",isbn:"978-1-80355-463-1",printIsbn:"978-1-80355-462-4",pdfIsbn:"978-1-80355-464-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"0c1bf8695b453c7d16f51eb4ec3c3ae6",bookSignature:"Dr. Redmond R. Shamshiri and Dr. Sanaz Shafian",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11343.jpg",keywords:"Digital Farming, Wireless Sensors, Internet-of-Things, Digital Twin, Cloud Computing, Big Data Analysis, Data Labeling, Data Sharing, Agriculture 4.0, Precision Technology, E-agriculture, Automated Farms",numberOfDownloads:37,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 10th 2021",dateEndSecondStepPublish:"November 18th 2021",dateEndThirdStepPublish:"January 17th 2022",dateEndFourthStepPublish:"April 7th 2022",dateEndFifthStepPublish:"June 6th 2022",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shamshiri is a Member of the International Society of Precision Agriculture and a Member of the American Society of Agricultural and Biological Engineering. He is a scientist at the Leibniz-Institut für Agrartechnik und Bioökonomie working toward digitization of agriculture for food security.",coeditorOneBiosketch:"Sanaz is an Assistant Professor of Smart Farming at Virginia Tech University. Prior to this, she was an assistant professor at the University of Idaho. Her expertise lies in using advanced technologies and methodologies for economically and environmentally sustainable crops and trees monitoring and management. She integrates satellite/drone images and AI to develop methodologies for environmental monitoring, crop modeling, and water, and nutrient conservation.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203413",title:"Dr.",name:"Redmond R.",middleName:null,surname:"Shamshiri",slug:"redmond-r.-shamshiri",fullName:"Redmond R. Shamshiri",profilePictureURL:"https://mts.intechopen.com/storage/users/203413/images/system/203413.png",biography:"Dr. Redmond R. Shamshiri holds a Ph.D. in agricultural automation with a focus on control systems and dynamics. He is a scientist at the Leibniz-Institut für Agrartechnik und Bioökonomie working toward digitization of agriculture for food security. His main research fields include simulation and modeling for closed-field plant production systems, LPWAN sensors, wireless control, and autonomous navigation. His work has appeared in over 100 publications, including peer-reviewed journal papers, book chapters, and conference proceedings. He is a member of the Adaptive AgroTech Consultancy Network and serves as a section editor and reviewer for various high-ranking journals in the field of smart farming.",institutionString:"Leibniz Institute of Agricultural Engineering and Bio-economy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Leibniz Institute for Agricultural Engineering Potsdam-Bornim",institutionURL:null,country:{name:"Germany"}}}],coeditorOne:{id:"429704",title:"Dr.",name:"Sanaz",middleName:null,surname:"Shafian",slug:"sanaz-shafian",fullName:"Sanaz Shafian",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003CPbhJQAT/Profile_Picture_1629955207151",biography:"Sanaz is an Assistant Professor of Smart Farming at Virginia Tech University. Prior to this she was assistant professor at University of Idaho. Her expertise lies in remote sensing research, with a focus on using advanced technologies and methodologies for economically and environmentally sustainable crops and trees monitoring and management. She integrates satellite/drone images and AI to develop methodologies for environmental monitoring, crop modeling and water and nutrient conservation and she has published widely on these topics. She has been involved in several USDA projects. With University of Idaho, she led an educational and outreach project to initiate Precision Agriculture certificate. 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1. Introduction
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Vitamin B12 deficiency remains a worldwide health problem in the 21st century. The advent of metabolite assays in the last few decades further expands the population with subclinical or tissue deficiency and thus the magnitude of the problem. The increasing recognition of its association with the use of metformin raises another controversy for clinicians regarding detection and treatment of vitamin B12 deficiency. Since the clinical use of metformin in 1957, malabsorption of vitamin B12 in diabetic patients treated with metformin was first noted in 1969 (Berchtold et al., 1969). Subsequent studies revealed both short-term and long-term use of metformin induces malabsorption of vitamin B12 and causes decreased serum vitamin B12 concentrations in 10% to 30% of diabetic patients (Tomkin et al., 1971; Bauman et al., 2000; Wulffele el al., 2003; Hermann et al., 2004). A randomized placebo controlled Dutch trial recently reconfirmed this finding and demonstrated treatment with metformin for a mean of 4.3 years resulted not only in a 19% persistent and progressive reduction of mean serum vitamin B12 concentrations, but also raised serum homocysteine concentrations (de Jager et al., 2010). Other case-control and cross-sectional studies identified duration and dosage of metformin use as risk factors for vitamin B12 deficiency (Ting et al., 2006). It is believed that if individuals with type 2 diabetes receiving metformin develop low serum vitamin B12 concentrations, a stage of asymptomatic tissue deficiency, would eventually progress to symptomatic clinical deficiency, as evidenced by reports of megaloblastic anaemia caused by metformin-related vitamin B12 malabsorption, unless they are duly treated (Gilligan, 2002; Filioussi et al., 2003; Liu et al., 2006).
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Metformin is now extensively used as the first line pharmacological agent for glycaemic control especially following the favourable results of the United Kingdom Prospective Diabetes Study (UKPDS 34) in 1998. This coupled with the rising incidence of type 2 diabetes in many parts of the world constitutes a driving force for relevant parties to make appropriate recommendations or guidelines concerning the detection and treatment of vitamin B12 deficiency among diabetic patients on metformin. Although the haematological and neurological manifestations of overt or clinical vitamin B12 deficiency are easy to diagnose, they are often overlooked and attributed to diabetic complications or aging among diabetic patients.
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The present study attempts to address the issue from the end spectrum of the disorder - florid vitamin B12 deficiency in type 2 diabetic patients. Through description and analysis of the clinical manifestations of overt vitamin B12 deficiency in a cohort of adult Chinese patients with type 2 diabetes, and delineation of the underlying aetiology of vitamin B12 deficiency, the study aims to highlight the characteristics of vitamin B12 deficiency in type 2 diabetic patients, and to evaluate the implications of metformin use in relation to the development of vitamin B12 deficiency of undetermined origin in diabetic patients.
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2. Materials and methods
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2.1. Patient source and stratification
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The patient source was from a longitudinal study of adult Chinese patients (≥ 18 years) presenting with megaloblastic anaemia and/or neurological deficits in association with low serum vitamin B12 levels serially encountered in a regional hospital in Hong Kong between May 1994 and October 2010 (Chan et al., 2008). According to whether they had type 2 diabetes as shown by the diagnostic codes in the medical records at the time of diagnosis of vitamin B12 deficiency, patients were stratified into diabetic and non-diabetic groups. Documentation of diagnosis of diabetes was at the discretion of in-charge physicians and the diagnostic criteria of World Health Organization (WHO, 1999) with fasting plasma glucose ≥7.0 mmol/L or 2-hour post prandial plasma glucose ≥11.1 mmol/L were adopted. Diabetes both with and without complications were included. Diabetic patients were further stratified according to whether they were on metformin at the time of diagnosis of vitamin B12 deficiency. Diabetic patients who had been on metformin for one or more years immediately before the diagnosis of vitamin B12 deficiency were counted as metformin users and assigned to the “on metformin” group. Other diabetic patients on dietary control, insulin, sulphonylureas, metformin for less than one year or longer period but having stopped in the one year before the diagnosis of vitamin B12 deficiency, were assigned to the “not on metformin” group.
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2.2. Data collection and analysis
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Baseline data were retrieved from patients’ medical records and investigators’ file of adult Chinese patients with vitamin B12 deficiency. Data entry included presenting clinical and laboratory features at the time of diagnosis of vitamin B12 deficiency; causes of vitamin B12 deficiency; medications including metformin, sulphonylureas, insulin, proton pump inhibitors (PPI), histamine 2 blockers (H2B), lipid lowering agents, antiplatelet agents, antihypertensive and cardiac agents; duration of metformin use; and duration of diabetic history.
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The sequence of data analysis was shown in Box 1.
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The presenting features and the causes of vitamin B12 deficiency were compared between patients with and without type 2 diabetes. The odds ratio (OR) of developing vitamin B12 deficiency of undetermined origin among diabetic patients to non-diabetic patients was determined.
The presenting features and the causes of vitamin B12 deficiency were compared between type 2 diabetic patients “on metformin” and diabetic patients “not on metformin”. The OR of developing vitamin B12 deficiency of undetermined origin among diabetic patients “on metformin” to patients “not on metformin” was determined.
For diabetic patients with undetermined aetiology of vitamin B12 deficiency, the presenting features and the medications prescribed at the time of diagnosis of vitamin B12 deficiency were compared between those “on metformin” and those “not on metformin”.
The duration of metformin use in relation to the onset of vitamin B12 deficiency was studied among all diabetic patients on metformin, irrespective of the underlying aetiology of vitamin B12 deficiency.
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2.3. Definitions
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Known causes of vitamin B12 deficiency include
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pernicious anaemia (PA) defined by the presence of serum intrinsic factor (IF) antibody and/or by abnormal Schilling test compatible with immune loss of IF;
probable PA (PPA) defined by the absence of demonstrable IF antibody, no performance of Schilling test, and the presence of at least 2 out of 3 immune features – gastric parietal cell (GPC) antibody, antithyroid antibodies, and histological evidence of autoimmune gastropathy (J.C.W. Chan & F.H.Y. Chan, 2011);
gastrointestinal disorders such as total gastrectomy and terminal ileal resection or diseases e.g. Crohn’s disease, ulcerative colitis;
nutritional deficiency in strict vegetarians. Only after excluding PA and PPA, the first two overriding causes, gastrointestinal and nutritional causes are considered.
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The cause of vitamin B12 deficiency is considered to be undetermined if none of the above conditions are present. Common predisposing factors for the development of vitamin B12 deficiency of undetermined causes include food cobalamin malabsorption, idiopathic gastric atrophy, Helicobacter pylori (HP) associated gastritis, use of PPI and H2B, metformin related malabsorption of vitamin B12, and a multitude of other conditions all of which currently lack easily available confirmatory tools and are diagnosed largely by exclusion. Known causes of vitamin B12 deficiency and the diagnostic approach to arrive at the conclusion of undetermined aetiology of vitamin B12 deficiency are summarized in Box 2.
