):S134-S145. DOI: 10.1097/IAE.0000000000002093\n'},{id:"B95",body:'\nGabr H, Chen X, Zevallos-Carrasco OM, Viehland C, Dandrige A, Sarin N, et al. Visualization from intraoperative swept-source microscope-integrated optical coherence tomography in vitrectomy for complications of proliferative diabetic retinopathy. Retina. 2018;38(Suppl 1):S110-S120. DOI: 10.1097/IAE.0000000000002021\n'},{id:"B96",body:'\nBressler SB, Odia I, Glassman AR, Danis RP, Grover S, Hampton GR, et al. Changes in diabetic retinopathy severity when treating diabetic macular edema with ranibizumab: DRCR.net Protocol I: 5-Year report. Retina. 2018;38(10):1896-1904. DOI: 10.1097/IAE.0000000000002302\n'},{id:"B97",body:'\nSivaprasad S, Prevost AT, Vasconcelos JC, Riddell A, Murphy C, Kelly J, et al., Clarity Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): A multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet. 2017;389(10085):2193-2203. DOI: 10.1016/S0140-6736(17)31193-5 [Epub May 7, 2017]\n'},{id:"B98",body:'\nBressler SB, Beaulieu WT, Glassman AR, Gross JG, Melia M, Chen E, et al., Diabetic Retinopathy Clinical Research Network. Photocoagulation versus ranibizumab for proliferative diabetic retinopathy: Should baseline characteristics affect choice of treatment? Retina. 2019. DOI: 10.1097/IAE.0000000000002377 [Epub ahead of print]\n'},{id:"B99",body:'\nJampol LM, Odia I, Glassman AR, Baker CW, Bhorade AM, Han DP, et al., Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation versus ranibizumab for proliferative diabetic retinopathy: Comparison of peripapillary retinal nerve fiber layer thickness in a randomized clinical trial. Retina. 2019;39(1):69-78. DOI: 10.1097/IAE.0000000000001909\n'},{id:"B100",body:'\nChelala E, Nehme J, El Rami H, Aoun R, Dirani A, Fadlallah A, et al. Efficacy of intravitreal ranibizumab injections in the treatment of vitreous hemorrhage related to proliferative diabetic retinopathy. Retina. 2018;38(6):1127-1133. DOI: 10.1097/IAE.0000000000001673\n'},{id:"B101",body:'\nBonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Ranti–vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina. 2019;39(3):426-434. Published online Jan 3, 2019. DOI: 10.1097/IAE.0000000000002422\n'},{id:"B102",body:'\nObeid A, Su D, Patel SN, Uhr JH, Borkar D, Gao X, et al. Outcomes of eyes lost to follow-up with proliferative diabetic retinopathy that received panretinal photocoagulation versus intravitreal anti-vascular endothelial growth factor. Ophthalmology. 2019;126(3):407-413. DOI: 10.1016/j.ophtha.2018.07.027 [Epub Aug 2, 2018]\n'},{id:"B103",body:'\nWubben TJ, Johnson MW, Anti-VEGF Treatment Interruption Study Group 1. Anti-VEGF therapy for diabetic retinopathy: consequences of inadvertent treatment interruptions. American Journal of Ophthalmology. 2019. DOI: 10.1016/j.ajo.2019.03.005. pii: S0002-9394(19)30103-5 [Epub ahead of print]\n'},{id:"B104",body:'\nLang GE. Laser treatment of diabetic retinopathy. Developments in Ophthalmology. 2007;39:48-68. DOI: 10.1159/000098499\n'},{id:"B105",body:'\nHorsley MB, Kahook MY. Anti-VEGF therapy for glaucoma. Current Opinion in Ophthalmology. 2010;21(2):112-117\n'},{id:"B106",body:'\nWang JW, Zhou MW, Zhang X, Huang WB, Gao XB, Wang W, et al. Short-term effect of intravitreal ranibizumab on intraocular concentrations of vascular endothelial growth factor-A and pigment epithelium-derived factor in neovascular glaucoma. Clinical & Experimental Ophthalmology. 2015;43(5):415-421\n'},{id:"B107",body:'\nOlmos LC, Sayed MS, Moraczewski AL, et al. Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab. Eye (London, England). 2016;30(3):463-472. DOI: 10.1038/eye.2015.259\n'},{id:"B108",body:'\nSrinivasan S, Raman R, Ganesan S, Roy R, Natarajan V, Sharma T. Four-year incidence and progression of visual impairment in a South Indian population with diabetes. Indian Journal of Ophthalmology. 2017;65(7):589-595. DOI: 10.4103/ijo.IJO_520_16\n'},{id:"B109",body:'\nChew EY, Benson WE, Remaley NA, Lindley AA, Burton TC, Csaky K, et al. 3rd Results after lens extraction in patients with diabetic retinopathy: early treatment diabetic retinopathy study report number 25. Archives of Ophthalmology. 