\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7935",leadTitle:null,fullTitle:"Renal Diseases",title:"Renal Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Renal diseases can be explosive and difficult to control or silent but progressive. Those that create acute and chronic renal failure become serious and often life-threatening burdens to patients and their families. Advanced diseases can be resistant to treatment and extremely expensive to manage. Early and precise diagnosis is the best solution to these problems. Renal biopsy is often the most efficient method for accurate diagnosis to allow disease-modifying therapy with steroids, anti-rejection immunosuppressive medication, plasmapheresis, or the new immunomodulating biological drugs. This book is a primer on the rationale for precise diagnosis of renal diseases to allow the greatest chance of stabilizing or remitting these diseases, which will otherwise create a permanent need for dialysis or transplantation. This collection of reports documents the type of disease that can be identified by renal biopsy. Reports from authors around the world describe their experience with the techniques, risk, and benefits of renal biopsy. These reports conclude that renal biopsy has become a universally used, safe, same-day, outpatient procedure that can give suggestions for treatments to prevent potentially devastating consequences.",isbn:"978-1-78985-132-8",printIsbn:"978-1-78985-131-1",pdfIsbn:"978-1-78985-913-3",doi:"10.5772/intechopen.77765",price:100,priceEur:109,priceUsd:129,slug:"renal-diseases",numberOfPages:78,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"44715ed141cf23ebdd35ff0d772492df",bookSignature:"Edward T. Zawada Jr. and Sohail Abdul Salim",publishedDate:"March 4th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7935.jpg",numberOfDownloads:5133,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 10th 2019",dateEndSecondStepPublish:"February 25th 2019",dateEndThirdStepPublish:"April 26th 2019",dateEndFourthStepPublish:"July 15th 2019",dateEndFifthStepPublish:"September 13th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr.",profilePictureURL:"https://mts.intechopen.com/storage/users/16344/images/system/16344.jpeg",biography:"Edward T. Zawada Jr. graduated summa cum laude from Loyola\nUniversity in 1969 and summa cum laude from Loyola-Stritch\nSchool of Medicine in 1973. He trained at the University of\nCalifornia at Los Angeles (UCLA) from 1973 to 1978. His faculty\npositions include UCLA, University of Utah, Medical College of\nVirginia, and University of South Dakota. Other positions include professor and chairman emeritus, Department of Internal\nMedicine, University of South Dakota, Sanford School of Medicine; and Bush Foundation of Minnesota Sabbatical Fellowship in Critical Care, Department of Anesthesiology at the University of Iowa in 2009. Dr. Zawada Jr. is board certified by the\nAmerican Board of Internal Medicine in Internal Medicine, Nephrology, Geriatrics, and Critical Care Medicine. Other board certifications include Nutrition and\nClinical Pharmacology. He is a Master of the American College of Physicians and\nFellow of the American College of Critical Care Medicine, the American Society of\nNephrology, the American Society of Hypertension, the American College of Chest\nPhysicians, the American College of Clinical Pharmacology, the American College\nof Nutrition, and the American Heart Association.",institutionString:"University of South Dakota",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"University of South Dakota",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"270379",title:"Dr.",name:"Sohail",middleName:null,surname:"Abdul Salim",slug:"sohail-abdul-salim",fullName:"Sohail Abdul Salim",profilePictureURL:"https://mts.intechopen.com/storage/users/270379/images/system/270379.jpg",biography:"Dr. Salim is an American Board Certified Nephrologist practicing in Jackson Mississippi. He finished his Internal medicine residency in 2011 from Brookdale Hospital medical center and fellowship in Nephrology and Hypertension in 2017 from University of Mississippi. He has received best abstract award from University of Mississippi and also Fellow scholarship from Annual dialysis conference. During the last 3 years he has authored around 10 poster presentations, 27 peer reviewed publications (most of them as first author) and written 2 book chapters. He has also lectured for multiple conferences the most recent been 'Nephrology Essentials” for Society of Hospital Medicine. He serves as a reviewer for at least 5 different Journals. His research interests are mostly related to nephrotoxic drugs affecting the kidney and its implications in clinical practice.",institutionString:"University of Mississippi Medical Center",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Mississippi Medical Center",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1163",title:"Nephrology",slug:"nephrology"}],chapters:[{id:"70176",title:"Introductory Chapter: Renal Diseases",doi:"10.5772/intechopen.90067",slug:"introductory-chapter-renal-diseases",totalDownloads:659,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Edward T. Zawada",downloadPdfUrl:"/chapter/pdf-download/70176",previewPdfUrl:"/chapter/pdf-preview/70176",authors:[{id:"16344",title:"Dr.",name:"Edward T.",surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],corrections:null},{id:"67549",title:"Role of Surgery in Nephrotic Syndrome",doi:"10.5772/intechopen.86732",slug:"role-of-surgery-in-nephrotic-syndrome",totalDownloads:752,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Nephrotic syndrome can occur at any age—adult or children—though the etiology and histopathology may be different in these groups. The management is mostly medical and supportive, but there is some role of surgery in certain complications of nephrotic syndrome, which are rarely discussed together. Here we would like to elaborate some of the areas that require the involvement of surgeons in patients with nephrotic syndrome, to list the complications, and to discuss in brief the surgeries involved. There is a need for randomized prospective studies of nephrotic syndrome patients needing surgical interventions to further project their precise relations and outcomes.",signatures:"Intezar Ahmed and Enono Yhoshu",downloadPdfUrl:"/chapter/pdf-download/67549",previewPdfUrl:"/chapter/pdf-preview/67549",authors:[{id:"281889",title:"Associate Prof.",name:"Intezar",surname:"Ahmed",slug:"intezar-ahmed",fullName:"Intezar Ahmed"},{id:"298703",title:"Dr.",name:"Enono",surname:"Yhoshu",slug:"enono-yhoshu",fullName:"Enono Yhoshu"}],corrections:null},{id:"68244",title:"Renal Biopsy: Appraisal of the Methods",doi:"10.5772/intechopen.86755",slug:"renal-biopsy-appraisal-of-the-methods",totalDownloads:782,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Renal biopsy is an invasive specialized test aimed at obtaining renal tissue for histologic diagnosis of a variety of kidney diseases. Common indications for renal biopsy in practice include adult nephrotic syndrome, steroid resistant or clinically atypical nephrotic syndrome in children, glomerulonephritis, acute kidney injury (AKI) of unknown aetiology, systemic diseases with renal involvement, and persistent proteinuria or haematuria with reduced renal function. Over the years there has been continuous refinement of renal biopsy techniques. It is now mostly performed percutaneously using imaging guidance and more sophisticated spring-loaded needles of varying sizes. Other non-percutaneous techniques such as transjugular, laparoscopic and open renal biopsy are also being performed especially in patients with contraindications to the percutaneous approach. Percutaneous ultrasound guided approach is standard care for biopsy of non-focal lesions. The CT-guided method can be used in obese patients and other patients who are unable to lay prone, patients with complex anatomy, and when the kidneys are not sufficiently visualised by ultrasound scan. The transjugular technique is most popular for combined liver and kidney biopsy. The major advantages of the laparoscopic and open biopsy techniques are the opportunity for direct visualization of the kidney and good intra-operative haemostasis.",signatures:"Ogochukwu Okoye",downloadPdfUrl:"/chapter/pdf-download/68244",previewPdfUrl:"/chapter/pdf-preview/68244",authors:[{id:"291196",title:"Dr.",name:"Ogochukwu",surname:"Okoye",slug:"ogochukwu-okoye",fullName:"Ogochukwu Okoye"}],corrections:null},{id:"68282",title:"Hemodialysis and Oral Health",doi:"10.5772/intechopen.87085",slug:"hemodialysis-and-oral-health",totalDownloads:805,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Changing lifestyle and sedentary schedule have led to the substantial increase in major noncommunicable diseases (NCDs) such as cardiac problems, cancers, diabetes, psychiatric disorders, and chronic respiratory diseases. Recent times have shown increased trends in incidence as well as prevalence of renal diseases. Hemodialysis is the most opted treatment modality for the patients of chronic renal diseases. Hence, the aim of the current chapter is to address the effect of renal diseases and its treatment on oral health. An extensive literature search from the year 2000 till 2015 was conducted to assess the effect of hemodialysis and renal diseases on various clinical parameters associated with oral health like dental caries, periodontal diseases, prevalence of calculus, etc. The literature review revealed that the dental health is compromised in the patients undergoing hemodialysis therapy. The oral health-related parameters get worsened with increasing duration of hemodialysis as well. The primary reason behind the debilitated periodontal condition among the patients may be attributed to the neglect of proper oral hygiene practices by the patient as they are preoccupied by more time-consuming and life-threatening kidney disease. A strong relation between oral health and hemodialysis has been observed. There is a need for further interdisciplinary research with emphasis on preventive dental treatment for the patients undergoing hemodialysis ensuring optimum outcome.",signatures:"Swati Jain, Kirti Jain and Basavaraj Patthi",downloadPdfUrl:"/chapter/pdf-download/68282",previewPdfUrl:"/chapter/pdf-preview/68282",authors:[{id:"292399",title:"Dr.",name:"Swati",surname:"Jain",slug:"swati-jain",fullName:"Swati Jain"},{id:"293787",title:"Dr.",name:"Kirti",surname:"Jain",slug:"kirti-jain",fullName:"Kirti Jain"},{id:"293790",title:"Dr.",name:"Basavaraj",surname:"Paththi",slug:"basavaraj-paththi",fullName:"Basavaraj Paththi"}],corrections:null},{id:"69134",title:"Post-Biopsy Complications Associated with Percutaneous Kidney Biopsy",doi:"10.5772/intechopen.89226",slug:"post-biopsy-complications-associated-with-percutaneous-kidney-biopsy",totalDownloads:813,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Renal physiology and physiopathology have been the object of studies aimed at developing exams that can assist in the early diagnosis of the base disease. Chronic kidney disease consists of the progressive, irreversible loss of kidney function. Early detection and appropriate treatment can minimize the progression of the disease, lower the inherent costs, and improve the quality of life of affected individuals. Kidney biopsy is the key method in this evaluation, as it enables the histological and immunohistochemical analysis of specimens in a fast, safe, and economical manner. The main indications for kidney biopsy are nephrotic syndrome, acute kidney failure of unknown etiology, persistent hematuria and proteinuria, chronic kidney disease with conserved kidney dimensions, and transplanted kidneys (to evaluate stages of rejection, infection, and/or sclerosis). However, as an invasive method, kidney biopsy is not without complications. Post-biopsy complication rates range from 5 to 15%, with 6.6% considered minor (macrohematuria with no need for blood transfusion) and another 7.7% considered major (hemorrhage requiring blood transfusion or other approaches). In this chapter, we address the main aspects of kidney biopsy, the technical procedures for its execution, and the management of the main complications stemming from this procedure.",signatures:"Paulo Ramos Botelho Antunes, Stanley Almeida Araújo, Silvana Maria Carvalho Miranda, Fabiano Franco Monteiro Prado, Luiz Felipe França Antunes, Elisa Carvalho de Siqueira, Fabrício Tinôco Alvim de Souza and Maria Carolina Barbosa Álvares",downloadPdfUrl:"/chapter/pdf-download/69134",previewPdfUrl:"/chapter/pdf-preview/69134",authors:[{id:"70060",title:"Dr.",name:"Maria Carolina",surname:"Barbosa Álvares",slug:"maria-carolina-barbosa-alvares",fullName:"Maria Carolina Barbosa Álvares"},{id:"78648",title:"Prof.",name:"Stanley",surname:"Araujo",slug:"stanley-araujo",fullName:"Stanley Araujo"},{id:"294062",title:"Ph.D.",name:"Grupo De Pesquisa Em Radiologia",surname:"Santa Casa Bh",slug:"grupo-de-pesquisa-em-radiologia-santa-casa-bh",fullName:"Grupo De Pesquisa Em Radiologia Santa Casa Bh"},{id:"294065",title:"Prof.",name:"Fabricio",surname:"Tinôco Alvim De Souza",slug:"fabricio-tinoco-alvim-de-souza",fullName:"Fabricio Tinôco Alvim De Souza"},{id:"294066",title:"Prof.",name:"Elisa",surname:"Carvalho De Siqueira",slug:"elisa-carvalho-de-siqueira",fullName:"Elisa Carvalho De Siqueira"},{id:"294067",title:"Prof.",name:"Paulo",surname:"Ramos Botelho Antunes",slug:"paulo-ramos-botelho-antunes",fullName:"Paulo Ramos Botelho Antunes"},{id:"294068",title:"Prof.",name:"Fabiano",surname:"Franco Monteiro Prado",slug:"fabiano-franco-monteiro-prado",fullName:"Fabiano Franco Monteiro Prado"},{id:"308260",title:"Dr.",name:"Luiz Felipe",surname:"França Antunes",slug:"luiz-felipe-franca-antunes",fullName:"Luiz Felipe França Antunes"},{id:"308293",title:"Dr.",name:"Silvana Maria",surname:"Carvalho Miranda",slug:"silvana-maria-carvalho-miranda",fullName:"Silvana Maria Carvalho Miranda"}],corrections:null},{id:"69943",title:"Causes and Pathophysiology of Nephrotic Syndrome in Childhood",doi:"10.5772/intechopen.86825",slug:"causes-and-pathophysiology-of-nephrotic-syndrome-in-childhood",totalDownloads:1322,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nephrotic syndrome is a general type of kidney disease seen in children. In the past, Roelans is credited with the first clinical description of nephrotic syndrome in the late fifteenth century. Nephrotic syndrome is appropriate to excessive hypoalbuminemia, edema, and proteinuria may be hyperlipidemia also present in some cases. Periorbital swelling with or without edema of the body is observed in first starting little period of life, frequently show in children with this condition. Nephrotic syndrome starts develops due functional and structural changes in the GFB, consequential difficulty to control protein in the urine. Nephrotic syndrome possibly causes due to some of glomerular diseases and systemic diseases, but significantly the mostly in childhood is unknown nephrotic syndrome. The first significant improvement with introduction of sulfonamides and then penicillin was seen in 1939. The beginning of adrenocorticotropic hormone and cortisone greater decrease in mortality (to 9%), in the 1950s it was noted to happen in association with spectacular declaration of proteinuria. Etiology of nephrotic syndrome is also age reliant. Most cases reported in the first 3 months of life are referred to as congenital nephrotic syndrome (CNS) and are due to genetic diseases.",signatures:"Nagaraju Vallepu, Saikiran Velpula, Bharath Kumar Dasari, Manish Kumar Thimmaraju, Sridhar Babu Gummadi, Neeraja Yelugam and Supraja Jannu",downloadPdfUrl:"/chapter/pdf-download/69943",previewPdfUrl:"/chapter/pdf-preview/69943",authors:[{id:"299209",title:"Mr.",name:"Nagaraju",surname:"Vallepu",slug:"nagaraju-vallepu",fullName:"Nagaraju Vallepu"},{id:"300126",title:"Mr.",name:"Saikiran",surname:"Velpula",slug:"saikiran-velpula",fullName:"Saikiran Velpula"},{id:"300128",title:"Dr.",name:"Manishkumar",surname:"Thimmaraju",slug:"manishkumar-thimmaraju",fullName:"Manishkumar Thimmaraju"},{id:"300130",title:"Dr.",name:"Sridhar Babu",surname:"Gummadi",slug:"sridhar-babu-gummadi",fullName:"Sridhar Babu Gummadi"},{id:"300131",title:"Mr.",name:"Bharathkumar",surname:"Dasari",slug:"bharathkumar-dasari",fullName:"Bharathkumar Dasari"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6537",title:"Evolving Strategies in Peritoneal Dialysis",subtitle:null,isOpenForSubmission:!1,hash:"76bb5dc2ce63f0026f7993b54f062861",slug:"evolving-strategies-in-peritoneal-dialysis",bookSignature:"Edward T. Zawada, Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/6537.jpg",editedByType:"Edited by",editors:[{id:"16344",title:"Dr.",name:"Edward T.",surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5314",title:"Challenges in Elder Care",subtitle:null,isOpenForSubmission:!1,hash:"1a1249d3819657dcd1f41ebb7dff4d17",slug:"challenges-in-elder-care",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/5314.jpg",editedByType:"Edited by",editors:[{id:"16344",title:"Dr.",name:"Edward T.",surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. 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Numerical weather prediction (NWP) models are one of the factors contributing to the complex process of providing an accurate weather forecast. A number of global NWP models forecast weather over the whole Earth seven or more days in advance. These large scale global models do not provide high-resolution details that can be important for the weather we feel in a particular point (sensible weather). These details are often provided by limited area models (LAMs) that cover a particular area of interest as will be exemplified in this chapter. The Croatian Meteorological and Hydrological Service (CMHS) uses ALADIN (Aire Limitée Adaptation Dynamique développement InterNational, ALADIN International Team, 1997) limited area model for the operational weather forecast. This chapter describes the operational NWP aspects in CMHS and provides an insight into high impact weather phenomena that are typical for this region.