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2.4. Measurements
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Serum cobalamin was measured with a fluorometric method using Abbott IMX analyzer (Abbott Laboratory, Chicago, IL) from 1994 to 2002; and with a chemiluminescent immunoassay using paramagnetic particles of Access Immunoassay System (Beckman Coulter, Fullerton, CA) from 2003 to 2010. Reference range for serum vitamin B12 level was 132–835 pmol/L from 1994 to 2002, and 180–914 ng/L from 2003 to 2010. To facilitate analysis, serum vitamin B12 levels in pmol/L were converted to ng/L by using the equation, 1 pmol/L=1.355 ng/L, (molecular mass of vitamin B12=1355 mol/g). Vitamin B12 deficiency was defined by serum vitamin B12 levels below 132 pmol/L or below 180 ng/L.
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, Illinosis, USA), version 15. Data were reported as means and standard deviation (SD), or as medians and interquartile range (IQR). The chi-square test was used for comparison between categorical variables, Student’s t test for continuous variables of normal distribution, and Mann-Whitney U test for continuous data of skewed distribution. P values of less than 0.05 were considered to indicate statistical significance. Among patients with B12 deficiency, a chi-square analysis (two-tailed; two-by-two table) was used to estimate the crude OR of having B12 deficiency of undetermined origin among patients with type 2 diabetes to those without diabetes, and another chi-square analysis (two-tailed; two-by-two table) was used to calculate the crude OR of having B12 deficiency of undetermined origin among patients taking metformin to the diabetic patients not taking metformin. Multivariate analysis using stepwise forward logistic regression were used to identify risk factors independently associated with vitamin B12 deficiency of undetermined origin in all patients and in diabetic patients; and in diabetic patients on metformin and not on metformin. Extended Mantel-Haenzel chi-square analysis was performed for linear trend.
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3. Results
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Between May 1994 and October 2010, 635 adult Chinese patients (excluding 1 patient with type 1 diabetes and PA diagnosed at the age of 14 years old) were diagnosed to have overt vitamin B12 deficiency in a regional hospital in Hong Kong. At the time of diagnosis of vitamin B12 deficiency, 191 (30%) patients had type 2 diabetes, and 444 (70%) were non-diabetics.
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3.1. Vitamin B12 deficiency: Type 2 diabetic and non-diabetic patients
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Concerning the demographic features (Table 1), 37% of 191 diabetic patients and 44% of 444 non-diabetic patients were male (p=0.079), and the mean ages of diabetic and non-diabetic patients were 75.6 years (SD 9.1) and 72.3 years (SD 14.5) respectively (p=0.001). The clinical manifestations of vitamin B12 deficiency were less symptommatic in diabetic than non-diabetic patients, as evidenced by 34% of diabetic and 47% of non-diabetic patients having anaemia (p=0.002), and 3% of diabetic and 7% of non-diabetic patients having peripheral
Comparison of presenting features and causes of vitamin B12 deficiency: type 2 diabetic and non-diabetic patients
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neuropathy and/or subacute combined degeneration of cord (p=0.036). Dementia was the presenting feature in 8% of diabetic and 9% of non-diabetic patients (p=0.574). The mean haemoglobin (Hb) concentrations of diabetic and non-diabetic patients were 9.8 g/L (SD 2.5) and 9.0 g/L (SD 2.9) respectively (p=0.001), and the mean mean corpuscular volume (MCV) of the two groups were 110.0 fl (SD 12.1) and 113.4 fl (SD 15.4) respectively (p=0.003). The mean serum vitamin B12 levels of diabetic and non-diabetic patients were 85.8 ng/L (SD 38.1) and 80.0 ng/L (SD 41.9) respectively (p=0.106). Serum IF antibody was detected in 26% of diabetic and 56% of non-diabetic patients (p<0.001); GPC antibody in 38% of diabetic and 56% of non-diabetic patients (p<0.001); and anti-thyroid antibodies in 16% of diabetic and 37% of non-diabetic patients (p<0.001). History of autoimmune thyroid disease (AITD) was obtained in 2% of diabetic and 7% of non-diabetic patients (p=0.021). Endoscopically proven gastric atrophy was detected in 31% of diabetic and 44% of non-diabetic patients (p=0.052), enterochromaffin cell hyperplasia (ECH) in 0% of diabetic and 3% of non-diabetic patients (p=0.114), and HP organisms in 13% of diabetic and 8% of non-diabetic patients (p=0.263).
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The underlying aetiology of vitamin B12 deficiency was undetermined in 68% of diabetic and 30% of non-diabetic patients (p<0.001); due to PA in 28% of diabetic and 60% of non-diabetic patients (p<0.001); PPA in 2% of diabetic and 3% of non-diabetic patients (p=0.384); related to gastrointestinal surgery or disorders in 1% of diabetic and 5% of non-diabetic patients (p=0.011); and malnutrition in 1% of diabetic and 2% of non-diabetic patients (p=0.484). The percentages of patients with vitamin B12 deficiency of undetermined origin, due to PA, and other known causes (PPA, gastrointestinal disorders, malnutrition) among diabetic and non-diabetic patients were shown in Figure 1. The crude OR of developing vitamin B12 deficiency of undetermined origin in type 2 diabetic patients compared with non-diabetic patients was 4.90 (95% CI, 3.41- 7.08). The adjusted OR (adjusted for sex, age, use of PPI/H2B) of developing vitamin B12 deficiency of undetermined origin in type 2 diabetic patients compared with non-diabetic patients was 5.54 (95% CI, 3.66 – 8.38).
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Figure 1.
Comparison of causes of vitamin B12 deficiency: type 2 diabetic and non-diabetic patients
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3.2. Vitamin B12 deficiency: type 2 diabetic patients “on metformin” and “not on metformin”
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Among the 191 patients with type 2 diabetes, 5 patients with unclear metformin history were excluded from analysis, and 186 patients – 128 (69%) “on metformin” and 58 (31%) “not on metformin” were analysed (Table 2). Of the 128 patients “on metformin”, 30% were male, and of the 58 patients “not on metformin”, 50% were male (p=0.008). The mean ages of patients “on metformin” and “not on metformin” were 75.3 years [SD 9.2] and 76.3 years [SD 9.2] respectively (p=0.463). Thirty one percent of patients “on metformin” and 36% of patients “not on metformin” presented with anaemia (p=0.505); 0.8% of patients “on metformin” and 7% of patients “not on metformin” had peripheral neuropathy and/or subacute combined degeneration of cord (p=0.017), and 9% of patients “on metformin” and 3% of “not on metformin” had dementia (p=0.156). The mean Hb concentrations of patients “on metformin” and “not on metformin” were 9.9 g/L [SD 2.4] and 9.7 g/L [SD 2.6] respectively (p=0.498), and the mean MCV 108.5 fl [SD 12.0] and 112.1 fl [SD 11.9] respectively (p=0.058). The mean serum
Comparison of presenting features and causes of vitamin B12 deficiency: type 2 diabetic patients “on metformin” and “not on metformin”
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B12 levels of patients “on metformin” and “not on metformin” were 90.3 ng/L [SD 37.6] and 76.7 ng/L [SD 38.6] respectively (p=0.026). Frequencies of IF antibody in the “on metformin” and “not on metformin” groups were 16% and 41% respectively (p<0.001), that of GPC antibody 32% and 52% respectively (p=0.012), and that of anti-thyroid antibodies 13% and 26% respectively (p=0.050). History of AITD was obtained in 2.3% of patients “on metformin” and 1.7% of patients “not on metformin” (p=0.787). Histological evidence of gastric atrophy was detected in 17% of patients “on metformin” and 46% of patients “not on metformin” (p=0.005), ECH in none of the patients in the two groups, and HP organisms in 17% of patients “on metformin” and 7% of patients “not on metformin” (p=0.236). The median duration of diabetic history for those “on metformin” (n=121) and “not on metformin” (n=41) were 10 years [IQR 6.5-11.5] and 4 years [IQR 1.5-8.5] respectively (p<0.001).
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Of the 128 diabetic patients “on metformin” and 58 diabetic patients “not on metformin”, the causes of vitamin B12 deficiency were undetermined in 80% of patients “on metformin” and in 47% of those “not on metformin” (p<0.001); due to PA in 17% of patients “on metformin” and 47% of “not on metformin” (p<0.001); PPA in 0.8% of patients “on metformin” and 5% of “not on metformin” (p=0.384); due to gastrointestinal disorders in 0.8% and 1.6% of patients “on metformin” and “not on metformin” respectively (p=0.011), and due to malnutrition in 1.5% and 0% of patients “on metformin” and “not on metformin” respectively (p=0.484). The percentages of patients with vitamin B12 deficiency of undetermined origin, due to PA, and other known causes (PPA, gastrointestinal disorders, malnutrition) among non-diabetic patients, diabetic patients “on metformin”, and diabetic patients “not on metformin” were shown in Figure 2. The crude OR of developing vitamin B12 deficiency of undetermined origin in type 2 diabetic patients “on metformin” compared with diabetic patients “not on metformin” was 4.50 (95% CI, 2.30 - 8.82). The adjusted OR (adjusted for sex, age, use of PPI/H2B) of developing vitamin B12 deficiency of undetermined origin in type 2 diabetic patients “on metformin” compared with diabetic patients “not on metformin” was 5.20 (95% CI, 2.33 - 11.60).
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Figure 2.