1999;117:1600-1606\n'},{id:"B110",body:'\nDiabetic Retinopathy Clinical Research Network Authors/Writing Committee, Baker CW, Almukhtar T, Bressler NM, Glassman AR, Grover S, et al. Macular edema after cataract surgery in eyes without preoperative central-involved diabetic macular edema. JAMA Ophthalmology. 2013;131:870-879\n'},{id:"B111",body:'\nDanis RP, Sadda S, Li XY, Cui H, Hashad Y, Whitcup SM. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials. The British Journal of Ophthalmology. 2016;100:796-801\n'},{id:"B112",body:'\nGreenberg PB, Tseng VL, Wu WC, Liu J, Jiang L, Chen CK, et al. Prevalence and predictors of ocular complications associated with cataract surgery in United States veterans. Ophthalmology. 2011;118:507-514\n'},{id:"B113",body:'\nEgan C, Zhu H, Lee A, Sim D, Mitry D, Bailey C, et al., UK AMD and DR EMR Users Group. The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: Baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema. The British Journal of Ophthalmology. 2017;101(1):75-80\n'},{id:"B114",body:'\nLiao SB. Ku WC Progression of diabetic retinopathy after phacoemulsification in diabetic patients: a three-year analysis. Chang Gung Medical Journal. 2003;26(11):829-834\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Maya Georgieva Pandova",address:"mpandova@kockw.com;, mayapandova@gmail.com",affiliation:'
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Its main modulation concept lies in single photon generation on sidebands of optical carrier and determination of photons ground state through its registration and the amplitude value of its carrier frequency as reference channel. So, it is necessary to solve problems of signal-to-carrier ratio of single photon detector (SPD) and aspects of photon number splitting (PNS) attack, nonlinear phase modulation (NPM) between carrier and sidebands in fiber, and finally, spectral selection of carrier in receiver. The technologies, based on the modulation conversion of an optical carrier, are widely used in microwave photonics. Due to the natural symmetry of modulated signals and the highest achievable ratio of the modulation conversions, amplitude-phase modulation with complete or partial suppression of the optical carrier has found a particularly wide application in MPS. The characteristics of advanced MPS for QKD with frequency coding and carrier suppression based on tandem amplitude modulation and phase commutation are presented. New systems can have classical symmetric or non-classical asymmetric structure for QKD based only on spectral selection of carrier and subcarriers without re-modulation.",book:{id:"5779",slug:"advanced-technologies-of-quantum-key-distribution",title:"Advanced Technologies of Quantum Key Distribution",fullTitle:"Advanced Technologies of Quantum Key Distribution"},signatures:"Oleg G. Morozov, Airat J. Sakhabutdinov, Gennady A. Morozov and\nIl’daris M. 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The ambiguities surrounding of the digital currency still leave enough space for the analysis of its unreserved acceptance, trust and anticipation, which are the main driver for the spread of the network. Banks should carefully consider the technology underlying these cryptocurrencies as a potential generic new way of transferring ownership of the value over the long term. The chapter provides an analysis of the use of cryptocurrencies in general, especially Bitcoin as the technology adoption in the presence of network externalities. The objective attitude is the future of the digital currency in the moment is still unsolved issue due to the existence of “critical mass”. Further, the chapter explores financial privacy which is very sensitive issue in using digital currency (or cryptocurrency) and discuss about private choices versus political rules. The research has shown that the future of cryptocurrencies can be bright if some institutional-formal conditions are met due to the fact that success evolution of e-money requires building safety payments through three criteria–standardization, compatibility and innovation.