The quality of NWP model forecast depends on the NWP model that is used to compute the meteorological forecast fields. Model forecast should improve with the improvements in the model equations and parameterizations used to describe the atmospheric processes (Pielke 2002, Durran 1999, Werner et. al 1997). Another factor is the quality and availability of the measured atmospheric data used as input for the data assimilation procedure that creates the initial conditions for the model forecast. Limited area models also require the lateral boundary conditions data which are another factor contributing to the quality of the weather forecast. Both initial and lateral boundary conditions are usually taken from a larger scale and lower resolution NWP model covering larger geographical area. The initial conditions can be modified using a local initialization procedure.
The operational forecast suite in CMHS uses the initial lateral boundary conditions from the ARPEGE (Action de Recherche Petite Echelle Grande Echelle, http://www.cnrm.meteo.fr/ gmapdoc/meshtml/guide_ARP/arpege.html) global NWP model run operationally at Meteo-France. Another set of initial and boundary conditions available in CMHS is from the Integrated Forecast System (IFS, http://www.ecmwf.int/research/ifsdocs/CY36r1/ index.html) of the European Centre for Medium-Range Weather Forecast (ECMWF).
The files received from Meteo-France and ECMWF do not contain the global model fields covering the whole Earth on the native ARPEGE or IFS grid and model levels. To optimize the data transfer, the model data is interpolated to a limited-area Lambert projection grid in a resolution similar to the one of the global model in that area and it is covering a wider geographical area than the local LAM that uses it. Since ALADIN is a spectral model, initial and boundary conditions contain the meteorological data covering the whole model domain in the form of spectral coefficients, and not only the data on the lateral boundaries.
The scheme of the steps taken when making the weather forecast
The number of levels in the vertical is reduced (from 70 in ARPEGE or 91 in IFS to 37 in ALADIN Croatia), since LAM does not have to reach as high in the atmosphere as the global models. The global models have considerably longer forecast range (10 to 15 days in advance) that require knowledge of the atmospheric processes as high as the stratosphere top and mesosphere. These processes have negligible impact in the 72 hour forecast range used for the operational ALADIN forecast in CMHS..
The forecast process (Fig 1) consists of several steps:
collect the measured data representative for the initial forecast time from upper-air soundings, surface stations, meteorological satellites, aircraft and radar data,
data quality control which removes measurements if values are too far from the first guess, removal of observations according to empirical (black)list and surface observations with too large height difference between model orography and real station height.
establishment of the initial and lateral boundary conditions using data obtained from a larger scale (global) model,
the NWP model forecast run that consists of:
the data assimilation procedure that produces the analysis (“best possible” approximation of atmospheric initial conditions for the model forecast run),
the NWP model forecast,
diagnostics of the derived parameters from the model variables during the forecast run,
post-processing of the model output data.
Weather forecasts are time-critical applications. This means that the value of the products quickly degrades with time. In other words, the model forecast run has to finish before a certain time in the day, according to the requirements of the users. The choices of the input data and the model complexity that are used operationally also depend on the hour at which the weather forecast products should be available to the users. It is desired to keep the time span between the data measurements and the availability of the weather forecast as short as possible or within a reasonable interval usually determined by procedures in the forecast office or requirements of the other users. The time required for each forecast step in Figure 1 is determined by technical limitations such as the capacity of data transfer to the institution providing the weather forecast as well as the speed of the mainframe computer executing the NWP model software. The amount of data used in points (1) and (2) is limited by the capacity of data storages and speed of the data transfer lines. The complexity of the operational NWP model, as well as the size and grid resolution of the model domain is determined by this time span and the computer power. ARPEGE model data was the primary choice for the ALADIN operational model input in CMHS since it is available much earlier than the IFS model data (Fig 2). IFS is available later than ARPEGE because the data assimilation procedure starts later since it waits to assimilate more measured data. On the other hand, ARPEGE provides two sets of input data, as will be described later.
The schedule and timing of the 00 UTC operational run in August 2011.
A considerable effort in the research and development of the ALADIN model has been devoted to the model optimization and various model options with an aim to provide the best possible forecast in the short time using available computer power (Yessad, 2011). To improve the 10 m wind forecast in severe wind situations, like bura (local name for bora) windstorms, a procedure that provides a high resolution forecast of the wind 10 m above ground has been established. The high-resolution dynamical adaptation (HRDA) of the wind field using a hydrostatic version of the ALADIN model has been introduced to the operational suite soon after the 8 km resolution operational forecast runs have started in 2000 (Ivatek-Šahdan & Tudor, 2004).
ALADIN has been developed by a group of scientists from 16 countries and shares a considerable part with the global models IFS and ARPEGE. Both global models are a result of a coordinated effort of ECMWF and Meteo-France. Another LAM developed on the basis of IFS global model is HIRLAM (High Resolution Limited Area Model, Unden et al 2002). These models share the same source code in many parts of the model. A considerable part of the dynamics and data assimilation is in common too. ALADIN can use the same vertical discretization, grid-point dynamics and the various physics options as the global model ARPEGE. This section describes the operational model characteristics, the domains and other options used in the operational suite.
The operational ALADIN model forecast is run on a Lambert-projection domain with 8 km horizontal resolution (Fig 3). The model fields are subsequently going through a dynamical adaptation procedure (Ivatek-Šahdan & Tudor, 2004) that produces 2 km resolution forecast of 10 m wind speed and gusts for a smaller domain shown in Figure 3. The procedure adapts the wind field of the 8 km resolution forecast and uses hydrostatic set-up of the ALADIN model with turbulence parameterization only. As an addition to the operational forecast, a 2 km resolution 24 hour forecast was established recently, that uses non-hydrostatic (NH) dynamics and the full parameterization set, including radiation, microphysics and convection schemes. This forecast is run for the same small domain (Fig 3).
The ALADIN model domains and terrain height used operationally in CMHS.
In the ALADIN community, the initial conditions for the model forecast can be obtained using different approaches:
using the large scale model data as initial conditions,
blending the large scale information from low resolution global model fields with the high resolution features from the previous LAM forecast,
using the data-assimilation procedure.
The first approach is used operationally in CMHS since the beginnings of the operational ALADIN forecast suite in 2000. There the upper-air and surface fields are taken from the ARPEGE global model and interpolated to the ALADIN grid. Afterwards, these fields are balanced using digital filter initialization (DFI) procedure (Lynch & Huang, 1994). However, the removal of the high-frequency wave energy from the initial conditions also affects the fast meteorological waves. Termonia (2008) showed how DFI can significantly reduce the depth of the eye of the storm and proposes a solution in the scale-selective DFI (SSDFI).
The second approach has not been used in CMHS, but blending has been used extensively in the ALADIN operational forecast suite in the Czech Meteorological and Hydrological Institute (CHMI, Brožkova et. al., 2001) as well as several other ALADIN member services (Hdidou, 2006). The blending procedure makes use of the fact that ALADIN is a spectral model. The initial model fields are constructed from the long waves coming from the low resolution model (ARPEGE) and short waves from the high resolution model (ALADIN).
Schematic view of the data assimilation cycle.
The last approach is to initialize ALADIN model using data assimilation and currently it is used in experimental configuration in CMHS. Data assimilation is a procedure wherein information coming from measurements is combined with some a priori estimate (usually a short range forecast often called first-guess or background field) and their associated observation and background model errors, respecting the model dynamical balances, to get the analysis - a maximal likelihood or “as best as possible” approximation of the true state of the atmosphere at a given time. There are different methods of solving this analysis problem (Hólm 2008) and at CMHS two of them are used: the optimal interpolation (OI, Courtier 1999) and the variational method (3DVAR, Hollingsworth et al, 1998). Optimal interpolation is used for updating land surface fields while 3DVAR is used for analysis of upper air fields. It was shown by Mahfouf (1991) that 2m analysis increments of temperature and humidity computed with OI can be used to update the land surface variables. As only the increments of 2m temperature and relative humidity are needed, and only the surface measurements are used, rather simple OI method was implemented for computing the 2m analysis increments. For the upper air fields more control variables are defined, more sources of data are used, and more sophisticated variational algorithm (3DVAR) is implemented. 3DVAR belongs to the group of intermittent variational data assimilation strategies, and whereas the true state of the atmosphere is never known, the principal challenge in determining the analysis is to estimate the background (model) errors. Namely, knowledge of the background error statistics is used to derive the analysis increments and transfer this information in horizontal and vertical directions in the atmosphere. The background error statistics is in CMHS estimated by using the so-called standard NMC method. In this approach, background error statistics is derived from a set of differences between forecasts that are valid at the same time, but at different forecast horizons, typically 12 and 36 hours. In addition, the multivariate formulation of the background error statistics that uses vorticity, divergence, temperature and surface pressure, and humidity as control variables (Berre, 2000), allows the propagation of the analysis increments from one to all the other variables, and thus increases the effect of each single observation. Finally, the potential use of the ensemble and seasonal formulations of the background error statistics is currently being investigated.
Practical implementation of data assimilation setup in CMHS is illustrated in Figure 4 that shows the scheme of one assimilation cycle. Because of limited computer resources the assimilation cycle is run in quasi-operational mode i.e. observation data is taken at the operational time, but the assimilation procedure is performed with certain time delay. An assimilation cycle is a sequence of a 6 hour forecast and analysis that is run on a daily basis. In the first step, SST in the 6h forecast from previous cycle (background) is replaced with SST taken from global model ARPEGE analysis. This replacement is done because no local SST analysis is implemented. In the second step, the background land surface variables are updated. As there are almost no or very little surface observations available, 2m observations are used to retrieve information about the surface temperature and soil water content. Therefore, after the quality control of the 2m observations, an optimal interpolation is used to calculate increments of 2m temperature and relative humidity. These increments in a more or less sophisticated way are propagated into the land surface equivalents and used for updating the land surface variables. In the next step, the background upper air fields are analysed using 3DVAR. The standard NMC background error statistics is calculated by the aforementioned procedure over a 100-day period, from 15 Feb – 25 May 2008. The background error matrix was not tuned a posteriori such as in some other NWP systems (Bölöni and Horvath, 2010). The 3DVAR procedure includes a quality control of available data (screening) and minimization procedure that as output produces an analysis which is used for initiating the 6h forecast. The assimilation cycle is repeated every 6 hours, at 00, 06, 12 and 18 UTC. It is also run with a time delay big enough to enable usage of long cut off ARPEGE coupling files (the ARPEGE model is run later and in assimilation all data is used) for boundary conditions of 6h ALADIN forecast. Also long cut off data is used in cycle (data available after the time period needed to collect all observations of interest). Production from the assimilation cycle is done following same steps as in the assimilation cycle but at its end, a 72h forecast is performed. However, to perform a quasi-operational 72 hours forecast, timing constrain does not allow to use long cut off data and long cut off ARPEGE files; thus short cut off data and ARPEGE files are used.