Comparison of causes of vitamin B12 deficiency: diabetic patients on metformin and not on metformin, non-diabetic patients
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3.3. Vitamin B12 deficiency of undetermined origin: “on metformin” and “not on metformin”
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Of the 191 diabetic patients with vitamin B12 deficiency, 62 patients (including 5 with unclear metformin history) had known causes of vitamin B12 deficiency. Excluding these 62 patients, 129 diabetic patients had vitamin B12 deficiency of undetermined aetiology - 102 (79%) “on metformin” and 27 (21%) “not on metformin” at the time of diagnosis of vitamin B12 deficiency (Table 3). Thirty two percent of patients “on metformin” were male, and 44% of patients “not on metformin” were male (p=0.241). The mean ages of patients “on metformin” and “not on metformin” were 76.4 years [SD 8.2] and 77.1 years [SD 10.3] respectively (p=0.721). Anaemia was the presenting feature in 25% of patients “on metformin”
Comparison of presenting features and medications of diabetic patients with vitamin B12 deficiency of undetermined aetiology: “on metformin” and “not on metformin”
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and 30% of patients “not on metformin” (p=0.588), peripheral neuropathy/subacute combined degeneration of cord in 1% of patients “on metformin” and 11% of patients “not on metformin” (p=0.007), and dementia in 9% of patients “on metformin” and 4% of patients “not on metformin” (p=0.376). The mean Hb concentrations of those “on metformin” and “not on metformin” were 10.2 g/L [SD 2.2] and 10.2 g/L [SD 2.4] respectively (p=0.988), the mean MCV of the two groups were 107.3 fl [SD 11.1] and 108.2 fl [SD 11.3] respectively (p=0.706), and the mean serum vitamin B12 levels were 93.7 ng/L [SD 38.1] and 86.0 ng/L [SD 43.5] respectively (p=0.369). GPC antibody was detected in 24% of patients “on metformin” and 44% of patients “not on metformin” (p=0.034), and anti-thyroid antibodies in 12% and 26% of the two groups respectively (p=0.120). AITD occurred in 1% of patients “on metformin” and none of the patients “not on metformin” (p=0.606). Histology of gastric atrophy was detected in 5% of patients “on metformin” and 23% of patients “not on metformin” (p=0.057), ECH in none of the patients in the two groups, and histological evidence of HP organisms in 21% and 8% of the two groups respectively (p=0.290).
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The median duration of diabetes for the “on metformin” (n=99) and “not on metformin” (n=20) patients were 10 years [IQR 6-10] and 3.5 years [IQR 1.3-6.8] respectively (p<0.001). Fifty three percent of the “on metformin” patients were also on sulphonylureas, and 41% of the “not on metformin” patients were on sulphonylurea alone (p=0.260). Nine percent of the “on metformin” patients were also on insulin, and 4% of the “not on metformin” patients were on insulin alone (p=0.376). Thirty eight percent of the “on metformin” patients were on metformin alone, and 55% of the “not on metformin” patients were not on any diabetic agents – 4 chronic renal insufficiency, 2 early deaths, 9 early stage of diabetes on dietary control alone (Table 3). Other concomitant medications of 101 (99%) “on metformin” and 26 (96%) “not on metformin” diabetic patients at the time of diagnosis of vitamin B12 deficiency were available for analysis. Twenty six percent of “on metformin” and 35% of “not on metformin” diabetic patients were on either PPI or H2B (p=0.815), 42% of “on metformin” and 23% of “not on metformin” diabetic patients were on antiplatelet agents, (p=0.083), 28% of “on metformin” and 12% of “not on metformin” diabetic patients were on lipid lowering agents (p=0.087), and 87% of “on metformin” and 69% of “not on metformin” diabetic patients were on antihypertensive agents and/or medications for ischaemic heart disease (p=0.028).
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3.4. Duration of metformin use in relation to development of vitamin B12 deficiency
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Of the 128 diabetic patients on metformin, 47 (37%) patients developed vitamin B12 deficiency of all causes within 1 to 5 years of metformin use, 71 (55%) within 6 to 10 years, and 10 (8%) after 10 years, as shown in Figure 3 (i). Among these 128 patients, 102 (80%) patients had vitamin B12 deficiency of undetermined aetiology, and 26 (20%) had known causes. Of the 102 patients with undetermined aetiology, 31 (30%) developed overt vitamin B12 deficiency within 1 to 5 years of metformin use, 63 (62%) within 6 to 10 years, and 8 (8%) beyond 10 years, up to 30 years. Of the 26 patients with known causes, 16 (62%) developed vitamin B12 deficiency within 1 to 5 years of metformin use, 8 (31%) within 6 to 10 years, and 2 (8%) after 10 years. The relationship between the duration of metformin use and the development of vitamin B12 deficiency of undetermined and known causes was shown in Figure 3 (ii). The Extended Mantel-Haenzel chi-square analysis for linear trend was 4.74 (p = 0.029 with one degree of freedom).
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Figure 3.
Relationship between duration of metformin use and development of vitamin B12 deficiency (i) of all causes (ii) of undetermined and known causes
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4. Conclusions
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4.1. Characteristics of vitamin B12 deficiency in type 2 diabetic patients
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The present study illustrates certain characteristics of vitamin B12 deficiency in adult Chinese patients with type 2 diabetes. Majority of the common causes of vitamin B12 deficiency encountered in the general population such as PA, gastrointestinal diseases and nutritional deficiency also occur in type 2 diabetic patients. The frequencies of occurrence of these causes however differ between diabetic and non-diabetic patients. Vitamin B12 deficiency of undetermined origin is more frequently encountered in diabetic than non-diabetic patients (68% versus 30%), whereas PA, the most common definitive cause of vitamin B12 deficiency, is more frequently detected in non-diabetic than diabetic patients (63% versus 30%). This preponderance of vitamin B12 deficiency of undetermined origin is even more conspicuous in diabetic patients on metformin than diabetic patients not on metformin (80% versus 47%). In this cohort of adult Chinese patients, the risk of developing vitamin B12 deficiency of undetermined origin is 5.5-fold higher in diabetic than non-diabetic patients, and diabetic patients taking metformin have a 5.2-fold higher risk of developing vitamin B12 deficiency of undetermined origin than patients not taking metformin.
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This remarkable difference in the aetiological pattern of vitamin B12 deficiency between diabetic and non-diabetic patients accounts for the differences in the clinical manifestations of vitamin B12 deficiency between the two groups of patients. PA as an autoimmune disease causes profound gastric atrophy, IF depletion and vitamin B12 malabsorption, and is often accompanied by immune features; whereas conditions causing vitamin B12 deficiency of undetermined origin are often non-immune processes. They tend to cause a less severe degree of vitamin B12 malabsorption and have a paucity of immune features. Diabetic patients with vitamin B12 deficiency of undetermined origin thus generally have a less severe degree of vitamin B12 deficiency, a less severe degree of anaemia, and less autoimmune features such as GPC and antithyroid antibodies, AITD, and autoimmune gastropathy compared with non-diabetic patients, as shown in the study.
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4.2. Implications of metformin use in type 2 diabetic patients
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4.2.1. Evidence of association of metformin use with vitamin B12 deficiency
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The finding of a greater proportion of type 2 diabetic patients especially those on metformin having vitamin B12 deficiency of undetermined origin in comparison with non-diabetic subjects implies the association of metformin use with vitamin B12 deficiency of undetermined origin. However, not all cases of vitamin B12 deficiency of undetermined origin are related to metformin. Vitamin B12 deficiency of undetermined origin actually has causative factors. Lack of easily available diagnostic tools bars the clarification or confirmation of these factors. In general, diagnostic approach to define the causes of vitamin B12 deficiency is first to look for nutritional deficiency and malabsorption syndromes notably PA and structural lesions of the stomach and intestine. These are the classical known causes of vitamin B12 deficiency. The previously less common or less well defined aetiologies of vitamin B12 deficiency, such as atrophic gastritis, gastric disease associated with Helicobacter pylori infection, gastric bypass for obesity, pancreatic insufficiency due to alcohol abuse, long-term use of metformin and acid-suppressive drugs like cimetidine, ranitidine, omeprazole, intestinal bacterial overgrowth, or even ageing and idiopathic, are principally diagnosed on clinical grounds and are grouped as vitamin B12 deficiency of undetermined origin, or now increasingly known as food cobalamin malabsorption, to be distinguished from the classical known causes (Clarke & Brown, 2003; Andres, 2008). Metformin-induced vitamin B12 deficiency is among one of the miscellaneous causes which are classified as “unknown” or “undetermined” simply because of lack of objective means to prove it as the sole agent or condition in the causation of vitamin deficiency.
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The present cohort study, comprising 186 type 2 diabetic patients with 128 on metformin, serves only to provide indirect evidence that metformin use constitutes a risk factor for the development of vitamin B12 deficiency, among other “unknown” factors which may also be present in these diabetic patients. The methodology adopted by the study is traditional - exclusion of the classical known causes. In this context, the study has the advantage that as part of a previously reported longitudinal study of PA (Chan et al., 2008), all patients had documented vitamin B12 deficiency, had IF and GPC antibody assay performed, and had Schilling test done during the period when it was available. This diagnostic approach to arrive at the conclusion of metformin-induced vitamin B12 deficiency is similar to that cited in the other reports (Table 4, Table 5).
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In addition, the study attempted to include medications other than metformin in the analysis of risk factors. Two principal categories of drugs that have been commonly reported to have interaction with vitamin B12 are biguanides and acid suppressive therapy. PPI and H2B have been shown to suppress acid secretion by parietal cells and impair the absorption of protein bound dietary vitamin B12 and thus contribute to the development of vitamin B12 deficiency (Howden, 2000; Ruscin et al., 2002; Force et al., 2003; den Elzen et al., 2008; Ali et al., 2009). The current evidence of vitamin B12 deficiency associated with long-term PPI use however is based on small nonrandomized retrospective studies (Steinberg et al., 1980; Marcuard et al., 1994; Termanini et al.,1998; Hirschowitz et al., 2008). Overall the current collective body of information supports the notion that prolonged use of PPI notably in the elderly and in persons on high doses of PPI is associated with increased risk of vitamin B12 deficiency (Thomas et al., 2010). In the present study, evaluation of medications prescribed at the time of diagnosis of vitamin B12 deficiency showed no significant differences in the utilization rates of PPI/H2B, between diabetic and non-diabetic patients, and diabetic patients “on metformin” and “not on metformin”. There were also no significant differences in the utilization rates of other medications such as lipid lowering agents, anti-platelet agents, sulphonylureas and insulin between diabetic patients “on metformin” and “not on metformin”. As all patients in one group were exposed to metformin compared to none in the other group, metformin in the study emerged as the most likely culprit for medication-related vitamin B12 malabsorption. The antihypertensive and cardiovascular agents were significantly more frequently used by diabetic patients “on metformin” than those “not on metformin” in the study. This could be related to the longer diabetic history and the associated more cardiovascular complications in the group of patients on metformin. Although there are studies reporting longer diabetic history might predispose to the development of vitamin B12 deficiency (Pfipsen et al., 2009), there is insufficient data for a definite conclusion to be drawn.