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Tatjana Boshkov",authors:[{id:"246137",title:"Ph.D.",name:"Tatjana",middleName:null,surname:"Boshkov",slug:"tatjana-boshkov",fullName:"Tatjana Boshkov"}]},{id:"63116",doi:"10.5772/intechopen.80450",title:"Quantum Key Distribution (QKD) over Software-Defined Optical Networks",slug:"quantum-key-distribution-qkd-over-software-defined-optical-networks",totalDownloads:1338,totalCrossrefCites:5,totalDimensionsCites:5,abstract:"Optical network security is attracting increasing research interest. Currently, software-defined optical network (SDON) has been proposed to increase network intelligence (e.g., flexibility and programmability) which is gradually moving toward industrialization. However, a variety of new threats are emerging in SDONs. Data encryption is an effective way to secure communications in SDONs. However, classical key distribution methods based on the mathematical complexity will suffer from increasing computational power and attack algorithms in the near future. Noticeably, quantum key distribution (QKD) is now being considered as a secure mechanism to provision information-theoretically secure secret keys for data encryption, which is a potential technique to protect communications from security attacks in SDONs. This chapter introduces the basic principles and enabling technologies of QKD. Based on the QKD enabling technologies, an architecture of QKD over SDONs is presented. Resource allocation problem is elaborated in detail and is classified into wavelength allocation, time-slot allocation, and secret key allocation problems in QKD over SDONs. Some open issues and challenges such as survivability, cost optimization, and key on demand (KoD) for QKD over SDONs are discussed.",book:{id:"7376",slug:"quantum-cryptography-in-advanced-networks",title:"Quantum Cryptography in Advanced Networks",fullTitle:"Quantum Cryptography in Advanced Networks"},signatures:"Yongli Zhao, Yuan Cao, Xiaosong Yu and Jie Zhang",authors:[{id:"199527",title:"Associate Prof.",name:"Yongli",middleName:null,surname:"Zhao",slug:"yongli-zhao",fullName:"Yongli Zhao"}]},{id:"59491",doi:"10.5772/intechopen.74234",title:"Security of Quantum Key Distribution Protocols",slug:"security-of-quantum-key-distribution-protocols",totalDownloads:1149,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Quantum key distribution (QKD), another name for quantum cryptography, is the most advanced subfield of quantum information and communication technology (QICT). The first QKD protocol was proposed in 1984, and since then, more protocols have been proposed. It uses quantum mechanics to enable secure exchange of cryptographic keys. In order to have high confidence in the security of the QKD protocols, such protocols must be proven to be secure against any arbitrary attacks. In this chapter, we discuss and demonstrate security proofs for QKD protocols. Security analysis of QKD protocols can be categorised into two techniques, namely infinite-key and finite-key analyses. Finite-key analysis offers more realistic results than the infinite-key one, while infinite-key analysis provides more simplicity. We briefly provide the background of QKD and also define the basic notion of security in QKD protocols. The cryptographic key is shared between Alice and Bob. Since the key is random and unknown to an eavesdropper, Eve, she is unable to learn anything about the message simply by intercepting the ciphertext. This phenomenon is beyond the ability of classical information processing. We then study some tools that are used in the derivation of security proofs for the infinite- and finite-length key limits.",book:{id:"5779",slug:"advanced-technologies-of-quantum-key-distribution",title:"Advanced Technologies of Quantum Key Distribution",fullTitle:"Advanced Technologies of Quantum Key Distribution"},signatures:"Mhlambululi Mafu and Makhamisa Senekane",authors:[{id:"196378",title:"Dr.",name:"Mhlambululi",middleName:null,surname:"Mafu",slug:"mhlambululi-mafu",fullName:"Mhlambululi Mafu"},{id:"210180",title:"Dr.",name:"Makhamisa",middleName:null,surname:"Senekane",slug:"makhamisa-senekane",fullName:"Makhamisa Senekane"}]},{id:"62627",doi:"10.5772/intechopen.79386",title:"Modeling Bitcoin Price and Bubbles",slug:"modeling-bitcoin-price-and-bubbles",totalDownloads:1692,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The goal of this chapter is to present recent developments about Bitcoin1 price modeling and related applications. Precisely, we consider a bivariate model in continuous time to describe the behavior of Bitcoin price and of the investors’ attention on the overall network. The attention index affects Bitcoin price through a suitable