The NWP model characteristics are usually described in the terms of the model numerics, dynamics and physics. Model numerics refers to the model computational domain, coordinate system, model resolution and grid as well as the mathematical methods used to solve the system of the prognostic differential equations.
Model dynamics refers to the resolvable processes that are resolved by the model grid and described by the set of model equations for horizontal and vertical momentum and conservation of mass and thermodynamic properties. These processes encompass advection, pressure gradient force and adiabatic changes of heat/temperature.
The model dynamics is computed using semi-implicit time integration scheme (Robert, 1982). An implicit treatment of the gravity wave equation is absolutely stable (Durran, 1999). The semi-implicit scheme treats implicitly only a linearized form of the adjustment terms in the shallow water equations. The method results in solving the Helmholtz equation in spectral space.
ALADIN is a shallow-water spectral limited-area model. It applies Fourier spectral representation of the model variables. That allows the advantage of fast Fourier transforms (FFTs) in both directions. An elliptic truncation that limits the Fourier series (Machenhauer & Haugen, 1987) ensures an isotropic horizontal resolution. The number of grid points in each horizontal direction of the whole integration area (N) is chosen so that N>3M+1, where M is the truncation wave-number in the same direction. This representation ensures that the nonlinear terms of the model equations are computed without aliasing. The model fields are transferred from spectral to grid-point space and back in each model time step.
The accumulation of energy at the shortest wavelengths, due to spectral blocking, is reduced by a common 4th order numerical diffusion at the end of the time step. Semi-Lagrangian interpolators can be more or less diffusive (Staniforth and Cote, 1991). Combining two interpolators of different diffusivity with the flow deformation as a weighting factor yields more physical horizontal diffusion scheme that is based on the physical properties of the flow (Vana et al., 2008). This semi-Lagrangian horizontal diffusion (SLHD) is combined with numerical diffusion that removes short waves from the high layers of the atmosphere.
The advection of the prognostic variables in the model is computed using two-time-level semi-Lagrangian scheme. The method takes the model grid-points as the arrival points of the trajectory. The trajectories are computed one time step backwards to the origin points.
The model prognostic variables that are involved in the semi-implicit computations in the hydrostatic version of the model are surface pressure, the horizontal wind components, temperature and water vapour. The non-hydrostatic dynamics involves two additional model variables: pressure departure and vertical divergence that are treated by the semi-implicit computations. The developments in physics have introduced more prognostic variables to the model, such as cloud water and ice, rain and snow, as well as convective updraft and downdraft vertical velocities and mesh fractions. These quantities can be (optionally) advected by the semi-Lagrangian scheme and diffused by SLHD but do not enter the semi-implicit computations. In the operational forecast run, all these variables are advected, but SLHD is applied only to water vapour, cloud water and ice. This configuration supports modelling the advection in the atmospheric front, but may spoil the forecast of rainfall due to orography or other local feature that does not move with the flow,
The finite difference method is used to solve the model equations in the vertical, on 37 levels of hybrid pressure type eta coordinate (Simmons & Burridge, 1981). The primitive prognostic equations are solved for the prognostic variables using the two time level, semi-implicit, semi-Lagrangian advection scheme with a second-order accurate treatment of the nonlinear residual (Gospodinov et al. 2001).
LAM uses the large scale model data in a narrow coupling zone on the lateral boundaries and at discrete time intervals. The coupling of the model variables is done using Davies (1976) relaxation scheme in a narrow zone on the lateral boundaries of the LAM domain (Fig 5). The model dynamics requires usage of time dependent and periodic LBCs (Haugen & Machenhauer, 1993). The coupling procedure has to be applied at the very beginning or end of the grid-point computations (Radnoti, 1995) due to constraints imposed by the model dynamics. Various schemes for the lateral boundary treatment are associated to different problems (Davies, 1983). Werner et al. (1997) give an overview of weaknesses of the LAM forecast caused by the LBCs.
The lateral boundary conditions (LBC) are operationally obtained with a 3 hour interval. This interval is a compromise between the need to reduce the amount of data that have to be transferred and stored and the need to capture fast cyclones, fronts and other meteorological phenomena that can enter the LAM domain through its lateral boundaries. The coupling scheme requires large scale data in the coupling zone for each LAM time step. The large scale model data in the coupling zone is interpolated linearly in time. The time span between the available LBC data of 3 hours and the coupling zone width is 8 grid-points in 8 km resolution. Three hours can be sufficiently long and 64 km can be narrow so that a particular meteorological feature can cross the coupling zone within the coupling interval (Fig 5). Solutions to this problem have been proposed, that include an alternative coupling scheme or interpolation in time (Tudor & Termonia, 2010), but have not been implemented to the operational model so far. The operational 2km resolution forecast uses LBC data from the operational 8 km resolution forecast with a 1 h interval.
In the two-way coupling approach, the flow information about the state of the atmosphere goes from the small-scale model to the large scale one, as well as in the opposite direction. This method requires simultaneous integration of both high and low resolution runs. For that reason, the operational 8km and 2 km resolution runs use one-way coupling that allows transfer of information only from the large-scale to the small-scale model run. The high resolution forecast starts only after the low resolution one is finished.
Schematic view illustrating the coupling problem.
Model physics describe the processes unresolved by the model grid, radiation, cloud microphysics and surface processes. The processes described by the model physics are said to be parameterized (Pielke, 2002). The sub-grid-scale and diabatic processes are parameterized so their contribution to the changes in the large-scale state of the atmosphere can be considered.
The convective processes redistribute momentum, heat and moisture in the vertical. The deep convection parameterization (Fig 6) used in ALADIN (Gerard & Geleyn, 2005) is a prognostic mass-flux scheme (Gerard, 2007) where convective processes are treated with the use of prognostic variables for updraft and downdraft vertical velocities and mesh fractions (Gerard et al., 2009).
Cloud microphysics describe the processes of condensation, evaporation, freezing and melting as well as the processes that transform the cloud water droplets and ice crystals into rain and snow (Fig 6). ALADIN uses a simple microphysics scheme with prognostic cloud water and ice, rain and snow (Catry et al., 2007) and a statistical approach for sedimentation of precipitation (Geleyn et al., 2008). The microphysics scheme of the resolved processes is kept as close as possible to the original scheme that was without the prognostic condensates. The original scheme is the Kessler (1969) type scheme with modifications (Geleyn et. al. 1994) that include melting and freezing and imposing a brutal transition from ice to water at the temperature triple point.
The radiation processes described in the model encompass the transfer, scattering, absorption and reflection of the shortwave solar radiation and long-wave thermal radiation of the Earth\'s surface and clouds. There are several radiation schemes available in the ALADIN model (Morcrette, 1989, Mlawer et. al. 1997), but the simplest one is used in the operational version. The operational scheme (Ritter and Geleyn 1992) is based on Geleyn and Hollingsworth (1979) scheme. It is simple and computationally cheap since it uses only one spectral band for long-wave and one for short-wave radiation computations. The scheme has been enhanced recently (Geleyn et. al. 2005a, 2005b) but these modifications did not improve the cloud and temperature forecast in the stratus and fog case (Tudor, 2010).
Schematic view of the scheme of the prognostic variables describing microphysics and convection and associated processes in the version of the ALADIN model used in CMHS.
The turbulence parametrization scheme describes the impact of the unresolved motion and surface roughness on the vertical transfer of heat, momentum and moisture. The turbulent exchange coefficients are modified from Louis et al. (1982) and are computed using prognostic values of TKE (turbulent kinetic energy) according to Geleyn et al. (2006) and Redelsperger et al. (2001).
The gravity wave drag and lift parameterization scheme describes the vertical momentum flux due to the atmospheric waves generated by the unresolved topographic features. The surface parameterization schemes describe the soil properties and their impact on the meteorological model variables. ISBA (Interaction Soil Biosphere Atmosphere) is the surface scheme used in the operational forecast (Noilhan & Planton, 1989) as well as in the surface data assimilation (Giard & Bazile, 2000). The scheme describes the exchange of heat and moisture between land surface and air using thermal and hydrological properties of particular soil types (described with dominant land-use type, percentages of clay, sand and silt, useful soil depth, thermal roughness length) and vegetation changes during the year (described by vegetation fraction, leaf-area index, surface resistance to evapotranspiration). The prognostic variables are temperature, liquid and solid water contents are computed on two layers representing the soil surface and deep soil properties, and additional variables describe surface snow reservoir, density and albedo and ice and water on leaves. Snow budget depends on snow precipitation, evaporation and melting as well as snow accumulated on vegetation.
Each parameterization scheme obtains the information on the state of the atmosphere from the model variables and possibly output from other parameterizations. Then it uses a set of closure assumptions that relate the parameterized process to the state of the atmosphere. The parameterization schemes have the largest impact on the prediction of the sensible weather at the Earth\'s surface (Pielke, 2002). These schemes became more complex over time and interact with each other, the numerical and dynamical parts of the model.
Model diagnostics produces the numerical values of the sensible weather fields from the model variables, such as the accumulated precipitation, instantaneous cloudiness or maximum wind gusts. Wind, temperature and humidity are interpolated from the model levels to the standard meteorological measurement heights (10 and 2 meters above surface) using a parameterized profile (Geleyn, 1988).
The Croatian mountains are relatively small in extend, many of them have width close to 10 km and length less than 50 km. But the mountain peaks reach over 1 km inland, and several mountain tops reach over 1.5 km very close to the coastline (Fig 3). These mountains are separated by deep and inhabited valleys while important roads and connections go through the mountain passes.
Weather in Croatia is in many ways modified or even controlled by orography (Zaninović et. al. 2008), but the large scale models do not resolve many of these local weather patterns. These weather patterns result from interaction of synoptic forcing with orography. Improved representation of orography in a meteorological model is expected to improve the forecast of weather phenomena that are strongly influenced by local orography (Horvath et. al., 2011, Bajić, 2007, Branković et. al., 2008).
m wind forecast with 8 km (a) and 2 km resolution (b) for 6 UTC 5th Feb 2003.
The dynamical adaptation method of Žagar & Rakovec (1999) has been adapted for the purpose of operational forecast of the 10 m wind. The method provided successful operational forecast of the 10 m wind (Ivatek-Šahdan & Tudor, 2004) an has been used extensively in research impact studies (Bajić et al., 2007) as well as case studies (Tudor & Ivatek-Šahdan, 2002) of severe wind.
The meteorological model fields are first interpolated from the low resolution (8km in this case) to a higher resolution (2km) grid, but on considerably lower number of model levels, from 37 to 15 levels in the vertical. The number of vertical levels is reduced to minimize the computational cost. The levels close to the ground are of similar density, but the levels higher in the atmosphere are mostly omitted. Then a hydrostatic version of the ALADIN model is run for 30 time steps with a 60 second time step. The same large scale model data is used for the initial and LBC data, therefore the fields on the lateral boundaries do not change during the adaptation procedure. Turbulence is the only parameterization scheme used. Contributions from the moist and radiation processes are not computed to accelerate the model run.
Vertical cross-section of wind speed (shaded), direction (vectors) and potential temperature (black isolines) for 6 UTC 5th Feb 2003.
HRDA improves 10 m wind forecast (by 15%), especially in weather situation with strong bura wind, since wind-speed and direction depend on the terrain configuration upstream. Figures 7a and 7b illustrates the impact of high resolution orography on the 10m wind forecast. HRDA wind is much weaker (reduces from 10-15 m/s to less than 5m/s) and changes the direction (up to 180°, depending on location) from the low resolution forecast in the valley upstream of the mountain. Downstream of the mountain, wind is much stronger (increases from 15 m/s in low resolution model to more than 30 m/s) in the high resolution model run as mountain wave breaks and windstorm reaches the mountain slope (Fig 8).
The 10 m wind forecast from HRDA has been used in several applications, and improved the safety of the traffic in the air, on the sea as well as on land. Unfortunately, there were also events of short bura episodes connected to a local pressure disturbance (Tudor & Ivatek-Šahdan, 2010) that were not predicted by HRDA. These were used in a further study to assess the impact of the neglected effects to these bura episodes. This procedure is able to forecast bura onset, duration and strength if it is a consequence of a synoptic forcing. It misses those cases initiated by small scale disturbances in the pressure fields. These disturbances have to be modelled first, using the non-hydrostatic model version on more levels in the vertical with full complexity of the physical parameterization package. These conclusions were based on analysis of a number cases of bura associated with a small scale pressure disturbance. Once a pressure disturbance is modelled, the wind field acts according to the measurements. The disturbances have to be detected first in the pressure measurements from the automatic stations that are performed on a less dense network than the wind measurements. The operational forecast using the latter configuration has been established only recently. The number of cases is still too short to make a thorough statistical analysis.