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Literature search found further evidence of metformin related vitamin B12 malabsorption. Impaired vitamin B12 absorption in patients who had been treated with metformin for up to 3 months were first reported in 1969 (Berchtold et al., 1969). In the ensuing 4 decades, both observational and interventional studies unequivocally demonstrated the association between metformin use and vitamin B12 deficiency (Table 4). An observational study described malabsorption of vitamin B12 in 30% of diabetic patients during biguanide therapy (Adams et al., 1983). A cross-sectional study demonstrated a 22% prevalence of metabolically confirmed vitamin B12 deficiency in type 2 diabetic patients, with those on metformin exhibiting a statistically higher risk for B12 deficiency (Pflipsen et al., 2009). Another cross-sectional study demonstrated 6.9% of diabetic patients on metformin had low serum vitamin B12 level (Nervo et al., 2011). A case-control study demonstrated impaired gastrointestinal absorption in 30% and decreased serum B12 levels in 6% of patients in the metformin arm compared to none in the control arm (Tomkin et al., 1971). Another case-control study similarly demonstrated significant falls in the mean serum B12 levels in the metformin arm compared to the control arm (Bauman et al., 2000). A nested case-control study comparing diabetic patients on metformin with and without vitamin B12 deficiency
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Table 4.
\n\t\t\t\t\t\t\t\t1years 2holotranscobalamin II 3homocysteine 4methylmalonic acid 5sulphonylurea 6insulin 7diet [1] observational / cross-sectional study [2] case control cohort study [3] randomized placebo controlled study† ± metformin § no metformin
Studies investigating associations between metformin use and vitamin B12 deficiency
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indicated both the dose and the duration of metformin use are risk factors for vitamin B12 deficiency (Ting et al., 2006). Other cross-sectional cohort studies in Sweden, Thailand and Turkey also pointed to patients on metformin had lower serum B12 levels compared with thenon-exposed control group (Hermann et al., 2004; Pongchaidecha et al., 2004; Sahin et al., 2007). Effects of short-term (16 weeks) and long-term (52 months) treatment with metformin on the serum concentrations of vitamin B12 in type 2 diabetic patients were investigated by a Dutch randomized placebo controlled trial and showed both short- and long-term use of metformin increased the risk of vitamin B12 deficiency (Wulffele et al., 2003; Stehouwer et al., 2010). All these studies defined vitamin B12 deficiency based on biochemical markers and did not evaluate the clinical importance.
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Concerning reports on the clinical manifestations of metformin-related vitamin B12 deficiency in diabetic patients (Table 5), there are case reports of megaloblastic anaemia related to long-term metformin treatment causing vitamin B12 deficiency (Callaghan et al., 1980; Gilligan, 2002; Liu et al., 2006; Lin et al., 2007). A case series showed metformin-related megaloblastic anaemia accounted for 6% (10/162) of all vitamin B12 deficiency patients (Andres et al., 2002), and another case series revealed a 9% prevalence (54/600) of megaloblastic anemia in diabetic patients taking long-term biguanides (Filioussi et al., 2003). Neurological deficits due to vitamin B12 deficiency manifest chiefly as peripheral neuropathy, subacute combined cord degeneration, and cognitive impairment. There are case reports of subacute combined degeneration and peripheral neuropathy related to metformin therapy (Liu et al., 2006; Bell, 2010), and a prospective case-control study demonstrating diabetic patients with concurrent symptomatic peripheral neuropathy had lower serum B12 levels and more severe neuropathy in the metformin treatment group in comparison with non-metformin treated patients (Wile & Toth, 2010).
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Table 5.
\n\t\t\t\t\t\t\t\t1years 2megaloblastic anaemia 3subacute combined degeneration 4deep vein thrombosis 5Schilling test 6intrinsic factor antibody 7gastric parietal cell antibody 8celiac disease ruled out 9not mentioned 10injection †on sulphonylurea/insulin [4] case report [5] case series [6] prospective case control study
Reports of metformin-related symptomatic vitamin B12 deficiency
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B12 malabsorption associated with long-term metformin treatment (Callaghan et al., 1980; Gilligan, 2002; Liu et al., 2006; Lin et al., 2007). A case series showed metformin-related megaloblastic anaemia accounted for 6% (10/162) of all established vitamin B12 deficiency patients (Andres et al., 2002), and another case series revealed a 9% prevalence (54/600) of megaloblastic anemia in diabetic patients taking long-term biguanides (Filioussi et al., 2003). Neurological deficits due to vitamin B12 deficiency manifest chiefly as peripheral neuropathy, subacute combined cord degeneration, and cognitive impairment. There are case reports of subacute combined degeneration and peripheral neuropathy related to metformin therapy (Liu et al., 2006; Bell, 2010), and a prospective case-control study demonstrating diabetic patients with concurrent symptomatic peripheral neuropathy had lower serum B12 levels and more severe neuropathy in the metformin treatment group compared with non-metformin treated patients (Wile & Toth, 2010).
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4.2.2. Duration and dosage of metformin use in relation to onset of vitamin B12 deficiency
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From the present study, for diabetic patients on metformin, about 30% developed vitamin B12 deficiency of undetermined origin within 5 years of metformin use, and 60% within 6 to 10 years; and for those with known causes especially those with PA, 60% within the first 5 years, and 30% within 6 to 10 years. The main determining factor in the latter group of patients was probably the known cause, e.g. PA, and whether metformin use contributed to or hastened the development of vitamin B12 deficiency in these patients is difficult to determine at this stage. Due to the retrospective nature of data collection concerning diabetic control and medications, precise analysis of metformin duration and dose in relation to the development of vitamin B12 deficiency is beyond the capacity of the present study. One practical message is that clinicians should be aware of the development of vitamin B12 deficiency with both short-term and long-term use of metformin ranging from 1 year to beyond 10 years. An equally important message corollary to this is that known causes of vitamin B12 deficiency such as PA occur in diabetic patients as in non-diabetic subjects, and the same diagnostic approach to delineate the underlying cause of vitamin B12 deficiency should be adopted for diabetic patients as for other patients in general.
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From the reports in the literature (Table 4), diminished absorption of vitamin B12, manifested as decreased serum B12 levels, occurred as early as 3 to 4 months after the use of metformin (Bauman et al., 2000; Wulffele et al., 2003). Symptomatic deficiency of the vitamin, according to most reports (Table 5), occurred 5 to 10 years after the use of metformin. This is in line with the established knowledge that the body store of vitamin B12 is huge (2500 μg) in comparison to daily loss/requirement (1-2 μg) (Carmel, 2008), and depletion of the pre-existing body store vitamin thus takes 12 to 15 years. The process of exhaustion of body store will be hastened in the presence of other predisposing factors for vitamin B12 deficiency such as partial gastrectomy.
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Two recent reports concerning metformin-related vitamin B12 deficiency suggested need for improved management of such patients. The increased risk of vitamin B12 deficiency with metformin use was re-emphasized by a nested case-control study of Chinese patients (Ting et al., 2006). It showed correlation between the dose and duration of metformin use with vitamin B12 deficiency. Compared with those receiving metformin for less than 3 years, the adjusted OR was 2.39 (95% CI, 1.46-3.91) for those using metformin for 3 years or more. After excluding subjects with borderline vitamin B12 concentrations, the metformin dose remained the strongest independent predictor of vitamin B12 deficiency. Each 1-g/day increment in metformin dose conferred an OR of 2.88 (95% CI, 2.15-3.87) of developing vitamin B12 deficiency. In a prospective randomized placebo controlled trial, the Dutch scientists found the fall in serum B12 levels with metformin persists and becomes more apparent with time (Stehouwer et al., 2010). It is reasonable to assume that harm will eventually occur in some patients with metformin-induced low vitamin B12 levels.
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4.2.3. Treatment of metformin-induced vitamin B12 deficiency
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There is no consensus on optimal treatment of metformin-induced vitamin B12 deficiency. In the present study, metformin was continued unless there were other reasons for discontinuation or switching to other anti-diabetic therapy such as renal insufficiency or poor glycaemic control. Vitamin B12 replacement was given intramuscularly, daily, monthly, and then 3-monthly as maintenance. Most authors of the case reports/series (Table 5) treated their patients’ metformin-induced megaloblastic anaemia with vitamin B12 either orally or parenterally at 1000 µg daily or on alternate days initially, and continued metformin therapy (Callaghan et al., 1980; Andres el al., 2002; Filioussi et al., 2003). In all these cases the anaemia responded but the neuropathy of one patient persisted (Bell, 2010).
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In general, two aspects of treatment have to be considered. Vitamin B12 replacement is mandatory and can be given either intramuscularly or orally. Parenteral route may be preferred for subjects with neurological deficits due to the potential risk of irreversibility. The rationale for oral vitamin B12 replacement is that there is evidence for an alternative pathway of vitamin B12 absorption that does not require IF or the presence of an intact ileum (Berlin et al., 1968; Kuzminski et al., 1998; Andres et al., 2008). For both routes of administration, large doses of crystalline cobalamin in the range of 1000 µg should be given. The duration of vitamin B12 supplementation depends on the removal of the triggering factor. If metformin is continued, appropriate vitamin B12 replacement should be administered. Although malabsorption of vitamin B12 is reversible 2 to 8 weeks after stopping metformin therapy (NeLM, 2005), withdrawal of metformin is not mandatory in view of its efficacy and safety, and most of the complications of vitamin B12 deficiency are remediable apart from irreversible damage to the central and peripheral nervous system which may occur if treatment is delayed.
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Up to now, the mechanism of metformin-related vitamin B12 malabsorption is still not fully understood. Metformin causes fall in blood glucose primarily through suppression of hepatic gluconeogenesis, enhancement of insulin sensitivity, and reduction of gastrointestinal absorption of glucose. This action is achieved through reduction of efficiency of ion exchange across cell membranes which is brought about through activation of AMP-activated protein kinase and perhaps other enzymes. This mode of action also underlies the untoward side effects of increased intestinal motility and lactic acidosis. Whether the process of malabsorption of vitamin B12 is also similarly mediated is unclear. Currently the most likely mechanism is impaired uptake of vitamin B12-intrinsic factor complex at the ileal cell membrane receptors. This uptake has been shown to be a calcium dependent process (Bauman et al., 2000). The hydrophobic tail of metformin extends into the hydrocarbon core of cell membrane and the protonated metformin group gives a positive charge to the membrane surface and displaces divalent cations. Thus by altering the membrane potentials and affecting the divalent cation membrane functions, especially those calcium-dependent ones, metformin may act as a calcium channel blocker. This postulation is supported by studies showing reversal of malabsorption by increasing calcium intake (Bauman et al., 2000). Other studies showed the malabsorption might be related to decreased IF secretion (Adams et al., 1983), or delay in intestinal transit and bacterial overgrowth in diabetic patients. Some studies however failed to show bacterial overgrowth in such patients (Bauman et al., 2000). Further research is required to clarify the mode of metformin-induced malabsorption of vitamin B12.