dependence on the drift and diffusion coefficients and a possible correlation between the sources of randomness represented by the driving Brownian motions. The model is fitted on historical data of Bitcoin prices, by considering the total trading volume and the Google Search Volume Index as proxies for the attention measure. Moreover, a closed formula is computed for European-style derivatives on Bitcoin. Finally, we discuss two possible extensions of the model. Precisely, we investigate the relation between the correlation parameter and possible bubble effects in the asset price; further, we consider a multivariate framework to represent the special feature of Bitcoin being traded on several exchanges and we discuss conditions to rule out arbitrage opportunities in this setting.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Alessandra Cretarola and Gianna Figà-Talamanca",authors:[{id:"246178",title:"Prof.",name:"Alessandra",middleName:null,surname:"Cretarola",slug:"alessandra-cretarola",fullName:"Alessandra Cretarola"},{id:"246179",title:"Prof.",name:"Gianna",middleName:null,surname:"Figà-Talamanca",slug:"gianna-figa-talamanca",fullName:"Gianna Figà-Talamanca"}]}],mostDownloadedChaptersLast30Days:[{id:"62481",title:"Blockchain and Digital Currency in the World of Finance",slug:"blockchain-and-digital-currency-in-the-world-of-finance",totalDownloads:2009,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"High-tech enables payment evolution and global competition. The ambiguities surrounding of the digital currency still leave enough space for the analysis of its unreserved acceptance, trust and anticipation, which are the main driver for the spread of the network. Banks should carefully consider the technology underlying these cryptocurrencies as a potential generic new way of transferring ownership of the value over the long term. The chapter provides an analysis of the use of cryptocurrencies in general, especially Bitcoin as the technology adoption in the presence of network externalities. The objective attitude is the future of the digital currency in the moment is still unsolved issue due to the existence of “critical mass”. Further, the chapter explores financial privacy which is very sensitive issue in using digital currency (or cryptocurrency) and discuss about private choices versus political rules. The research has shown that the future of cryptocurrencies can be bright if some institutional-formal conditions are met due to the fact that success evolution of e-money requires building safety payments through three criteria–standardization, compatibility and innovation.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Tatjana Boshkov",authors:[{id:"246137",title:"Ph.D.",name:"Tatjana",middleName:null,surname:"Boshkov",slug:"tatjana-boshkov",fullName:"Tatjana Boshkov"}]},{id:"63090",title:"Cryptocurrency Returns",slug:"cryptocurrency-returns",totalDownloads:1450,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"One of the most significant innovations in the world of finance has been the creation and evolvement of cryptocurrencies. These digital means of exchange have been the focus of extensive news coverage, especially the Bitcoin, with a primary focus on the tremendous potential return and the high level of accompanying risk. In this chapter, we examine the risk-return pattern for an array of cryptocurrencies, contrasting the pattern with those of conventional currency and equity investments. We find the measures of cryptocurrency returns and risk to be a very high multiple of those of conventional investments, and the pattern is determined to be robust relative to the time frame. Consequently, cryptocurrencies are determined to provide an alternative to investors that involves tremendously high risk and return.