In CMHS, the operational ALADIN forecast is run twice per day, starting from 00 and 12 UTC analyses. The operational ALADIN model forecast is run 72 hours in advance on a Lambert-projection domain with 8 km horizontal resolution on 37 hybrid sigma-pressure levels in the vertical. The model fields are subsequently going through a dynamical adaptation procedure (Ivatek-Šahdan and Tudor, 2004) that produces 2 km resolution forecast of 10 m wind speed and gusts. There are two more sets of initial and LBC data available from both ARPEGE and IFS. The analyses at 06 and 18 UTC are used for cycling of the data-assimilation procedure. Only 6 hour forecasts are produced from these analyses and they are used as a first guess in the data assimilation procedure for the next analysis time (12 and 00 UTC) that initiates the 72 hour forecast. Alternative 8 km resolution 72 h forecasts run from the initial fields created in 00 and 12 UTC data-assimilation. These runs provide an alternative forecast fields that differs slightly from the first operational run. As an addition to the operational forecast, 2 km resolution 24 hour forecast was established recently, that uses the non-hydrostatic (NH) dynamics in the ALADIN model and the ALADIN’s full parameterization set, including the convection scheme. This forecast runs is performed once per day, following the 00 UTC operational 8 km resolution forecast. It uses the 6 hour forecast from the 8 km resolution operational run as input initial file and runs with SSDFI. This high-resolution forecast is run for 24 hours, until 6 UTC on the next day. This procedure allows covering the 24 hour period used to collect precipitation data from the rain-gauges.
High impact weather events are often forecasted by means of their predictability. ALADIN has been used in several predictability studies (e.g. Branković et al., 2007) as well as the Limited Area Ensemble Forecasting (Wang et al., 2011) system. In most of these studies, ECMWF ensemble forecasts were dynamically downscaled for several severe weather cases. Therefore, the initial conditions come from perturbations generated by singular vectors of ECMWF. Wang et al. (2011) combined different initial and boundary conditions from the perturbed global model with other aspects of forecast uncertainty, such as blending, multi-physics approach and breeding.
Predictability studies of bura cases have found little sensitivity to different initial conditions (Ivatek-Šahdan & Ivančan-Picek, 2006). Horvath et al. (2009) suggested a small effect of uncertainties in the upstream initial conditions on the bura events in the southern Adriatic Sea. Another study of severe bura (Branković et al., 2007) exemplified a case of gale force bura that was predicted with a probability exceeding 95%. Dynamical downscaling of ECMWF fields from 40 to 8 km resolution improves the precipitation rate and pattern in the intensive precipitation cases (Branković et al., 2008) too, the predicted precipitation is roughly double in the high resolution forecasts, but still reaches only 20% of the observed precipitation maximum.
The capability of the ALADIN model to predict high-impact weather events in Croatia is illustrated by several exemplary cases that encompass various weather types.
Bura is a local word describing a downslope windstorm on the eastern Adriatic coast. It is a northeasterly wind with high gustiness that is mostly controlled by the upstream topography of Dinaric Alps. During a windstorm episode, several roads and ferry lines to the islands get closed. The strength and variability of bura wind varies from case to case (e.g. Horvath et al., 2009) and reaches up to 69 m/s and varies in space, although several places became famous for it. The processes that control bura occurrence and strength are briefly illustrated. Grisogono & Belušić (2009) give a comprehensive review of recent advances in bura research.
m wind forecast with 8 km (a) and 2 km resolution (b), for 15 UTC 7th Nov 1999.
MAP Special Observing Period 15 (SOP 15), from 7th to 9th Nov 1999, was characterized by severe bura on the eastern Adriatic Sea (Fig 9). The bura was associated with an intensive cyclone that was slowly moving over central Italy. A cold air outbreak from northeast intensified the pressure gradient over the coastal mountains and intensified wind in the lower layers of the atmosphere. During SOP 15, special measurements were taken from ELECTRA aircraft, through a northwest-southeast transect, parallel to the eastern Adriatic coast (Grubišić, 2004). The measurements were taken on levels 330 m and 660 m above the sea level and in the period from 15 to 16 UTC on 7th Nov 1999 (Fig 10). The 8km resolution forecast underestimated wind speed in the vicinity of the coastal mountains by 30% on average (Fig 9a). The wind forecast improved considerably (up to 10% over or under estimation of wind speed) using HRDA (Fig 9b). But the wind above the open sea (where the aircraft flew) was similar, both at surface (Fig 9) and at flight levels (Fig 10). The wind maximum at 660 m level is well predicted, as well as the northern minimum. The southern minimum is weaker by 5 m/s than measured and moved further south. On the lower level, at 330 m, model overestimates the maximum of the wind component normal to the flight direction by 3 m/s.
Comparison of measured and model normal wind components on flight levels 660 m (a) and 330 m, for 15-16 UTC 7th Nov 1999.
The strongest wind gust ever measured in Croatia was 69.0 m/s on Maslenica station (Bajić 2003) that was still operational during December 2003. During severe bura in that area, the 10 m wind speed is usually underestimated by the 8 km resolution forecast by 30 m/s on average (Fig 11a). The HRDA forecast improves the surface wind forecast as it puts the wind speed maximum closer to the surface (Fig 11b), especially to the slope of the mountain as the mountain wave breaks. The wind maximum is still underestimated by 10-12%.
Vertical cross-section of wind speed (shaded), direction (vectors) and potential temperature (black isolines) from 8 km (a) and 2km (b) runs, for 3 UTC 24th Dec 2003.
There were several severe wind episodes in December 2003 (Fig 12), particularly in the period from December 22 to 26 2003, during which infrastructure was damaged on the highway going through the area hit by the severe bura, including the Baričević meteorological station (Fig 12a). The 2 km resolution forecast is in better agreement to the measured data for strong bura events (Fig 12a) as well as the most severe one (Fig 12b). In the absence of atmospheric soundings, these results confirm that the vertical structure of the meteorological fields in the lower troposphere also improves in high resolution for this case.
Comparison of measured 10 minute maximum (light blue) and average (blue), 8 km resolution mean wind forecast (red), 2 km resolution mean wind (orange) and wind gust forecast (yellow) at Baričević (a) and Maslenica (b) for December 2003.
The bura variability in space and time has a pronounced influence on road traffic. Therefore, knowing bura characteristics is a necessary condition for road transport safety. To properly organize the traffic safety system, special emphasis should be given to the quality of measured long term wind speed and direction data and low resolution atmospheric forecast models.
The ANEMO-ALARM user interface. The measured (thick lines) and modelled (thin line) mean wind speed is shown on a graph as blue line, wind gusts are red and direction is green.
An application, named ANEMO-ALARM (Bajić et. al., 2008), has been developed that assists road authorities in managing the traffic on the roads affected by strong wind and turbulence. The application is based on measured and forecasted wind speed and gusts for a choice of locations on Croatian roads that are most affected by severe wind. The application communicates with the user through a graphical user interface (Fig 13). The interface shows current and expected alarm status for road traffic safety conditions for any of the three categories of vehicles (green is for open road, yellow for preparedness status and expected road closure and red indicated that the road is closed).
Prognosed cloud water and ice, rain and snow mixing ratios are valuable output of the operational model forecast. Their three-dimensional distribution helps in identifying the areas that are a potential threat to aviation. This data can provide important information on the state of the atmosphere inside a cloud, especially when in-situ and remote measurements are sparse or insufficient to describe more detailed structure of the cloud. This value is briefly illustrated by means of a case when weather contributed to the crash of an airplane on the Velebit Mountain.
On 5th February 2009, a Cesna 303, crashed 500m north of the Vagan peak of the Velebit Mountain. The small airplane flew from Zagreb to Zadar, first at 2600 m, then at 2000 m feet. Before the crash, the airplane descended from 1900 to 1600 m. The time of the accident was recorded as 13:53 UTC when air traffic control lost contact with the pilot.
Strong southwest wind prevailed throughout the troposphere. Wind speed increased with height, upstream of the mountain, in Zadar, the maximum wind speed of 20 knots was reached at 750m reaching 45 knots just below 3 km in the Zagreb radiosonde measurements. Temperatures on Zadar airport (88 m) and in Zagreb (128 m) were 14 to 15 °C. On Zavižan peak (1594 m) of the Velebit mountain temperature was 0.3°C, relative humidity was 100% and there was very low visibility, indicating that the mountain top was in a cloud. The satellite images show Velebit mountain covered by a thick cloud and mountain waves in the lee (Fig 14a). The cloud-top temperature was below 0°C (Fig 14b).
Satellite picture of clouds (a) and cloud top temperature (b) for 14 UTC 5th Feb 2009.
The model vertical cross-section of vertical velocity and potential temperature (Fig 15a) shows strong downward motion above and north of Vagan peak and variable vertical velocity downstream. Changes in the vertical velocity are accompanied by waves in the isolines of potential temperature (blue lines in Fig 15a). As the airplane flew from Zagreb to Zadar, it faced strong opposing wind and changing upward and downward motions that were stronger as the airplane approached the Vagan peak.
Vertical cross-sections of (a) vertical velocity (shaded), wind vectors parallel to the cross-section (vectors), potential temperature (K, blue lines) and (b) cloud water and ice (shaded), relative humidity (blue lines) and temperature (°C, red lines) for 14 UTC February 5, 2009. The flight levels are shown as horizontal green lines.
The mountain was covered by layers of clouds consisting of both cloud water and ice (Fig 15b) and high relative humidity existed in the cloud free area. The 0oC-isoline was above the 6500 feet flight level over the valley close to Zagreb, but the 0°C isoline descends below that height above the mountains close to Vagan peak (Fig 15b). Turbulent kinetic energy had high values above and downstream of the mountain (more than 2.5*104 m2/s2).
The Adriatic region is often affected by another severe wind that is rather familiar to the local population. Jugo is a local word describing the southeasterly wind in the eastern Adriatic. It interupts the ferry lines to the islands as well as other activities on the sea and the coast since it generates large sea waves due to the long fetch. It is often associated with heavy rainfall. The strength of jugo wind is often underestimated in southern Adriatic, especially in Dubrovnik and on Palagruža, Lastovo and Vis islands by 15% (2 km resolution) to 30% (8km resolution) on average. The time-variability of jugo wind speed and direction is underestimated over the open sea (at least in some cases), as was revealed in the comparison with the measurements in the open sea during the DART (Dynamics of the Adriatic in Real-Time) oceanic research cruise in March 2006 (Tudor, 2011). The model error of the wind speed forecast is not uniform and can exceed 50% in some intervals for both 8 and 2 km resolution forecast.
Comparison of measured (purple), 2 km (full lines) and 8 km resolution wind speed forecast (dashed) for Palagruža (a), Dubrovnik (b), Hvar (c) and Mljet (d) for 7th-9th Nov 2010.
Large amounts of rain (> 100 mm) that fall during a short time period (< 6 hours) can cause flash floods, especially in places where the terrain supports accumulation of water as on low slope coast below a mountain. The ability of the operational ALADIN model to predict such cases is exemplarily illustrated by two cases.
On September 25, 2010, just after midnight an intensive rain hit Pula city on the southern part of the Istria Peninsula, Croatia. The rain was intensive for several hours and the rainfall rate measured by the ombrograph reached 43.9 mm per hour. Several rain-gauges in the area measured more than 150 mm/24h. The operational ALADIN forecast severely underestimated (the forecast maximum was below 10mm) the rainfall over the Istria peninsula during the night from September 24 to 25, 2010 (Fig 17a). The wind field is shown for 00 UTC on September 25, 2010 the time that is close to the period of the maximum rain intensity. The parallel suite rainfall structures were slightly better (Fig 17b) than the operational one, with second maximum of rainfall over the Istria peninsula reaching more than 35mm, but the predicted rainfall amount was far below the measured one. It is assumed that the observed severe precipitation was caused by convective activity supported by the synoptic conditions and/or local conditions that were not represented correctly in the initial conditions (as suggested by the result of the data assimilation forecast, Fig 17b) or the model was not able to represent its development. The last hypothesis has been tested using the non-hydrostatic set-ups of the ALADIN model and in higher resolution using different initial and boundary conditions (from 8 km runs with or without 3Dvar and using ARPEGE and IFS initial and boundary conditions) One run generated additional intensive rain band over an island 25 km east of Pula.
Accumulated precipitation from the operational (a) and data assimilation (b) forecast for 25th Sep 2010.
The flash flood hit Dubrovnik, Croatia, on November 22, 2010. The rain gauge measurements exceeded 100 mm/24h in the area and the one in Dubrovnik measured 161.4 mm/24h (the highest on record by that time), with a peak intensity of 71.5 mm/h (Fig 18b). The flood water level reached 1.5 m caused damage and endangered lives.
The operational and parallel suite model results forecast large 24 hour accumulated rainfall amounts in the area around Dubrovnik, with the maxima over 100 mm located above the surrounding areas of Montenegro and Bosnia and Herzegovina. The results of the high-resolution (2 km) non-hydrostatic ALADIN model run showed a dependency of the forecasts on the input data from initial and lateral boundary conditions. The position and time of the precipitation maxima in the high resolution ALADIN output fields (Fig 18a) was similar to the lower resolution (8 km) run used for initial and lateral boundary conditions. The peak intensity of precipitation in all model runs was late (3 hours in runs coupled to Arpege, 6 hours for IFS). The reason for this delay is yet unknown and could be attributed to the absence of measurements over the southern Adriatic.