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4.3. Future direction
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The prevalence of vitamin B12 deficiency is expected to increase with time in view of the ageing population and the more widespread use of sensitive metabolite assays to detect subtle cobalamin deficiency. Among the population over the age of 60, the prevalence of metabolically confirmed vitamin B12 deficiency ranges from 12% to 23% (Pennypacker et al., 1992; Lindenbaum et al., 1994; Johnson et al., 2003). Type 2 diabetes, at the same time, is becoming more common almost everywhere in the world. The global prevalence of type 2 diabetes is 2.8% ( 171 million people) in 2000 (Wild et al., 2004), 6.6% (285 million) in 2010, and will be reaching 7.8% (438 million) in 2030 (The Diabetes Atlas, 2009). The global prevalence of age-standardized adult diabetes, according to a recent large international study, was 9.8% (8.6-11.2) for men, and 9.2% (8.0-10.5) for women in 2008 (Danaei et al., 2011). In Hong Kong, the prevalence of type 2 diabetes in elderly subjects above the age of 60 is estimated to range between 9.8% (Woo et al., 1987) and 10.7% (Kung et al., 1996), and the age-standardized prevalence of type 2 diabetes for the 35-64 age group was 9.5% for men and 10.2% for women (Lam et al., 2000).
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(new paragraph) Concerning anti-diabetic therapy, metformin remains one of the two oral anti-diabetic drugs in the WHO model list of essential medicine in 2010, in spite of a large array of new therapeutic agents available in the pharmaceutical market. It is the only anti-diabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. The drug remains active after months or years of therapy and its efficacy is little dependent on the residual effective β-cell mass. It causes less weight gain and fewer hypoglycaemic attacks compared with sulphonylureas and insulin. It is now recommended as the initial therapy for type 2 diabetes by the National Institute for Health and Clinical Excellence of the United Kingdom, the American Diabetes Association, and the European Association for the Study of Diabetes. As metformin has been available in the United Kingdom since 1958, in Canada since 1972, in the United States since 1995, and for over 40 years in Hong Kong, the pool of diabetic patients with metformin-induced vitamin B12 deficiency, diagnosed or undiagnosed, could be considerable in the present era. Concomitant occurrence of two comorbid conditions, diabetes and vitamin B12 deficiency, in one subject is apparently undesirable. Florid deficiency of vitamin B12 is accompanied and actually preceded by reciprocal rise of homocysteine levels imposing an increased risk of cardiovascular complications (Hoogeveen et al., 2000; The Homocysteine Studies Collaboration, 2002). Neurological deficits, one of the major manifestations of vitamin B12 deficiency can often be diagnostically confused with diabetic neuropathy, one of the long-term microangiopathic complicaitons of diabetes. Clinicians should therefore have a high index of suspicion for metformin-induced vitamin B12 deficiency in diabetic patients.
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To prevent vitamin B12 deficiency, it is reasonable to consider formulating appropriate screening strategy for diabetic patients on metformin. According to the WHO’s criteria, a condition is worthwhile screening if it is an important health problem, if there are simple tests available to detect the condition at an early and treatable stage, and if effective and safe treatment is available (Wilson & Junger, 1968). The condition of vitamin B12 deficiency fulfills these criteria. Before such screening guidelines are available, appropriate preventive measures may be instituted. These may include monitoring of vitamin B12 levels at regular intervals such as annually or biannually; or giving vitamin B12 prophylactically as dietary supplement or more conveniently as annual injection at 1000 µg, a dose sufficient to cover vitamin B12 needs for at least a year.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/22101.pdf",chapterXML:"https://mts.intechopen.com/source/xml/22101.xml",downloadPdfUrl:"/chapter/pdf-download/22101",previewPdfUrl:"/chapter/pdf-preview/22101",totalDownloads:2840,totalViews:231,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:17,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"November 17th 2010",dateReviewed:"May 22nd 2011",datePrePublished:null,datePublished:"November 4th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/22101",risUrl:"/chapter/ris/22101",book:{id:"1038",slug:"topics-in-the-prevention-treatment-and-complications-of-type-2-diabetes"},signatures:"Chan Chee Wun Joyce, Chan Hoi Yan Florence, Wong Ho Nam Howard and Yeung Chun Yip",authors:[{id:"45769",title:"Dr.",name:"Chee Wun Joyce",middleName:null,surname:"Chan",fullName:"Chee Wun Joyce Chan",slug:"chee-wun-joyce-chan",email:"joycecwchan@hotmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/45769/images/219_n.jpg",institution:{name:"Pamela Youde Nethersole Eastern Hospital",institutionURL:null,country:{name:"China"}}},{id:"56638",title:"Dr.",name:"Hoi Yan Florence",middleName:null,surname:"Chan",fullName:"Hoi Yan Florence Chan",slug:"hoi-yan-florence-chan",email:"chy134@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"82881",title:"Dr.",name:"Ho Nam Howard",middleName:null,surname:"Wong",fullName:"Ho Nam Howard Wong",slug:"ho-nam-howard-wong",email:"hnwong28@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Pamela Youde Nethersole Eastern Hospital",institutionURL:null,country:{name:"China"}}},{id:"82882",title:"Dr.",name:"Chun Yip",middleName:null,surname:"Yeung",fullName:"Chun Yip Yeung",slug:"chun-yip-yeung",email:"yeungcy97@yahoo.com.hk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Pamela Youde Nethersole Eastern Hospital",institutionURL:null,country:{name:"China"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and methods",level:"1"},{id:"sec_2_2",title:"2.1. Patient source and stratification",level:"2"},{id:"sec_3_2",title:"2.2. Data collection and analysis",level:"2"},{id:"sec_4_2",title:"2.3. Definitions ",level:"2"},{id:"sec_5_2",title:"2.4. Measurements",level:"2"},{id:"sec_6_2",title:"2.5. Statistical analysis ",level:"2"},{id:"sec_8",title:"3. Results",level:"1"},{id:"sec_8_2",title:"3.1. Vitamin B12 deficiency: Type 2 diabetic and non-diabetic patients ",level:"2"},{id:"sec_9_2",title:"3.2. Vitamin B12 deficiency: type 2 diabetic patients “on metformin” and “not on metformin” ",level:"2"},{id:"sec_10_2",title:"3.3. Vitamin B12 deficiency of undetermined origin: “on metformin” and “not on metformin” ",level:"2"},{id:"sec_11_2",title:"3.4. Duration of metformin use in relation to development of vitamin B12 deficiency",level:"2"},{id:"sec_13",title:"4. Conclusions",level:"1"},{id:"sec_13_2",title:"4.1. Characteristics of vitamin B12 deficiency in type 2 diabetic patients ",level:"2"},{id:"sec_14_2",title:"4.2. Implications of metformin use in type 2 diabetic patients",level:"2"},{id:"sec_14_3",title:"4.2.1. Evidence of association of metformin use with vitamin B12 deficiency ",level:"3"},{id:"sec_15_3",title:"4.2.2. Duration and dosage of metformin use in relation to onset of vitamin B12 deficiency",level:"3"},{id:"sec_16_3",title:"4.2.3. Treatment of metformin-induced vitamin B12 deficiency",level:"3"},{id:"sec_18_2",title:"4.3. Future direction ",level:"2"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdams\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClark\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIreland\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKesson\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatson\n\t\t\t\t\t\t\tW. 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BMJ\n\t\t\t\t\t 340\n\t\t\t\t\tc2181.\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tden Elzen\n\t\t\t\t\t\t\t W. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGroeneveld\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Ruijter\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSouverijn\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tle Cessie\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAssendelft\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGussekloo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tLong-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 6\n\t\t\t\t\t27\n\t\t\t\t\t491\n\t\t\t\t\t497\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEvans\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDonnelly\n\t\t\t\t\t\t\tL. 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Lancet\n\t\t\t\t\t352\n\t\t\t\t\t9131\n\t\t\t\t\t854\n\t\t\t\t\t865 .\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWild\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoglic\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreen\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSicree\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKing\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tGlobal prevalence of diabetes: estimates 2000 and projections for 2030.\n\t\t\t\t\tDiabetes Care\n\t\t\t\t\t27\n\t\t\t\t\t5\n\t\t\t\t\t1047\n\t\t\t\t\t1053 .\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWile\n\t\t\t\t\t\t\tDaryl.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToth\n\t\t\t\t\t\t\tCory.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. 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G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKooy\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLehert\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBets\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgterop\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBorger Der\n\t\t\t\t\t\t\tBurg. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDonker\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStehouwer\n\t\t\t\t\t\t\tCDA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Journal of Internal Medicine\n\t\t\t\t\t254\n\t\t\t\t\t5\n\t\t\t\t\t455\n\t\t\t\t\t463 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Wun Joyce Chan Chee",address:null,affiliation:'
Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China SAR
Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China SAR
'}],corrections:null},book:{id:"1038",type:"book",title:"Topics in the Prevention, Treatment and Complications of Type 2 Diabetes",subtitle:null,fullTitle:"Topics in the Prevention, Treatment and Complications of Type 2 Diabetes",slug:"topics-in-the-prevention-treatment-and-complications-of-type-2-diabetes",publishedDate:"November 4th 2011",bookSignature:"Mark B. Zimering",coverURL:"https://cdn.intechopen.com/books/images_new/1038.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:null,printIsbn:"978-953-307-590-7",pdfIsbn:"978-953-51-6552-1",reviewType:"peer-reviewed",numberOfWosCitations:26,isAvailableForWebshopOrdering:!0,editors:[{id:"39545",title:"Prof.",name:"Mark",middleName:null,surname:"Zimering",slug:"mark-zimering",fullName:"Mark Zimering"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1013"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"22092",type:"chapter",title:"Burden of Diabetes Type 2 Through Modelling and Simulation",slug:"burden-of-diabetes-type-2-through-modelling-and-simulation",totalDownloads:2162,totalCrossrefCites:1,signatures:"Maja Atanasijević-Kunc and Jože Drinovec",reviewType:"peer-reviewed",authors:[{id:"57424",title:"Prof.",name:"Maja",middleName:null,surname:"Atanasijević-Kunc",fullName:"Maja Atanasijević-Kunc",slug:"maja-atanasijevic-kunc"},{id:"57437",title:"Prof.",name:"Jože",middleName:null,surname:"Drinovec",fullName:"Jože Drinovec",slug:"joze-drinovec"}]},{id:"22093",type:"chapter",title:"Alzheimer’s Disease and Type 2 Diabetes: Different Pathologies and Same Features",slug:"alzheimer-s-disease-and-type-2-diabetes-different-pathologies-and-same-features",totalDownloads:2588,totalCrossrefCites:2,signatures:"Marta Di Carlo, Pasquale Picone, Rita Carrotta, Daniela Giacomazza and P.L. 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1. Introduction
Agriculture, being man’s most fundamental profession, has benefitted immensely from technological advancements ranging from shifting cultivation to high precision farming. With the advent of civilization, man learned about additional crops and began to produce a variety of crops. As the human population grew and civilization progressed, people began to dwell in one location and farm the same land year after year. Now that agriculture has evolved into a profession, it is known as commercial agriculture, with precision agriculture and sustainable agriculture as key components.