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Mike Cudd, Kristen Ritterbush, Marcelo Eduardo and Chris Smith",authors:[{id:"254939",title:"Dr.",name:"Mike",middleName:null,surname:"Cudd",slug:"mike-cudd",fullName:"Mike Cudd"}]},{id:"62430",title:"On the Origin of the Value of Cryptocurrencies",slug:"on-the-origin-of-the-value-of-cryptocurrencies",totalDownloads:1297,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Bitcoin and other cryptocurrencies received a lot of criticism during the last 9 years. It is not surprising that this criticism came from organizations that are threatened by the crypto revolution (banks, government, central banks, finance companies, etc.). Nevertheless, it is very surprising to hear criticism from economics schools, which oppose central banking and advocate free choice in currencies (such as the Austrian school of economics). Unlike the ordinary criticism (that Bitcoin is a scam, a bubble, etc.), which can easily be refuted, the criticism of part of the Austrian school economists is based on interesting arguments, which requires a different level of explanation. For example, it was claimed that Bitcoin should be worthless; otherwise, it contradicts Mises’ regression theorem. The object of the chapter is twofold: first to explain why the criticism is unfounded and second to analyze the origin of the value of Bitcoin and other cryptocoins from the perspective of the Austrian school of economics. In particular, it is explained that Bitcoin does not contradict the regression theorem for two reasons. First, the initial value estimation can be a random event, and second, the Bitcoin network (even now) has a nonmonetary value.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Er'el Granot",authors:[{id:"181601",title:"Prof.",name:"Er'El",middleName:null,surname:"Granot",slug:"er'el-granot",fullName:"Er'El Granot"}]},{id:"62627",title:"Modeling Bitcoin Price and Bubbles",slug:"modeling-bitcoin-price-and-bubbles",totalDownloads:1692,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The goal of this chapter is to present recent developments about Bitcoin1 price modeling and related applications. Precisely, we consider a bivariate model in continuous time to describe the behavior of Bitcoin price and of the investors’ attention on the overall network. The attention index affects Bitcoin price through a suitable dependence on the drift and diffusion coefficients and a possible correlation between the sources of randomness represented by the driving Brownian motions. The model is fitted on historical data of Bitcoin prices, by considering the total trading volume and the Google Search Volume Index as proxies for the attention measure. Moreover, a closed formula is computed for European-style derivatives on Bitcoin. Finally, we discuss two possible extensions of the model. Precisely, we investigate the relation between the correlation parameter and possible bubble effects in the asset price; further, we consider a multivariate framework to represent the special feature of Bitcoin being traded on several exchanges and we discuss conditions to rule out arbitrage opportunities in this setting.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Alessandra Cretarola and Gianna Figà-Talamanca",authors:[{id:"246178",title:"Prof.",name:"Alessandra",middleName:null,surname:"Cretarola",slug:"alessandra-cretarola",fullName:"Alessandra Cretarola"},{id:"246179",title:"Prof.",name:"Gianna",middleName:null,surname:"Figà-Talamanca",slug:"gianna-figa-talamanca",fullName:"Gianna Figà-Talamanca"}]},{id:"62478",title:"The Condition of the Cryptocurrency Market and Exchanges in Poland",slug:"the-condition-of-the-cryptocurrency-market-and-exchanges-in-poland",totalDownloads:1042,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The development of the cryptocurrency market and the implications for the whole economy and finance for all traders cause a keen interest in this subject. The chapter discusses the functioning of a financial system based on cryptocurrencies and its significance for economies. In this chapter, the development of the global cryptocurrency market was presented and the history of the most popular cryptocurrency, bitcoin, was analyzed. The analysis and the assessment of the state and structure of the Polish cryptocurrencies market were presented on the background of the global cryptocurrency market. Also, we presented the possible development paths for the cryptocurrencies market in Poland and in the world.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Ireneusz Miciuła",authors:[{id:"243649",title:"Dr.Ing.",name:"Ireneusz",middleName:null,surname:"Miciuła",slug:"ireneusz-miciula",fullName:"Ireneusz Miciuła"}]}],onlineFirstChaptersFilter:{topicId:"531",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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