Accumulated 24 h precipitation from the 2 km resolution run (a) and measured (b) for 23rd Nov 2010.
Although far less dramatic than the previous ones, fog is also a weather event that can have a large impact since it is a nuisance to the traffic. The results of the operational model forecasts were not satisfactory for 2m temperature and cloudiness in a case of fog and low stratus accompanied with a temperature inversion in December 2004. The problems remained through several weeks of December 2004, as fog and low stratus remained covering the inland parts of Croatia, as well as Hungary and other valleys surrounding eastern Alps.
Comparison of the model 2m temperature evolution with the data measured (violet) in Križevci meteorological station. Exp1 to exp5 are obtained with the operational radiation scheme, and in exp6 to exp10 a new, enhanced, radiation scheme has been used. Experiments with random maximum overlap are shown with circles and those with random overlap are shown with squares. Open marks show experiments with the operational critical relative humidity profile and full marks show the experiments with the new critical relative humidity profile.
The operational forecast of low (shades of red), medium (shades of violet) and high (shades of blue) cloudiness for 06 UTC on December 15, 2004.
As
Subsequent operational model forecasts kept underestimating the cloud coverage with 30-60% on average when compared to observations by the crew from the synoptic stations. Consequently, the amplitude of the 2 m temperature diurnal cycle was much larger (5-10°C) than measured (Fig 19). Actually, the measured 2m temperature changed only slightly during the day (0-2°C), as well as from one day to another. This behaviour has made the 2m temperature forecast as useless as the cloudiness forecast.
These results have encouraged an extensive case study to find a model set-up that would produce an acceptable forecast of the low clouds as well as 2m temperature diurnal cycle (Tudor, 2010). The model initially recognizes the existence of the temperature inversion and the layer of air adjacent to the surface is almost saturated. But the cloud scheme diagnoses little cloudiness or fog, far less than exists in reality (Fig 20). Consequently, the radiation scheme heats the ground and breaks the inversion, making the situation even worse. In reality, a fog or low stratus layer keeps the longwave radiation from ground and reflects the shortwave radiation keeping the temperature of the surface layer almost constant. Longwave radiation flux divergence and shortwave reflection at the top of the cloud supports cooling and formation of a temperature inversion.
The study (Tudor 2010) has shown that the combination of Xu-Randall cloud diagnosing scheme (Xu & Randall, 1996), new critical relative humidity profile, maximum overlap and operational (Ritter and Geleyn, 1982) radiation scheme produces forecast of low clouds and 2 m temperature of 1-3°C that is closest to the observed values. This result stayed nearly the same even when the more sophisticated radiation schemes were used. The introduction of prognostic microphysics improved the results too by increasing cloud coverage by 5-10% and reducing the temperature amplitude only slightly (up to 0.3°C). The introduction of more physical semi-Lagrangian horizontal diffusion (SLHD) has improved the fog and low stratus forecast close to terrain slopes by increasing cloud coverage by up to 50%. The numerical diffusion mixes the temperature and moisture along model levels that follow orography. Consequently, in the model the cloud layer from the valley is mixed with the clear air on the mountain ridge and the cloud in the valley reduces. Replacement of numerical diffusion with SLHD reduces this mixing and supports cloud formation on slopes of the valleys.
This chapter gives an overview on weather forecasting using the set-up of the NWP model ALADIN that is used for operational weather forecast in CMHS as an example for operation weather forecasting. ALADIN is a state-of-the-art modern NWP model. Using ALADIN we exemplarily discuss short-comings and challenges in modern operational weather forecasting. A high-resolution LAM is intended to predict the sub-synoptic weather features forced by topography or other local characteristics that can be absent in the main synoptic pattern. Successful prediction of these small-scale features enables usage of the LAM forecast in predicting the conditions important for the flight safety, vehicle road safety or navigation at sea. The operational suite has to be tuned in order to predict the high-impact weather events of local character that could be missing in the large scale forecast. The domain properties as well as the forecast model complexity are formed according to the needs of the forecast users and the computing capabilities.
High impact weather events can be of local origin, or determined by small scale characteristics particular to a certain region. Croatia is not spared from severe weather events, such as severe windstorms (bura and jugo wind), torrential rain and flash floods. Such events are often forecast in terms of probability via the ensemble prediction system of a global model. The severity of the event can be controlled by mechanisms not resolved by the global model, and dynamical adaptation of the individual EPS members improves the predictability of the severe weather events (Branković et al., 2007). The NWP section of CMHS has invested most effort in the deterministic high-resolution forecast based on analysis of numerous high impact weather cases.
The operational 8 km resolution forecast is run using DFI with the initial file from the global model ARPEGE since most of the measured data is assimilated in the global model. The data-assimilation suite has been established and runs parallel to the operational suite forecast. This parallel run has revealed the benefits of doing the data-assimilation in higher resolution (8 km) than in the global model (see the Pula flash flood case).
Forecasting the formation and distribution of fog is controlled by subtle variations in humidity and temperature fields and require maintenance of a sensitive balance between the advection, radiation and turbulent fluxes. The profound influence of topography on the atmospheric flow reflects itself in a number of features that affect local weather, such as upslope, downslope and gap winds, coastal barrier jets as well as land sea breezes.
The operational high-resolution (2 km) forecast of the 10 m wind is achieved through the dynamical adaptation method adapted from Žagar & Rakovec (1999). The prediction of severe wind variability and strength is improved in weather situations with strong flow over complex topography, like bura in Croatia (Ivatek-Šahdan & Tudor, 2004). This high resolution wind forecast has provided warnings in numerous cases severe wind as well as to forecast the road conditions, assess the wind energy potential (Horvath et al., 2011) and has been used in numerous applications.
The forecast abilities of HRDA and similar packages are limited to the severe windstorms related to a synoptic forcing. Omitting moist and radiation processes prevents it from being useful in forecasting other phenomena could benefit from the high resolution, such as local convective storms. The windstorm that is a consequence of a local pressure disturbance requires a full forecast run in 2 km resolution using more complex NH ALADIN model set-up (Tudor & Ivatek-Šahdan, 2010). Several air crash investigations have revealed that this "full-run" high resolution ALADIN forecast enables the prediction of lee waves and zones of increased turbulence as well as icing zones.
These flaws of the operational suite have encouraged the introduction of the 2 km resolution 24 hour forecast with NH ALADIN set-up using the complete set of physics parameterizations to the operational suite at the beginning of summer 2011. Several case studies of high-impact weather phenomena have been used to set-up the model configuration used operationally. The results from these studies have provided encouraging results.
Multiple sclerosis (MS) is a demyelinating disorder with an underlying neuroinflammatory disease process affecting approximately 2.5 million people worldwide [1]. Traditionally, the disease has a greater prevalence in locations which are geographically north of the equator. In a study from 2015, North America and Europe had an average prevalence of greater than 100/100,000 individuals, whereas East Asia and Sub-Saharan Africa had rates of 2/100,000 individuals [2].
\nTo better understand this disparity, an umbrella systemic review looked at the possible environmental risk factors involved in the development of multiple sclerosis [3]. An analysis of 44 potential risk factors was filtered down to 3 which were found to be profoundly significant: anti-Epstein-Barr Virus Nuclear Antigen IgG seropositivity, infectious mononucleosis, and smoking [3]. The hypothesis behind anti-EBVNA IgG suggests that late adolescence exposure to EBV leads to infectious mononucleosis with significantly elevated IgG titers when compared to individuals who were exposed at a younger age [4, 5]. These titers in turn correlate to an increased risk of developing multiple sclerosis. One study done on this, “high-hygiene” population found that individuals of the same age who were not infected with EBV had a 10-fold lower risk of developing multiple sclerosis when compared to their EBV infected counterparts [4]. The pathology linking EBV titers to the initiation of multiple sclerosis are not yet clear, however it may increase the risk for an autoimmune type response as was seen with Systemic Lupus Erythematous and EBV [4, 6].
\nSeveral studies have shown a direct correlation between cigarette smoking and incidence of multiple sclerosis [4, 7, 8, 9, 10]. There is some variability in the literature between gender and age groups. One study suggests cigarette smoking at a younger age (<26.4 years) is associated with a 50% increased risk that was alleviated in individuals who were older [8]. A Canadian study comparing gender and smoking history and found that 71.5% males diagnosed with multiple sclerosis had previously smoked compared to 63.6% of females [10]. Smoking has previously been defined in several pathologies including cancer, asthma, atherosclerosis and heart disease, but within multiple sclerosis, the mechanism is still not understood.
\nGenetic risk factors have come to the forefront of current research as some have been linked with modulation of the immune response. Initial studies linked loci of the Major Histocompatibility Complex (MHC) and Human Leukocyte Antigen (HLA) as contributing risk in the development and progression of multiple sclerosis [4, 11, 12, 13, 14]. In particular, HLA-
In 2001, the McDonald criteria were created to streamline the diagnosis of multiple sclerosis even with its heterogeneous clinical presentation. The initial criteria introduced the utility of magnetic resonance imaging (MRI) and integration of multiple clinical symptoms while removing “clinically definite” and “possible multiple sclerosis” as alternatives [17]. Since 2001, 3 additional revisions have been made to the initial McDonald criteria: 2005, 2010 and 2017 [18, 19, 20, 21]. Diagnosis of multiple sclerosis is now approached based on dissemination of time (temporal) and space. Dissemination in space is defined by either clinical presentation or MRI. Clinically, an individual must have symptoms which are distinct to different anatomical locations of the central nervous system. Usually, individuals present with optic neuritis or ocular symptoms and later acquire gait disturbances or peripheral weakness [18, 22]. On MRI, dissemination in space requires T2 evident lesions located in at least two distinct zones such as periventricular, infratentorial, juxtacortical or within the spinal cord [18, 22]. Dissemination in time requires the presence of a gadolinium-enhancing lesion on MRI, indicating an acute or active lesion, along with a non-enhancing lesion [18, 22]. The presence of a new lesion alone can meet the criteria if it is performed on a follow up scan. Essentially, dissemination in time seeks to distinguish multiple sclerosis symptomatology both typical and atypical from other neurological disorders which may share certain characteristics. As of McDonald 2010, CSF analysis is not required in order to make a definitive diagnosis [19, 20, 21, 22]. Analysis of CSF typically presents with mildly elevated white blood cell count, protein, and IgG oligoclonal bands which are not typically seen in serum analysis [22]. IgG oligoclonal bands can be found in 90% of multiple sclerosis patients, but it may have a greater role in distinguishing individuals with clinically isolated syndrome (CIS) [20]. Some studies demonstrated that CSF oligoclonal bands increase the specificity of MR imaging in adults with CIS and pediatrics with radiologically isolated syndrome (RIS) [23, 24]. Beyond the diagnosis of multiple sclerosis, CSF analysis may help distinguish other immune mediated neurological and non-neurological pathologies.
\nThe disease course of multiple sclerosis is usually defined into four clinical subtypes: clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, and primary progressive multiple sclerosis. A majority of patients have a disease course defined by stages of relapses and remission which may later translate into the secondary progressive form [25]. Clinically, relapses are defined as distinct episodes of neurological dysfunction which can present as a wide array of symptoms including sensory defects of the limbs, visual loss, motor defects, gait disturbances, vertigo, heat sensitivity (Uhthoff phenomenon), Lhermitte sign and fatigue [22, 26]. However, multiple sclerosis can present atypically in younger individuals, making it difficult to diagnosis properly. The initial episodes are followed by periods of remission where the patient will fully or partially regain normal function and be deemed neurologically stable [27]. In the long term, as some individuals transition from the relapsing-remitting form to secondary progressive, relapses no longer occur, yet patients will experience worsening neurological function [27]. After 10 years of disease, 50% of individuals with relapsing-remitting multiple sclerosis will convert to secondary-progressive, whereas after 25 years of the disorder, more than 90% of the individuals have secondary progressive multiple sclerosis [14].
\nPrior to establishing criteria for dissemination in time and space, individuals may present with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS). Clinically isolated syndrome is defined as a clinical episode resembling a multiple sclerosis attack, after which there is full or partial recovery of neurological function [14, 20, 27]. Studies have shown that individuals with CIS may have an increased rate of conversion to multiple sclerosis especially with the presence of CSF oligoclonal bands and gadolinium enhancing lesions on MRI [14, 18, 20]. Incidental findings of cerebral and spinal cord plaques without a clinical phenotype are defined as radiologically isolated syndrome (RIS). In a 5-year study of 451 patients with RIS, 34% of individuals developed a clinical event for which 9.6% were defined as primary progressive multiple sclerosis [28]. Interestingly, this study was able to strongly correlate the presence of cervical or thoracic spinal cord lesions with the first clinical event [28]. With this increase risk of progression to multiple sclerosis, the utility of disease-modifying therapies and longitudinal monitoring of CIS and RIS has become a priority for clinicians.