The world’s population is rapidly increasing these days. To meet the rising demand for food, the agricultural community must produce more and more. Because it is difficult to bring additional land under cultivation (extensive farming) in the current scenario, when land is a limited issue, the agricultural community should take on the task of producing more and more food with the land that is available (intensive farming). On the contrary, growing worldwide concern for human health and the environment opposes the use of higher levels of pesticides and fertilizers, as well as genetically modified plants. The latter, on the other hand, are present technologies that have the potential to improve food production.
Crop needs and soil/land conditions influence adaptability. Suitability is determined by matching the land features to the crop needs. Suitability is a measure of whether a land unit’s features meet the needs of a certain type of land use (FAO). Aside from land and soil qualities, additional driving elements that might impact crop choices include socioeconomic, market, and infrastructural factors.
The FAO Land Evaluation Framework is based on previous land capabilities methodologies. In this case, the overall land appropriateness of a land area for a particular land use is assessed using a series of more or less independent land attributes, each of which may limit the land-use potential. These assessments are frequently used to classify map units in natural resource inventories. A soil survey’s legend categories are divided into suitability subclasses based on the quantity and severity of land use restrictions.
In the FAO framework, there are two sorts of categories based on the scale of measurement of appropriateness.
Qualitative: in reconnaissance investigations, the classes are rated based on the physical production potential of the land. It is employed to assess environmental, social, and economic factors.
Quantitative: the classes are specified in numerical terms that allow for comparison of the objectives. There are a lot of economic parameters employed here.
By introducing quantification of land suitability indicators over a whole area, quantified land evaluation [1] revolutionized land suitability evaluation. The area is divided into small grid cells, and cell-based modeling has started. The indicators, on the other hand, must be quantitative. Geographical information systems and geostatistical approaches are commonly used in such land suitability analyses.
The FAO Framework identifies four categories of increasing details, as shown in Table 1.
S. No.
Categories
Explanation
1
Land Suitability Orders
Reflecting kinds of suitability
2
Land Suitability Classes
Reflecting degrees of suitability within Orders
3
Land Suitability Subclasses
Reflecting kinds of limitation, or main kinds of improvement measures required, within Classes
4
Land Suitability Units
Reflecting minor differences in required management
Table 1.
FAO structure of land suitability classification.
Land appropriateness is a factor in determining a land use’s long-term viability. The sustainability of a land use is defined by its suitability and vulnerability. Maximum appropriateness and minimum vulnerability should be the goals of sustainable land use (Figure 1) [2].
Figure 1.
Land use sustainability (after [2]).
According to Rossiter [3], land is distinctive in every location, and this uniqueness has an impact on land usage. He also mentions how land evaluation might help with agricultural support services.
The multi-criteria land suitability was evaluated in a non-spatial manner, assuming spatial homogeneity across the study region. However, in circumstances like land suitability studies, when decisions are made based on factors that change over space, this is impossible [4]. Non-spatial traditional MCDM techniques average or total the effects that are judged appropriate for the entire area under consideration to address the spatial decision [5]. Jankowski [6] suggests that making, MCE, and GIS can all be combined. For many crops, MCE appears to be applicable in GIS-based land suitability analyses [7].
Ranking and rating are two widely used MCE approaches in land suitability evaluations. These methods lack a theoretical underpinning in determining the weights. The weights are assigned quite haphazardly in these procedures. They do not take into account comparisons between criteria and classifications. Furthermore, the results of such an investigation are grouped together using a simple Boolean overlay or weighted aggregation.
Since its beginnings, several researchers have examined the Analytic Hierarchy Process (AHP) [8]. The Analytic Hierarchy Process (AHP) is a method for making multi-criteria decisions (MCDM). The earliest reference we have identified is from 1972 [9]. The method was then discussed in detail in a paper published in the Journal of Mathematical Psychology [10]. The vast majority of applications continue to use AHP in the manner specified in this first article, oblivious to subsequent developments. This study draws out the significant trends in methodological advancements and future research in this vital topic.
AHP has been widely used since its introduction, for example, in flexible manufacturing system [11], Machine selection [12], industrial R&D project selection and resource allocation [13], Delphi method [14], Computer-aided machine-tool selection [15], evaluating machine tool alternatives [16], Integrating fuzzy theory and hierarchy concepts to evaluate software quality [17], product design in concurrent engineering [18]. Issue resolution for conceptual design using AHP [19]. Selection of appropriate schedule delay analysis method [20].
2. Study area and data used
2.1 Study area
Northern region India is a city in India’s Punjab state. On July 27, 2011, Northern region India was formally designated as a district of Punjab state (Previously it was a Tehsil of Gurdaspur district, Punjab). Northern region India district is located in Punjab’s northernmost region (Figure 2).
Figure 2.
Location of the study area.
It is where the three northern states of Punjab, Himachal Pradesh, and Jammu and Kashmir come together. Northern region India serves as a transportation hub for the three northern states due to its strategic location. It is the last city in Punjab on the national highway that connects Jammu and Kashmir to the rest of the country. Northern region India is also a major educational center for the nearby states of Jammu and Kashmir and Himachal Pradesh. It is located in the Jalandhar division, between the Ravi and the Beas rivers.
Northern region India district is located between 32°23′31″ and 32°23′52″ north latitudes and 75°39′55″ to 75°56′12″ east longitudes and covers an area of 27,123 ha. On a 1:50 K scale, the Survey of India 43 P/11, 43 P/14, and 43 P/15 top sheets cover the area.
The shuttle radar topography mission (SRTM) elevation data (30 m resolution) obtained from USGS explorer (https://earthexplorer.usgs.gov/) was used to create a digital elevation model (DEM) of the study area. Using the DEM data slope, aspect, drainage density, Elevation thematic layers were built using ArcGIS 10.5. The land use and land cover data is downloaded by Nasa earth data ORNL DAAC (https://daac.ornl.gov/cgi-bin/dsviewer.pl?ds_id=1336). Soil map was obtained from European soil data center (ESDAC) which was published by National atlas and thematic map organization, Department of science and technology (https://esdac.jrc.ec.europa.eu/content/national-atlas-india-northern-india-plate-199-soil-regions).Geology and Geomorphology data of Northern region India is downloaded from Bhukosh (http://bhukosh.gsi.gov.in/Bhukosh/MapViewer.aspx). Sentinel2 data of the study area is downloaded from Copernicus(https://scihub.copernicus.eu/). Using the Sentinel 2 data NDWI was built in ArcGIS 10.5.These resulted thematic maps: Slope, LULC, NDWI and Drainage density were integrated in ArcGIS 10.5 and finally soil suitability map was obtained (Figures 3–11; Tables 3–11).
Figure 3.
Slope map.
Figure 4.
Elevation map.
Figure 5.
Aspect map.
Figure 6.
Drainage map.
Figure 7.
Land use and land cover.
Figure 8.
Moisture index map.
Figure 9.
Soil map.
Figure 10.
Geology map.
Figure 11.
Geomorphology landform map.
Slope angle (°)
Area (ha)
0–3
66049.4
3–6
13244.1
6–12
8884
12–18
6252.5
18–36
5234.1
36–58
144.8
Table 3.
Slope angle and its area coverage.
Elevation (m)
Area (ha)
224–300
46573.82
300–400
21522.16
400–550
16241.04
550–700
13350.39
700–960
2098.89
Table 4.
Elevation and its area coverage.
Aspect
Area (ha)
East, West
25205.63
North
10275.67
Northeast, Northwest
21756.82
South, Southwest, Southeast
42581.89
Table 5.
Aspect and its area coverage.
Drainage density
Area (ha)
High
24970.4
Medium
37780.1
Low
35291.3
Table 6.
Drainage density and its area coverage.
Class
Area (ha)
Water bodies
8967.44
Evergreen broad leaf forest
595.94
Crop land
57921.61
Built up area
6828.81
Deciduous broadleaf forest
19649.35
Shrub land
1749.07
Permanent wetland
210.61
Wasteland
2236.91
Mixed forest
623.53
Table 7.
LULC and its area coverage.
Moisture index
Area (ha)
Good Soil Moisture
13341.96
Medium Soil Moisture
37086.93
Less Soil Moisture
28455.66
Very Less and Dry Soil Moisture
16474.77
Water Bodies
4453.2
Table 8.
Moisture index and its area coverage.
Soil type
Area (ha)
Alfisol (alluvial soil)
25614.38
Entisol (bhabar soil)
46344.83
Ultisol (brown, red clay soil)
27851.02
Table 9.
Soil and its area coverage.
Geology type
Area (ha)
Miocene
8693.8
Miocene - Pliocene
6611.5
Pliocene - Pleiostocene
3241.69
Table 10.
Geology and its area coverage.
Geomorphology landform
Area (ha)
Active Flood plain
6612
Older Flood plain
12,852
Low and moderated Dissected Hills and Valleys
11,488
Water bodies
5848
Older Alluvial Plain
34,920
Highly Dissected Hills and Valleys
12,364
Channel Island / Bar
572
Younger Alluvial plain
9736
Table 11.
Geomorphology landform and its area coverage.
3. Methodology
Because all the selected criteria are in different units, they must be converted to the same units in order to use the Weighted Overlay Method, which necessitates the use of a standardized value. Standardization techniques transform measurements into uniform units, and the resulting score loses its dimension as well as the unit of measurement for every criterion [21]. All the criteria maps’ vector layers were transformed to raster layers. After that, all raster layers were categorized and utilized as input data for the weighted overlay method, which resulted in the creation of the agricultural suitability map. The sub-criteria were ranked on a scale of one to ten, with one being the least significant and ten being the most significant.
One of the most important multicriteria decision-making strategies is the analytical hierarchy process. The procedure is used for a set of criteria or sub-criteria to create a hierarchical structure by assigning weight to each criterion [22].
The analytic hierarchy process provides a structural foundation for quantifying the strong comparison of design criteria and elements in a paired technique, reducing the decision-making process’s complexity [10, 23]. The weight values are determined using a pairwise comparison technique based on the relative significance of the criterion, two at a time [23]. By picking the eigenvalue corresponding to the highest eigenvector of the completed matrix and normalizing the total of the factors to unity, the analytic hierarchy method derives the weights for each individual criterion using the pairwise comparison matrix [4, 24, 25].
The pairwise comparison matrix was generated using the analytic hierarchy procedure described above, using a scale of 1–9, where 9 represents important relevance and 1 indicates equal relevance of the in between criterion of the matrix presented in (Table 12) [4, 24, 25].
Relative importance
Definition
Explanation
1
Equal importance
Two criteria enrich equally to the objective criteria
3
Low importance of one over another
Judgments and experience slightly favor one criteria over another
5
Strong or essential importance
Judgments and experience strongly favor
7
Established importance
A criteria is strongly favored and its dominance established in practice
9
Absolute or high importance
The evidence favoring one criteria over another is of the highest probable order of affirmation
2,4,6,8
Intermediate values between the two adjacent importance or judgments
When adjustment is needed
Table 12.
The fundamental scale for pairwise comparison matrix [25].
Reciprocals if criteria i has one of the above numbers designated to it when compared with criteria j, then j has the reciprocal value when compared with i.
The reciprocity criteria are mostly used in the comparison matrix, which is mathematically stated as n (n−1)/2 for the n number of components in a pairwise comparison matrix [25, 26]. The relative weights and eigenvectors are calculated using Saaty’s technique [25] after the pairwise matrix has been computed (Tables 14 and 15). Furthermore, one of the major properties of the analytic hierarchy method is that it finds and calculates the inconsistencies of decision makers [24, 25, 27]. The consistency relationship (CR), which is measured by Eq. (1), is used to estimate the efficiency criteria of the analytic hierarchy method.
CR=CI/RIE1
The CR is represented by Eq. (1), where CI stands for consistency index and RI stands for random index.
The consistency relationship aids in the determination of possible events and measures the decision maker’s/judgments’ logical inconsistencies [28, 29, 30]. It denotes the probability that the matrix judgments were produced at random [10, 31]. The Consistency Index and Random Index are the most important factors in determining the CR.
CI=λmax−n/n−1E2
Equation (2) represents the Consistency Index (CI), in which k max is the principle or highest eigenvector of the computed matrix and n is the matrix order.
The Random Index (RI) is the mean value of the consistency index based on the computed matrix order as demonstrated by Saaty [10] (Table 13). If the CR value is [0.10], the weight values in the matrix show irregularities, and the approach (AHP) may not produce relevant results [25]. The calculated CR in this investigation was 0.0669, which is within acceptable limits, and the computed weight values are accurate. The obtained weight values are then transformed to percentages in GIS for weighted overlay analysis (WOA), as shown in Tables 14 and 15 (Figure 12).
n
1
2
3
4
5
6
7
8
9
10
RI
0
0
0.58
0.90
1.12
1.24
1.32
1.41
1.46
1.49
Table 13.
Random inconsistency indices (RI) for n = 10.
Criteria
Slope
Elevation
LULC
Soil moisture
Soil
Geomorphology
Drainage
Geology
Aspect
Slope
1
2
2
3
4
6
7
8
9
Elevation
1/2
1
2
3
4
5
7
7
8
LULC
1/2
1/2
1
4
5
4
6
7
8
Soil moisture
1/3
1/3
1/4
1
3
4
5
6
7
Soil
1/4
1/4
1/5
1/3
1
3
4
5
6
Geomorphology
1/6
1/5
1/4
1/4
1/3
1
3
4
4
Drainage
1/7
1/7
1/6
1/5
1/4
1/3
1
2
3
Geology
1/8
1/7
1/7
1/6
1/5
1/4
1/2
1
3
Aspect
1/9
1/8
1/8
1/7
1/6
1/4
1/3
1/3
1
Table 14.
Pairwise comparison matrix for multi-criteria decision problems.
Criteria
Slope
Elevation
LULC
Soil moisture
Soil
Geomorphology
Drainage
Geology
Aspect
Weights
Slope
0.319
0.426
0.326
0.248
0.223
0.252
0.207
0.198
0.184
0.264
Elevation
0.159
0.213
0.326
0.248
0.223
0.209
0.207
0.173
0.163
0.214
LULC
0.159
0.106
0.163
0.330
0.278
0.168
0.177
0.173
0.163
0.190
Soil moisture
0.105
0.070
0.040
0.083
0.167
0.168
0.148
0.149
.0143
0.119
Soil
0.079
0.053
0.032
0.027
0.056
0.126
0.118
0.124
0.122
0.082
Geomorphology
0.054
0.043
0.040
0.020
0.018
0.042
0.089
0.099
0.081
0.054
Drainage
0.045
0.030
0.027
0.016
0.014
0.014
0.029
0.049
0.061
0.034
Geology
0.039
0.030
0.023
0.014
0.011
0.010
0.015
0.025
0.061
0.025
Aspect
0.035
0.027
0.020
0.012
0.009
0.010
0.009
0.008
0.020
0.018
Table 15.
Normalized pairwise comparison matrix for multi-criteria decision making.
Procedure followed in generating agricultural land use suitability map.
4. Results and discussion
Weighted Overlay Analysis was carried out to generate the land suitability for agriculture in the Northern region India district using the weight values of selected factors derived from the Analytic Hierarchy Process and specified scores of sub-criteria (Table 16). Land suitability for agriculture is classified into five levels, according to the Food and Agricultural Organization (FAO): highly suitable agricultural land, moderately suitable agricultural land, marginally suitable agricultural land, land currently not suitable for agriculture, and permanently not suitable for agricultural production (Table 17).
Main criteria
Weight
Influence (%)
Sub-criteria
Score
Slope
0.264
26.4
0–3
10
3–6
8
6–12
6
12–18
4
18–36
2
36–58
1
Elevation
0.213
21.4
224–300
10
300–400
9
400–550
8
550–700
7
700–960
5
LULC
0.190
19
Crop Land
10
Shrub Land
4
Wasteland
3
Evergreen Broad leaf Forest
Restricted
Mixed Forest
Restricted
Deciduous Broadleaf Forest
Restricted
Built up Area
Restricted
Permanent wetland
Restricted
Water bodies
Restricted
Soil Moisture
0.119
11.9
Good Soil Moisture
10
Medium Soil Moisture
7
Less Soil Moisture
4
Very Less and Dry Soil Moisture
1
Water Bodies
Restricted
Soil
0.082
8.2
Alfisol (alluvial soil)
9
Entisol (bhabar soil)
6
Ultisol (brown, red clay soil)
3
Geomorphology
0.054
5.4
Younger Alluvial plain
10
Older Alluvial Plain
9
Older Flood plain
8
Low and moderated Dissected Hills
3
Active Flood plain
2
Channel Island / Bar
1
Highly Dissected Hills and Valleys
1
Water bodies
Restricted
Drainage
0.034
3.4
High
9
Medium
7
Low
4
Geology
0.025
2.5
Quaternary
9
Pliocene - Pleiostocene
7
Miocene - Pliocene
5
Miocene
3
Aspect
0.018
1.8
South, Southwest, Southeast
9
East, West
5
Northeast, Northwest
4
North
2
Table 16.
Weights of the criteria and scores of the sub-criteria.
Suitability level
Suitable areas for agricultural production
Area(ha)
%
High suitability
390442.28
41.2
Moderate suitability
13498.76
14.3
Marginally suitable
3993
4.2
Currently not suitable
1766.6
1.9
Permanently not suitable
36372.6
38.4
Table 17.
Areal and percentile distribution of agricultural land suitability analysis results.
High altitude (224–960 m), high slope (3–58) with higher gully erosion intensity, and less drainage availability of the study area were significant factors, resulting in a smaller area or lower rate of highly appropriate agricultural land in Northern region India (Figure 13 and Table 18).
Figure 13.
Agriculture land suitability map of northern region India.
Suitability level
Suitable areas for agricultural production
Land qualities/characteristics
Remarks
Area (ha)
%
High suitability
390442.28
41.2
Gentle slopes (0–3) with gullies, high soil moisture with lower elevation, alluvial soil, good drainage capacity
Most suitable for agriculture, favorable area for intensive agriculture if irrigation facilities are available
Moderate suitability
13498.76
14.3
Gentle to stiff slopes (3–10) with micro terracing, medium soil moisture with lower elevation, moderate drainage capacity
Suitable land for farming practices with proper management, suitable for terrace cultivation
Marginally suitable
3993
4.2
(10–20) slope, less soil moisture with higher elevation, coarse loamy to gravel loamy soil, low drainage availability
Less suitable land for agriculture with careful farm management, necessary protections from drainage and intensive erosion
Currently and permanently not suitable
38139.2
40.3
Precipitous slope with rocky lands, dry soil, dense forest, barren land, loamy skeletal soil, no drainage availability
The land is not suitable for agriculture, areas under dense vegetation, settlement, barren lands, open rocks are not suitable for agriculture
Table 18.
Land suitability levels and their land characteristics.