\nThe direct cause of multiple sclerosis still eludes the scientific community; however, several hypotheses have emerged which have been utilized to develop disease-modifying therapies (DMTs) and alter the course of disease. Traditionally, multiple sclerosis has been considered a demyelinating disease of the white matter tracts leading to peripheral symptomatology with an underlying autoimmune cause. Recently, demyelination located in the cerebral cortex and deep gray matter has emerged as a marker of progressing neurological disability [13, 29, 30]. Damage seen to the CNS with infiltration of immune cells suggests the role of peripheral immune response leading to damage of the blood brain barrier prior to established demyelination. Peripheral inflammation in this case may be a result of a foreign pathogen (virus), autoimmune activation, or a combination of multiple events. Malpass [31] characterized the term “outside-in” based on evidence of cortical inflammation originating in the subarachnoid space in multiple sclerosis patients which transitioned into the white matter [32]. This further strengthens the argument for modulation of the peripheral inflammatory response which is facilitating early multiple sclerosis disease through activation of CD4 T lymphocytes. Once within the CNS, regional activation of microglia, astrocytes and macrophages occurs through expression of cytokines and chemokines from infiltration of T lymphocytes [13, 29, 30, 33]. Activation of specific subsets of CD4 lymphocytes dictates which cytokines are released. Pro-inflammatory cytokines are expressed after direct activation of Th1 and Th17 cells, whereas anti-inflammatory cytokines are a product of Th2 and T-regulatory cells [34, 35, 36]. Histopathology of the CNS white matter plaques has shown an abundance of macrophages, CD8, CD4 T lymphocytes, and B lymphocytes [13, 29, 30, 35]. Over time, the prolonged inflammation and infiltration of T and B lymphocytes leads to a disruption of the axonal-glial interaction which results in an increase in gray matter atrophy and axonal loss with marked demyelination [13, 29]. During the remission phase following each flare, there is some evidence to suggest a possible role for regulatory T cells with the induction of Foxp3 [37]. It is possible that during remission, a baseline level of inflammation is present; however, the expression of specific phenotypes of T lymphocytes shifts toward anti-inflammatory/regulatory rather than pro-inflammatory mechanisms. Based on these observations, vitamin D has emerged as a potential homeopathic regulator of immune cell function [2, 3, 38].
\nCurrently, there is no definitive treatment for multiple sclerosis. Most approved therapies are focused on controlling peripheral inflammation and preventing migration across the blood brain barrier thereby reducing the incidence of acute flares [13, 30, 39, 40]. A majority of these therapies are administered orally, as an injection or through an infusion. With both invasive and non-invasive methods, side effects include increases in liver enzymes, injection site reactions, nausea, diarrhea, and most importantly, progressive multifocal leukoencephalopathy (PML) [39]. The primary therapies prescribed at our institution are Copaxone®, Gilenya®, and Tecfidera®. Copaxone®, glatiramer acetate is an immunomodulator that is FDA approved to reduce the frequency of relapses. Gilenya®, fingolimod, is also an immunomodulator that targets reduction in the number of relapses more than progression of disease. Tecfidera®, dimethyl fumarate, is a combination of fumaric acid esters that was originally approved for oral treatment of psoriasis. Because of the inconsistent or incomplete outcomes from treatment, as well as the evolving nature of the disorder, other biotherapies have been used as adjuvants.
\nOne alternative biotherapeutic is the use of low doses of naltrexone (LDN), an opioid receptor antagonist. LDN is often used as an adjuvant to disease-modifying therapy to target fatigue associated with either the disorder or the medication. LDN has a strong profile of safety and tolerability [41, 42, 43, 44]. Pilot studies utilizing LDN demonstrated that MS patients had an improvement in peripheral spasticity and mental health composite scores without inducing any side effects [42, 45]. In a retrospective analysis which compared LDN patients with LDN plus Copaxone® patients, there was no significant difference between the groups with respect to MRI, complete blood count, liver enzymes and the 25-foot walk test [44].
\nA number of published studies, clinical trials and anecdotal stories have supported the use of LDN as a beneficial therapy for multiple sclerosis [41, 42, 43, 44, 45, 46, 47, 48]. The mechanism of action for this general antagonist is to block the interaction of Opioid Growth Factor (OGF) (chemically termed [Met5]-enkephalin) from interacting at the nuclear-associated receptor OGFr. In addition to being a neurotransmitter, OGF is an inhibitory growth factor that suppresses proliferation of cells, including T and B cells associated with autoimmune disorders. Naltrexone was initially developed to treat opioid use disorder and alcoholism at a dosing of 50 mg where it acts as an opioid receptor antagonist for mu, delta, and kappa opiate receptors. At a dosage less than 5 mg, LDN acts as a biotherapeutic and modulates the activity of endogenous enkephalins and endorphins [49, 50]. In the multiple sclerosis patient population, endogenous [Met5]-enkephalin (i.e., OGF) is reduced when compared to non-multiple sclerosis patients [51]. It is hypothesized that the reduction in serum levels of this inhibitory growth factor are unable to control the increase in T cell proliferation that occurs with immune-related flares. These T cells are the source of other pro-inflammatory cytokines that exacerbate the symptomatology of multiple sclerosis. The decreased serum levels of OGF appear to be compensated by low dosages of naltrexone (LDN).
\nAnimal studies have been used to study both the mechanisms of LDN, as well as to establish the role of LDN as a biotherapy in mice with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. In these studies, mice were immunized with antigens against myelin proteins—either myelin oligodendrocyte glycoprotein 35–55 or proteolipid peptides 139–151. The key component in the mechanistic pathway is the duration of opioid receptor blockade. This work is detailed in animal studies [51, 52, 53, 54, 55, 56, 57]. LDN produces an intermittent blockade of OGFr preventing OGF from binding and thereby increasing cellular replication, similar to what is seen with high doses of Naltrexone (HDN) through a prolonged blockade of OGFr [49]. Conversely, after the blockade has subsided, within 4–6 h, there is over proliferation of endogenous OGF and OGFr and a resulting exaggerated expression of p16 and p21 leading to promotion of cellular senescence [49].
\nA newly discovered pathway involves the antagonism of Toll-like receptor 4 (TLR4) by LDN as means to reduce neuroinflammation or persistent pain [58, 59]. Specifically, activation of Toll-like receptor 4 (TLR4) initiates the release of inflammatory cytokines: interleukin 1 (IL-1), tumor necrosis factor α (TNFα), nitric oxide (NO), and interferon β (IFNβ) [48, 60]. Currently, the relationship of the Toll-like receptor pathway to pro-inflammatory cytokine activation is not completely understood.
\nSeveral studies have been conducted to evaluate multiple sclerosis patients who are prescribed LDN. The use of enkephalins, particularly OGF, has been demonstrated to be safe and tolerable in Phase I and Phase II studies of pancreatic cancer [61, 62]. LDN is widely used for treatment of other autoimmune disorders including Crohn’s disease [63] and fibromyalgia [64].
\nClinical trials using LDN for multiple sclerosis were conducted more than a decade ago, and most likely because it is widely used with no side-effects, government agencies are reluctant to support new trials. Three clinical trials have suggested that LDN increased the quality of life of patients with relapse-remitting or secondary progressive multiple sclerosis, without serious adverse effects [42, 43, 45]. Two retrospective studies examining charts of patients prescribed LDN alone, as well as in combination with the disease-modifying therapy Copaxone®, revealed no exacerbation of the disease or any substantial side effect for patients in either cohort [44]. In this study, the average length of disease was 14 years, with an average of 3 years on LDN alone. Clinical laboratory data revealed that patients on LDN alone had no significant differences in their blood chemistry, nutrition or liver data from patients on disease-modifying therapies.
\nHowever, these studies did not measure serum enkephalins, endorphins, or cytokines in an effort to gain more information on the mechanism of action for this biotherapeutic. A small study obtained stored serum from relapsing-remitting multiple sclerosis subjects and reported that enkephalin (i.e., OGF) levels were depressed relative to controls [51]. In the few individuals on LDN alone, serum OGF levels were elevated 2-fold in comparison to multiple sclerosis subjects on Copaxone® alone, suggesting that LDN may be effective at restoring serum enkephalin. Given this information, studies on both the mouse model of EAE and multiple sclerosis have been pursued to evaluate select cytokines that may be dysregulated in multiple sclerosis and possibly modulated by LDN (and enkephalin levels) and restored to normal levels.
\nA retrospective clinical study was designed to examine serum levels of cytokines and endogenous peptides, including [Met5]-enkephalin.
\nPatients were identified through the Institute of Personalized Medicine at the Pennsylvania State University College of Medicine and had a clinically definitive diagnosis of relapsing–remitting multiple sclerosis [17, 18, 21, 36]. Selected individuals were between 18 and 70 years of age, of which 17 were males and 36 were females. Cohorts were established based on the disease-modifying therapy each of these patients was receiving. The five groups included multiple sclerosis patients receiving dimethyl fumarate, glatiramer acetate, low-dose naltrexone, or no disease-modifying therapy and a control group of non-multiple sclerosis patients. The 13 non-multiple sclerosis patients were recruited from the Neuroscience Institute and were age and gender matched to the study population. All patients were de-identified to the study team.
\nBlood was collected and stored in non-heparinized ethylenediaminetetraacetic acid (EDTA) tubes to prevent formation of a clot [65, 66]. Whole blood was centrifuged at 4°C for 10 min at 2500 rpm [65, 66]. Serum was aliquoted and stored long term at −80°C in 200 μL vials to prevent repeated freeze and thaw cycles.
\nSerum was analyzed using commercially produced sandwich or competitive enzyme labeled immunosorbent assay (ELISA). Opioid growth factor (MBS990622), β-endorphin (MBS770600), IL17A (MBS00565) and IL17 (MBS772095) ELISA kits were manufactured by MyBioSource (San Diego, CA); whereas the TNFα ELISA kit (EK0525) was purchased from BosterBio (Pleasanton, CA). Assays were completed following the manufacturer’s recommendations; all samples and standards were run in duplicate and averaged for the data analyses. Chemiluminescence was measured using a BioTek microplate spectrophotometer and Gen5 software at 450 nm. To ensure redundancy and reproducibility, duplicate samples were run on multiple ELISA kits from the same manufacturer.
\nData analysis was performed using GraphPad Prism 8.0 software. Parametric data were analyzed using one-way analysis of variance (ANOVA) with post-hoc comparisons made using Newman-Keuls. Correlations were determined using Pearson’s Correlation Coefficient (R). Significance was determined with a p value less than 0.05.
\nA cohort of 53 patients was analyzed in this study, 40 of whom were individuals with an established diagnosis of relapsing-remitting (RR) multiple sclerosis and 13 who did not have multiple sclerosis. Patients with multiple sclerosis who received no disease-modifying therapy were designated as controls along with the 13 individuals with no diagnosis of multiple sclerosis. Within the control population, 17 were females and 7 males, whereas the study population had 19 females and 10 males. The age distribution between the cohorts of patients on treatment ranged between 25 and 69 years of age while the control cohort ranged in age from 25 to 78 years. Length of disease in the multiple sclerosis patient group was similar between the no-drug, dimethyl fumarate and LDN group which had mean lengths of 14.3, 10.4 and 16.5 years, respectively.
\nSerum OGF levels differed substantially between multiple sclerosis patients who declined therapy and control subjects considered non-multiple sclerosis (Figure 1A). OGF levels were more than three-fold higher in non-multiple sclerosis cohort relative to the no-drug cohort (93 ± 26 pg/ml). Because there is no diagnosis provided for the no-drug volunteers, it is difficult to more fully assess these data. Mean serum levels for RR-multiple sclerosis subjects prescribed disease-modifying therapy were comparable to serum values for the no-drug cohort, and significantly less than serum values for the non-multiple sclerosis cohort (Figure 1B). RR-multiple sclerosis patients receiving dimethyl fumarate had serum OGF values of 125 ± 22 pg/ml whereas those individuals receiving glatiramer acetate had serum levels of 136 ± 30 pg/ml. RR-multiple sclerosis subjects receiving LDN had mean OGF serum levels of 217 ± 29 mg/ml; these values did not differ from the non-multiple sclerosis cohort. Correlations between serum OGF levels and age or length of disease for cohorts of no drug, DMTs, or LDN are presented in Figure 2A and B, respectively. The association between age and serum OGF had an overall significance, with dimethyl fumarate subjects revealing a corresponding decrease in OGF serum values with increasing age (p = 0.03). Regarding the length of disease, RR-multiple sclerosis subjects taking LDN had comparable OGF serum values irrespective of having disease for 2 months or 33 years (Figure 2B). RR-multiple sclerosis subjects not taking any drugs (no-drug cohort) also displayed a biphasic response, suggesting that length of disease does not impact OGF serum. Analyses of OGF serum values by gender indicated that females had a pattern similar to that in Figure 1B. A majority of the males in this study received dimethyl fumarate and had serum OGF levels that ranged from 25 to 200 pg/ml; the small number of male subjects in the other cohorts prevented data analyses.
\nScatterplots of serum OGF levels (pg/ml) in (A) control subjects who were either non-multiple sclerosis subjects or (B) RR-MS patients who were not receiving any therapy (no drug) or RR-multiple sclerosis patients receiving dimethyl fumarate, glatiramer acetate, or low dose naltrexone (LDN). One-way ANOVA or t-tests were used to show the differences between groups. Significantly different from non-multiple sclerosis values at p < 0.01 (**).
Expression levels of serum OGF (pg/ml) measured by ELISA as a function of the age (years) of subject (A) or the length of disease (years) (B). Correlations were determined by Pearson’s Correlation Coefficient (R) tests. P values less than 0.05 were considered significant.
Serum β-endorphin levels were also measured in three cohorts of RR-multiple sclerosis subjects and non-multiple sclerosis subjects. Levels of serum β-endorphin ranged between ~1 ng/ml (no-drug and dimethyl fumarate cohorts) to the mean of 2.3 ng/ml (non-multiple sclerosis cohorts); individual samples ranged as high as 4 ng/ml in the non-multiple sclerosis cohort. Despite the variation, significant two-fold increases were recorded for non-multiple sclerosis and glatiramer acetate cohorts relative to no drug and dimethyl fumarate RR-multiple sclerosis individuals. Associations between age and β-endorphin revealed that endorphin levels were relatively stable within the population of RR-multiple sclerosis subjects on DMT.
\nWith regard to serum levels of inflammatory cytokines, expression levels of two cytokines in serum are presented in Figure 3. Serum levels of IL-17 (A) and TNFα (B) were measured in RR-multiple sclerosis subjects on DMTs, LDN, or no-drug, as well as non-multiple sclerosis controls. Mean IL-17A (not shown) concentrations ranged from 27 ± 3 pg/ml (dimethyl fumarate) to 39 ± 10 pg/ml (glatiramer acetate group). Only one sample of blood from RR-multiple sclerosis patients on LDN was assayed; serum IL-17A value was 46 pg/ml. No differences in serum levels were noted between any therapeutic treatment and controls. IL-17 levels ranged from the mean 0.12 ng/ml recorded for non-multiple sclerosis cohort to 0.92 ± 0.35 ng/ml for the dimethyl fumarate group (Figure 3A); levels of the IL-17 cytokine recorded for these subjects differed significantly from glatiramer acetate and no-drug cohorts. RR-multiple sclerosis patients had a mean IL-17 cytokine level of near 0, whereas some individuals using dimethyl fumarate had more than 3 pg/ml IL-17 levels.
\nScatterplots of serum cytokines IL-17 (A) and TNFα (B) measured by ELISA tests (pg/ml) in RR-multiple sclerosis patients receiving DMTs or no drug; controls include volunteer non-multiple sclerosis subjects. Data was analyzed using one-way ANOVA with subject comparisons made by Newman-Keuls tests. Significantly different at p < 0.05 (*) and p < 0.01 (**).
Non-multiple sclerosis and RR-multiple sclerosis patients not taking any DMT had comparable TNFα values (16 ± 10 and 22 ± 3 pg/ml, respectively) (Figure 3B). RR-multiple sclerosis cohorts on DMTs had TNFα serum values that were at least 6-fold higher and differed significantly from the non-multiple sclerosis levels. Correlation analyses indicated that OGF (Figure 4A) and IL-17A (Figure 4B) were positively associated (R = 0.82), whereas TNFα values did not correlate (R = 0.20) with OGF serum values.
\nAssociations of cytokine expression between IL-17A (pg/ml) and OGF (pg/ml) (A) or TNFα (pg/ml) and OGF (B) for RR-multiple sclerosis subjects receiving a DMT. Data were analyzed by Pearson’s Correlation Coefficient (R) tests. P values less than 0.05 were considered significant.
Cohorts of RR-multiple sclerosis patients on disease-modifying therapy, as well as a group of individuals diagnosed with RR-multiple sclerosis and taking LDN only were compared with control volunteers. in an assessment of peripheral serum levels of two endogenous neuropeptides—OGF (chemically termed methionine enkephalin) and β-endorphin, as well as 3 cytokines that are known to be involved in RR-multiple sclerosis, specifically IL-17, IL-17A, and TNFα [67, 68, 69, 70, 71]. Inclusion criteria restricted our analyses to RR-MS subjects to those receiving glatiramer acetate or dimethyl fumarate. A few RR-multiple sclerosis subjects in this study were only prescribed LDN as an off-label product.
\nThe restricted access to blood samples and corresponding patient data in this retrospective study limited the findings, as did inclusion of RR-multiple sclerosis patients on no drug. No rationale was reported in the REDCap database to explain why the RR-multiple sclerosis patients had denied therapy. It is conjured that some multiple sclerosis patients who have stabilized over a long period of time request to be removed from therapy.
\nThe focus of this study was to determine the relationship between serum expression levels of endogenous neuropeptides, specifically OGF, and a select group of pro-inflammatory cytokines. OGF levels in the serum of RR-multiple sclerosis subjects declined with age and were not associated with the length of disease. In general, the OGF levels of RR-multiple sclerosis patients using DMTs, or those on no therapy, were substantially lower than RR-multiple sclerosis subjects on LDN. This relationship between OGF and RR-multiple sclerosis has been reported previously [51], suggesting that the biotherapeutic LDN treatment is producing enkephalins. Clinical studies have reported that LDN treatment resulted in perceived increased quality of life [42, 43] and stabilization of disease symptomatology [44]. A second neuropeptide, β-endorphin, is known as the “feel-good” hormone and has been reported to increase during exercise and pregnancy [72] and to increase during multiple sclerosis remission [73]. In this study, β-endorphin levels were comparable in all subjects suggesting that these RR-multiple sclerosis patients had stabilized endorphins. Based on the scatter gram plots of individual expression levels of endorphin, some of the individuals in the glatiramer acetate group may have been in remission. Moreover, whereas OGF levels fluctuate with RR-multiple sclerosis and different therapies, β-endorphin does not appear to be altered by DMTs in RR-multiple sclerosis.
\nThe proinflammatory cytokine IL-17 may be a prime indicator of RR-multiple sclerosis progression [69, 71]. The IL-17 family of cytokines is produced by CD4+ T-helper cells known as Th17 cells. At least 7 polymorphisms have been identified, with IL-17A and IL-17F most frequently associated with neutrophils activation in autoimmunity [67, 69]. IL-17A has been identified in the CNS following migration of Th17 cells in response to a pro-inflammatory event [74]. Clinical studies have reported that IL-17A may be responsible for breakdown of the blood-brain barrier facilitating the entrance of other inflammatory cytokines into the CNS [71]. IL-17A has been shown in preclinical studies to accelerate glial activation leading to neuroinflammation and neurodegeneration [68]. Thus, it would be expected that IL-17A levels may be lowest in RR-multiple sclerosis individuals who are in remission or most responsive to therapy [67]. Moreover, recent preclinical studies have reported that both IL-17A and IL-17F increase pro-inflammatory cytokine IL-6 secretion [70].
\nIn the present study, TNFα, a proinflammatory marker has been shown to increase in RR-multiple sclerosis [75, 76] and to be consistently elevated regardless of the status of disease type (i.e., clinically isolated syndrome, primary progressive, or relapsing-remitting), with serum levels 40–50% higher in multiple sclerosis subjects relative to controls. Preclinical studies have reported an association between TNFα and impaired memory in mice with EAE [77] and implicated astrocyte signaling as the downstream target of overexpression of the cytokine. Despite studies whereby TNFα knockdown mice had more severe EAE [69] and therapeutic administration of the cytokine protected against the disease [74], this cytokine is reported to be a major contributor to cognitive deficits related to late stages of multiple sclerosis. In the present study, age, gender, number of relapses, or length of disease had no effect of TNFα levels, but in general, the expression levels of this cytokine were elevated in RR-multiple sclerosis subjects relative to cohorts of RR-multiple sclerosis patients presumably in remission or non-multiple sclerosis.
\nLDN is an off-label therapeutic used in substantially lower dosages than prescribed for drug overdose or alcohol use (3 vs. 50 mg). Its use is increasing worldwide [78, 79] and is consistently reported to be well-tolerated over extended periods of time [46]. Small clinical trials have reported few, if any, side effects [42, 43]. In this study, OGF serum levels appear to be correlated with IL-17A. Alternatively, whereas β-endorphin has been associated with the propensity to avoid alcohol or opioids, it was not related to RR-multiple sclerosis. The serum levels of cytokines IL-17A and TNFα did not appear to be discriminating biomarkers at least with the current population of RR-multiple sclerosis subjects. Perhaps with additional study, and possibly other DMTs, these cytokines will be able to discern progression of disease.
\nIn summary, the preclinical and clinical data illustrate that enkephalin levels (i.e., OGF) are decreased in animals with EAE and humans with relapsing remitting multiple sclerosis. LDN as a biotherapy is associated with elevating enkephalins and from all aspects, appears to reduce symptomatology of multiple sclerosis. LDN therapy to upregulate the body’s own production of enkephalins has been shown by a number of clinical trials to be a safe adjuvant, or primary, treatment for RR-multiple sclerosis. LDN continues to be associated with stabilizing multiple sclerosis and does not appear to interfere with other disease-modifying therapies. Whether enkephalin levels directly or indirectly alter the therapeutic pathways is unclear at this time. Moreover, it is difficult to determine at this point whether specific disease-modifying therapies are more advantageous for manipulating enkephalin levels. However, it is evident that restored serum enkephalin expression is associated with reduced inflammatory cytokines and better patient outcome. Moving forward, studies will be conducted to determine the mechanistic role of OGF in modulating both pro and anti-inflammatory cytokines. Collectively the data from published studies as well as the new data presented in this report demonstrate that the biotherapeutic LDN and resulting enkephalin (specifically OGF) levels play a role in disease progression of multiple sclerosis. By integrating animal model work and patient serum analysis, future studies will try and understand the role of OGF during initiation of disease and definitive diagnosis of disease. The efficacy of LDN alone needs to be evaluated in prospective, randomized, controlled studies, but unfortunately this design is not forthcoming as most physicians will prescribe the off-label drug based on its safety record.
\nThis research was supported in part by a generous gift from The Paul K. and Anna E. Shockley Family Foundation, and private donations to the Penn State LDN Fund.
\nThe authors acknowledge the support of Indira Purushothaman from the McLaughlin and Zagon lab as well as Syndi Reed and Trang Doan from the Institute of Personalized Medicine at Penn State College of Medicine.
\nAt the time of preparation of this manuscript, PJM, ISZ, and CLP had no personal or financial conflicts or disclosures, and GAT was on the speaker bureau for Biogen, but had no equity interest in the product (Tecfidera®).