5. Conclusion
The primary goal of this research was to identify potential agricultural land in the Northern region India district. For the evaluation, an analytical hierarchy approach with a combination of geographic information systems (GIS) was used, and nine different criteria were chosen. The Analytic Hierarchy Process with GIS Integration was shown to be quite useful in determining the best agricultural site. Only 41.2% (39044.28 ha) of the study area was largely suitable for farming at the end of the evaluation, while 40.3% (38139.2 ha) was permanently and temporarily unsuitable for agricultural production. However, inefficient production problems are caused by geomorphological qualities such as very high elevation, steep slope, reduced soil moisture, the presence of bare rocks, and a lack of irrigation system availability. As a result of all these concerns, a moderate quantity of land in the study district has been identified as appropriate for agricultural production. The established result can be implemented into the agricultural production decision-making process in the study area, as it provides insight into determining suitable sites. By critically assessing the procedures and approaches used, the results can be more precise. Physical elements (topographical properties, soil and geological characteristics, etc.) are only part of the analysis, which must also include economic and social conditions for agricultural production. Because the pairwise comparison approach is based on expert judgments, which are primarily subjective in nature, it is used in the analytic hierarchy process. As a result, any incorrect judgment on any of the selected factors can be effectively communicated to the score assignment and weight designation. This is the main disadvantage of the analytic hierarchy approach; hence, weights and scores must be carefully chosen [32, 33]. For more helpful and accurate results, the study should focus on a few key species, such as several therapeutic plants and species that have substantial economic worth and also influence the advancement of rural tourism. The use of very high-resolution satellite images will aid in the assessment of finer areas. Before the ultimate implementation, the indicated locations must also be documented on the ground with various other local and regional parameters.
Acknowledgments
Authors are very much grateful of the Director, Defense Research & Development Organization, (DRDO) Govt. of India, New Delhi, for providing infrastructure and facilities during the work was carried out.
\n',keywords:"land suitability, AHP, FAO, northern region India, multi-criteria decision analysis, pairwise comparison matrix",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80925.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80925.xml",downloadPdfUrl:"/chapter/pdf-download/80925",previewPdfUrl:"/chapter/pdf-preview/80925",totalDownloads:29,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 22nd 2021",dateReviewed:"January 3rd 2022",datePrePublished:"March 22nd 2022",datePublished:null,dateFinished:"March 22nd 2022",readingETA:"0",abstract:"The purpose of this study was to identify adequate agricultural sites in Punjab’s Northern region India district (India). This research employed the “Analytic Hierarchy Process (AHP)” approach, which is extensively used in land use appropriateness studies. Great soil type, land use, land cover, soil moisture, slope, aspect, elevation, drainage, geology, and geomorphology were all incorporated into the application. The ranks of influencing criteria were calculated using expert judgments and correlation analysis, while the weights were determined using a pairwise comparison matrix. The scores for sub-parameters with internal variations in the criteria assigned based on field work and published norms. The study area is considered to be highly appropriate for agricultural production in 41.2% (39044.28 ha), moderately suitable in 14.3% (13498.76 ha), and marginally suitable in 4.2% (3993 ha). Furthermore, it was discovered that 1.9% of the land is now unfit for agricultural production (1766.6 ha), while 38.4% of the area is permanently unsuitable (36372.6 ha). The following facts were also discovered to be important in achieving these results: a large portion (approximately 45%) of the study area is covered with forests, built-up areas, and water bodies, the soil depth is insufficient for agricultural production, the slope in the study area is quite steep, and thus the erosion degree is high.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80925",risUrl:"/chapter/ris/80925",signatures:"Mujahid Ali Khan, Rizwan Ahmad and Haris Hasan Khan",book:{id:"11134",type:"book",title:"Geographic Information System",subtitle:null,fullTitle:"Geographic Information System",slug:null,publishedDate:null,bookSignature:"Prof. Yuanzhi Zhang and Dr. Qiuming Cheng",coverURL:"https://cdn.intechopen.com/books/images_new/11134.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-742-7",printIsbn:"978-1-80355-741-0",pdfIsbn:"978-1-80355-743-4",isAvailableForWebshopOrdering:!0,editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. 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USA and Canada: John Wiley & Sons; 1999'},{id:"B5",body:'Tkach RJ, Simonovic SP. A new approach to multi-criteria decision making in water resources. Journal of Geographic Information and Decision Analysis. 1997;1(1):25-43'},{id:"B6",body:'Jankowski P. Integrating geographical information systems and multiple criteria decision making methods. International Journal of Geographic Information System. 1995;3(2):251-273'},{id:"B7",body:'Pereira JMC, Duckstein L. A multiple criteria decision-making approach to GIS- based land suitability evaluation. International Journal of Geographical Information Science. 1993;7(5):407-424'},{id:"B8",body:'Ishizaka A, Labib A. Review of the main developments in the analytic hierarchy process. Expert Systems with Applications. 2011;38(11):14336-14345'},{id:"B9",body:'Saaty T. An Eigenvalue Allocation Model for Prioritization and Planning. In Working Paper. Pennsylvania: Energy Management and Policy Center University of Pennsylvania; 1972'},{id:"B10",body:'Saaty TL. A scaling method for priorities in hierarchical structure. Journal of Mathematical Psychology. 1977;15:3'},{id:"B11",body:'Shang J, Sueyoshi T. A unified framework for the selection of a flexible manufacturing system. European Journal of Operational Research. 1995;85(2):297-315'},{id:"B12",body:'Myint S, Tabucanon MT. A multiple-criteria approach to machine selection for flexible manufacturing systems. International Journal of Production Economics. 1994;33(1–3):121-131'},{id:"B13",body:'Liberatore MJ. An extension of the analytic hierarchy process for industrial R&D project selection and resource allocation. IEEE Transactions on Engineering Management. 1987;1:12-18'},{id:"B14",body:'Khorramshahgol R, Moustakis VS. Delphic hierarchy process (DHP): A methodology for priority setting derived from the Delphi method and analytical hierarchy process. European Journal of Operational Research. 1988;37(3):347-354'},{id:"B15",body:'Duran O, Aguilo J. Computer-aided machine-tool selection based on a fuzzy-AHP approach. Expert Systems with Applications. 2008;34(3):1787-1794'},{id:"B16",body:'Ayağ Z, Özdemir RG. A fuzzy AHP approach to evaluating machine tool alternatives. Journal of Intelligent Manufacturing. 2006;17(2):179-190'},{id:"B17",body:'Chang CW, Wu CR, Lin HL. Integrating fuzzy theory and hierarchy concepts to evaluate software quality. Software Quality Journal. 2008;16(2):263-276'},{id:"B18",body:'Xu L, Li Z, Li S, Tang F. A decision support system for product design in concurrent engineering. Decision Support Systems. 2007;42(4):2029-2042'},{id:"B19",body:'Lin YJ, Huang CW, Tseng JC, Shiau JY. Issue resolution for conceptual design using AHP. In: Intelligent Systems in Design and Manufacturing. Vol. 5605. Bellingham: SPIE; 2004. pp. 47-53'},{id:"B20",body:'Adhikari I, Kim SY, Lee YD. Selection of appropriate schedule delay analysis method: Analytical hierarchy process (AHP). In: Proceedings on PICMET. IEEE: Istanbul, Turkey; 2006'},{id:"B21",body:'Effat HA, Hassan OA. Designing and evaluation of three alternatives highway routes using the analytical hierarchy process and the least-cost path analysis, application in Sinai peninsula, Egypt. Egyptian Journal of Remote Sensing and Space Science. 2013;16(2):141-151'},{id:"B22",body:'Kiker GA, Bridges TS, Varghese A, Seager TP, Linkov I. Application of multicriteria decision analysis in environmental decision making. Integrated Environmental Assessment and Management. 2005;2:95-108'},{id:"B23",body:'Miller W, Collins W, Steiner FR, Cook E. An approach for greenway suitability analysis landscape and urban planning. International Journal of Geographical Information Science. 1998;42(2–4):91-105'},{id:"B24",body:'Feizizadeh B, Jankowski P, Blaschke T. A GIS based spatially-explicit sensitivity and uncertainty analysis approach for multi-criteria decision analysis. Computational Geosciences. 2014;64:81-95'},{id:"B25",body:'Thomas PG, Doherty PC. The analytic hierarchy. In: Process: Planning Priority Setting, Resource Allocation. New York: McGraw-Hill; 1980'},{id:"B26",body:'Akinci H, Ozalp AY, Turgut B. Agriculture land use suitability analysis using GIS and AHP technique. Computers and Electronics in Agriculture. 2013;97:71-82'},{id:"B27",body:'Garcia JL, Alvarado A, Blanco J, Jimenez E, Maldonado AA, Cortés G. Multi-attribute evaluation and selection of sites for agricultural product warehouses based on an analytic hierarchy process. Computers and Electronics in Agriculture. 2014;100:60-69'},{id:"B28",body:'Cengiz T, Akbulak C. Application of analytical hierarchy process and geographic information systems in land-use suitability evaluation: A case study of Dumrek village. The International Journal of Sustainable Development & World Ecology. 2009;16(4):286-294'},{id:"B29",body:'Chen H, Liu G, Yang Y, Ye X, Shi Z. Comprehensive evaluation of tobacco ecological suitability of Henan Province based on GIS. Agricultural Sciences in China. 2010a;9(4):583-592'},{id:"B30",body:'Chen Y, Yu J, Khan S. Spatial sensitivity analysis of multi-criteria weights in GIS-based land suitability evaluation. Environmental Modelling & Software. 2010;25(12):1582-1591'},{id:"B31",body:'Park S, Jeon S, Kim S, Choi C. Prediction and comparison of urban growth by land suitability index mapping using GIS and RS in South Korea. Landscape and Urban Planning. 2011;99(2):104-114'},{id:"B32",body:'Kritikos TRH, Davies TRH. GIS-based multi-criteria decision analysis for landslide susceptibility mapping at northern Evia, Greece [GIS-basierte multikriterielle Entscheidungsanalysen zur Kartierung von Massenverlagerungspotenzialen im nördlichen Evia. Griechenl]. Z. Dtsch. Ges. Für Geowiss. 2011;162:421-434'},{id:"B33",body:'Nefeslioglu HA, Sezer EA, Gokceoglu C, Ayas Z. A modified analytical hierarchy process (M-AHP) approach for decision support systems in natural hazard assessments. Comput. Geosci. 2013;59:1-8'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Mujahid Ali Khan",address:null,affiliation:'
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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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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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