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Reyes-Cerpa, Kevin Maisey, Felipe Reyes-López, Daniela Toro-Ascuy, Ana María Sandino and Mónica Imarai",authors:[{id:"92841",title:"Dr.",name:"Mónica",middleName:null,surname:"Imarai",slug:"monica-imarai",fullName:"Mónica Imarai"},{id:"153780",title:"Dr.",name:"Sebastian",middleName:null,surname:"Reyes-Cerpa",slug:"sebastian-reyes-cerpa",fullName:"Sebastian Reyes-Cerpa"},{id:"157025",title:"Dr.",name:"Kevin",middleName:null,surname:"Maisey",slug:"kevin-maisey",fullName:"Kevin Maisey"},{id:"157026",title:"Dr.",name:"Felipe",middleName:"Esteban",surname:"Reyes-López",slug:"felipe-reyes-lopez",fullName:"Felipe Reyes-López"},{id:"157027",title:"MSc.",name:"Daniela",middleName:null,surname:"Toro-Ascuy",slug:"daniela-toro-ascuy",fullName:"Daniela Toro-Ascuy"},{id:"157028",title:"Dr.",name:"Ana",middleName:null,surname:"Sandino",slug:"ana-sandino",fullName:"Ana Sandino"}]},{id:"39623",doi:"10.5772/50192",title:"Use of Yeast Probiotics in Ruminants: Effects and Mechanisms of Action on Rumen pH, Fibre Degradation, and Microbiota According to the Diet",slug:"use-of-yeast-probiotics-in-ruminants-effects-and-mechanisms-of-action-on-rumen-ph-fibre-degradation-",totalDownloads:7902,totalCrossrefCites:17,totalDimensionsCites:38,abstract:null,book:{id:"2991",slug:"probiotic-in-animals",title:"Probiotic in Animals",fullTitle:"Probiotic in Animals"},signatures:"Frédérique Chaucheyras-Durand, Eric Chevaux, Cécile Martin and Evelyne Forano",authors:[{id:"151065",title:"Dr.",name:"Frederique",middleName:null,surname:"Chaucheyras-Durand",slug:"frederique-chaucheyras-durand",fullName:"Frederique Chaucheyras-Durand"},{id:"151068",title:"Mr.",name:"Eric",middleName:null,surname:"Chevaux",slug:"eric-chevaux",fullName:"Eric Chevaux"},{id:"151069",title:"Dr.",name:"Evelyne",middleName:null,surname:"Forano",slug:"evelyne-forano",fullName:"Evelyne Forano"},{id:"160177",title:"Dr.",name:"Cécile",middleName:null,surname:"Martin",slug:"cecile-martin",fullName:"Cécile Martin"}]},{id:"28679",doi:"10.5772/32100",title:"Values of Blood Variables in Calves",slug:"values-of-blood-variables-in-calves",totalDownloads:9601,totalCrossrefCites:16,totalDimensionsCites:36,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Martina Klinkon and Jožica Ježek",authors:[{id:"90171",title:"Prof.",name:"Martina",middleName:null,surname:"Klinkon",slug:"martina-klinkon",fullName:"Martina Klinkon"}]},{id:"16107",doi:"10.5772/16563",title:"Effect of Cryopreservation on Sperm Quality and Fertility",slug:"effect-of-cryopreservation-on-sperm-quality-and-fertility",totalDownloads:15471,totalCrossrefCites:10,totalDimensionsCites:35,abstract:null,book:{id:"185",slug:"artificial-insemination-in-farm-animals",title:"Artificial Insemination in Farm Animals",fullTitle:"Artificial Insemination in Farm Animals"},signatures:"Alemayehu Lemma",authors:[{id:"25594",title:"Dr.",name:"Alemayehu",middleName:null,surname:"Lemma",slug:"alemayehu-lemma",fullName:"Alemayehu Lemma"}]},{id:"57645",doi:"10.5772/intechopen.71780",title:"Antibiotics in Chilean Aquaculture: A Review",slug:"antibiotics-in-chilean-aquaculture-a-review",totalDownloads:1931,totalCrossrefCites:17,totalDimensionsCites:29,abstract:"Aquaculture in Chile has been practiced since the 1920s; however, it was not until the 1990s that aquaculture became an important sector here. Important species in Chilean aquaculture include salmonids, algae, mollusks, and turbot. Salmonids are the dominant species in Chilean aquaculture for both harvest volume and export value, their production reaching greater than 800-thousand tons in 2015. However, this growth has been accompanied by an increase in disease presence, requiring greater drug use to control. This increase in drug use is an environmental and public health concern for the authorities, the salmon industry itself, and the destination markets. In this chapter, we review the literature on drug use, antibiotic resistance, regulatory framework, and alternatives, with focus on Chile.",book:{id:"6179",slug:"antibiotic-use-in-animals",title:"Antibiotic Use in Animals",fullTitle:"Antibiotic Use in Animals"},signatures:"Ivonne Lozano, Nelson F. Díaz, Susana Muñoz and Carlos Riquelme",authors:[{id:"208847",title:"Dr.",name:"Ivonne",middleName:null,surname:"Lozano",slug:"ivonne-lozano",fullName:"Ivonne Lozano"},{id:"208895",title:"Dr.",name:"Nelson F.",middleName:null,surname:"Díaz",slug:"nelson-f.-diaz",fullName:"Nelson F. Díaz"},{id:"208897",title:"Dr.",name:"Carlos",middleName:null,surname:"Riquelme",slug:"carlos-riquelme",fullName:"Carlos Riquelme"},{id:"208898",title:"MSc.",name:"Susana",middleName:null,surname:"Muñoz",slug:"susana-munoz",fullName:"Susana Muñoz"}]}],mostDownloadedChaptersLast30Days:[{id:"56612",title:"Reproduction in Goats",slug:"reproduction-in-goats",totalDownloads:2892,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Reproductive activity of the goat begins when the females reach puberty, which happens at 5 months of age. The ovarian or estrous cycle is the period between two consecutive estrus. It is also the time that lasts the development of the follicle in the ovary, until rupture occurs and ovulation takes place, which coincides with the appearance of estrus. This chapter will describe the physiological and endocrinological bases of estrus in the goat. Likewise, factors affecting the presence of estrus and ovulation will be described. At another point, synchronization of estrus and ovulation, factors affecting the presence of estrus and external symptoms of estrus, will be described. To achieve synchronization of estrus or induction of ovulation within or outside the breeding season, it may be necessary to manage light hours, male effect, and/or use of hormones. The importance of artificial insemination is described, as well as the current situation of this technique worldwide. Currently, the techniques of artificial insemination in goats have been limited worldwide, due to the lack of resources of producers and trained technicians. The techniques of artificial insemination with estrous synchronization programs and ovulation with current research results will be described.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"Fernando Sánchez Dávila, Alejandro Sergio del Bosque González\nand Hugo Bernal Barragán",authors:[{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila"},{id:"206127",title:"Dr.",name:"Alejandro Sergio",middleName:null,surname:"Del Bosque-Gonzalez",slug:"alejandro-sergio-del-bosque-gonzalez",fullName:"Alejandro Sergio Del Bosque-Gonzalez"},{id:"206128",title:"Dr.",name:"Hugo",middleName:null,surname:"Bernal-Barragán",slug:"hugo-bernal-barragan",fullName:"Hugo Bernal-Barragán"}]},{id:"58095",title:"The Innovative Techniques in Animal Husbandry",slug:"the-innovative-techniques-in-animal-husbandry",totalDownloads:3766,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Technology is developing rapidly. In this development, the transfer of computer systems and software to the application has made an important contribution. Technologic instruments made farmers can work more comfortable and increased animal production efficiency and profitability. Therefore, technologic developments are the main research area for animal productivity and sustainability. Many technologic equipment and tools made animal husbandry easier and comfortable. Especially management decisions and applications are effected highly ratio with this rapid development. In animal husbandry management decisions that need to be done daily are configured according to the correctness of the decisions to be made. At this point, smart systems give many opportunities to farmers. Milking, feeding, environmental control, reproductive performance constitute everyday jobs most affected by correct management decisions. Human errors in this works and decisions made big effect on last product quality and profitability are not able to be risked. This chapter deal with valuable information on the latest challenges and key innovations affecting the animal husbandry. Also, innovative approaches and applications for animal husbandry are tried to be summarized with detail latest research results.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Serap Göncü and Cahit Güngör",authors:[{id:"215579",title:"Prof.",name:"Serap",middleName:null,surname:"Goncu",slug:"serap-goncu",fullName:"Serap Goncu"},{id:"218971",title:"Dr.",name:"Cahit",middleName:null,surname:"Güngör",slug:"cahit-gungor",fullName:"Cahit Güngör"}]},{id:"58486",title:"Quality of Chicken Meat",slug:"quality-of-chicken-meat",totalDownloads:3290,totalCrossrefCites:18,totalDimensionsCites:26,abstract:"Chicken meat is considered as an easily available source of high-quality protein and other nutrients that are necessary for proper body functioning. In order to meet the consumers’ growing demands for high-quality protein, the poultry industry focused on selection of fast-growing broilers, which reach a body mass of about 2.5 kg within 6-week-intensive fattening. Relatively low sales prices of chicken meat, in comparison to other types of meat, speak in favor of the increased chicken meat consumption. In addition, chicken meat is known by its nutritional quality, as it contains significant amount of high-quality and easily digestible protein and a low portion of saturated fat. Therefore, chicken meat is recommended for consumption by all age groups. The technological parameters of chicken meat quality are related to various factors (keeping conditions, feeding treatment, feed composition, transport, stress before slaughter, etc.). Composition of chicken meat can be influenced through modification of chicken feed composition (addition of different types of oils, vitamins, microelements and amino acids), to produce meat enriched with functional ingredients (n-3 PUFA, carnosine, selenium and vitamin E). By this way, chicken meat becomes a foodstuff with added value, which, in addition to high-quality nutritional composition, also contains ingredients that are beneficial to human health.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Gordana Kralik, Zlata Kralik, Manuela Grčević and Danica Hanžek",authors:[{id:"207236",title:"Dr.",name:"Gordana",middleName:null,surname:"Kralik",slug:"gordana-kralik",fullName:"Gordana Kralik"},{id:"227281",title:"Prof.",name:"Zlata",middleName:null,surname:"Kralik",slug:"zlata-kralik",fullName:"Zlata Kralik"},{id:"227283",title:"Dr.",name:"Manuela",middleName:null,surname:"Grčević",slug:"manuela-grcevic",fullName:"Manuela Grčević"},{id:"227284",title:"BSc.",name:"Danica",middleName:null,surname:"Hanžek",slug:"danica-hanzek",fullName:"Danica Hanžek"}]},{id:"56453",title:"Goat System Productions: Advantages and Disadvantages to the Animal, Environment and Farmer",slug:"goat-system-productions-advantages-and-disadvantages-to-the-animal-environment-and-farmer",totalDownloads:4328,totalCrossrefCites:5,totalDimensionsCites:21,abstract:"Goats have always been considered very useful animals. Goats success is related to its excellent adaptability to the difficult mountain conditions, extreme weather and low value feed acceptance, versatile habits and high production considering their size. These are some reasons because goats are among the first animals to be domesticated. In terms of evolution, goats could be separated by their dispersion area in three large groups: the European, the Asian, and the African. Global goat populations, mainly in Africa and in Asia, have increased for centuries but very strongly in the past decades, well above the world population growth. They are also used for forest grazing, an integrated and alternative production system, very useful to control weed growth reducing fire risk. Despite some exceptions, no large‐scale effort to professionalize this industry has been made so far. There are consumers for goat dairy products and there is enough global production, but misses a professional network between both. Regarding goat meat, the world leadership also stays in Africa and Asia, namely in China, and there is a new phenomenon, the spreading of goat meat tradition through Europe due to migrants from Africa and other places with strong goat meat consumption.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"António Monteiro, José Manuel Costa and Maria João Lima",authors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"},{id:"203680",title:"Prof.",name:"Maria João",middleName:null,surname:"Lima",slug:"maria-joao-lima",fullName:"Maria João Lima"},{id:"203683",title:"MSc.",name:"José Manuel",middleName:null,surname:"Costa",slug:"jose-manuel-costa",fullName:"José Manuel Costa"}]},{id:"70760",title:"Induction and Synchronization of Estrus",slug:"induction-and-synchronization-of-estrus",totalDownloads:1716,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Estrus cycle is a rhythmic change that occur in the reproductive system of females starting from one estrus phase to another. The normal duration of estrus cycle is 21 days in cow, sow, and mare, 17 days in ewe, and 20 days in doe. The species which exhibit a single estrus cycle are known as monstrous and species which come into estrus twice or more are termed polyestrous animals. Among them some species have estrus cycles in a particular season and defined as seasonal polyestrous. It includes goats, sheep, and horses. On the other hand, cattle undergo estrus throughout the year. The estrus inducers can grossly be divided into two parts, that is, non-hormonal and hormonal. Non-hormonal treatments include plant-derived heat inducers, mineral supplementation, uterine and ovarian massage, and use of Lugol’s iodine. The hormones that are used in estrus induction are estrogen, progesterone, GnRH, prostaglandin, insulin, and anti-prolactin-based treatment. Synchronization can shorten the breeding period to less than 5 days, instead of females being bred over a 21-day period, depending on the treatment regimen. The combination of GnRH with the prostaglandin F2α (PGF2α)- and progesterone-based synchronization program has shown a novel direction in the estrus synchronization of cattle with the follicular development manipulation.",book:{id:"8545",slug:"animal-reproduction-in-veterinary-medicine",title:"Animal Reproduction in Veterinary Medicine",fullTitle:"Animal Reproduction in Veterinary Medicine"},signatures:"Prasanna Pal and Mohammad Rayees Dar",authors:[{id:"299126",title:"Dr.",name:"Mohammad Rayees",middleName:null,surname:"Dar",slug:"mohammad-rayees-dar",fullName:"Mohammad Rayees Dar"},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal"}]}],onlineFirstChaptersFilter:{topicId:"25",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82457",title:"Canine Hearing Management",slug:"canine-hearing-management",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105515",abstract:"The United States military employs multipurpose canines as force multipliers. A newly developed baseline audiology program applicable to noise effects on the hearing threshold for these dogs has just been developed by the University of Cincinnati FETCHLAB using brainstem auditory evoked potentials to detect estimated threshold shifts in this population. Dogs that are routinely deployed are subject to consistent exposure to noise in the field. Few investigations have focused on the effects of transport noise on the auditory system in multipurpose dogs. The consequence of these dogs having a significant hearing threshold shift is a failure of the dog to properly respond to voice commands and to miss critical acoustic cues while on target. This chapter specifically discusses the baseline protocol for audiological testing of special operations’ multipurpose canines related to helicopter transport.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Peter M. Skip Scheifele, Devan Marshall, Stephen Lee, Paul Reid, Thomas McCreery and David Byrne"},{id:"82285",title:"Parvovirus Vectors: The Future of Gene Therapy",slug:"parvovirus-vectors-the-future-of-gene-therapy",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105085",abstract:"The unique diversity of parvoviral vectors with innate antioncogenic properties, autonomous replication, ease of recombinant vector production and stable transgene expression in target cells makes them an attractive choice as viral vectors for gene therapy protocols. Amongst various parvoviruses that have been identified so far, recombinant vectors originating from adeno-associated virus, minute virus of mice (MVM), LuIII and parvovirus H1 have shown promising results in many preclinical models of human diseases including cancer. The adeno-associated virus (AAV), a non-pathogenic human parvovirus, has gained attention as a potentially useful vector. The improved understanding of the metabolism of vector genomes and the mechanism of transduction by AAV vectors is leading to advancement in the development of more sophisticated AAV vectors. The in-depth studies of AAV vector biology is opening avenues for more robust design of AAV vectors that have potentially increased transduction efficiency, increased specificity in cellular targeting, and an increased payload capacity. This chapter gives an overview of the application of autonomous parvoviral vectors and AAV vectors, based on our current understanding of viral biology and the state of the platform.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Megha Gupta"},{id:"81793",title:"Canine parvovirus-2: An Emerging Threat to Young Pets",slug:"canine-parvovirus-2-an-emerging-threat-to-young-pets",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.104846",abstract:"Canine parvovirus-2 (CPV-2) is a highly contagious and key enteropathogen affecting the canine population around the globe by causing canine parvoviral enteritis (CPVE) and vomition. CPVE is one of the the leading causes of morbidity and mortality in puppies and young dogs. Over the years, five distinct antigenic variants of CPV-2, namely CPV-2a, CPV-2b, new CPV-2a, new CPV-2b, and CPV-2c, have emerged throughout the world. CPV-2 infects a diverse range of wild animals, and the newer variants of CPV-2 have expanded their host range to include felines. Despite the availability of highly specific diagnostics and efficacious vaccines, CPV-2 outbreaks have been reported globally due to the emergence of newer antigenic variants, expansion of the viral host range, and vaccination failures. The present chapter describes the latest information pertaining to virus properties and replication, disease manifestations in animals, and an additional recent updates on diagnostic, prevention and control strategies of CPV-2.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Mithilesh Singh, Rajendran Manikandan, Ujjwal Kumar De, Vishal Chander, Babul Rudra Paul, Saravanan Ramakrishnan and Darshini Maramreddy"},{id:"81271",title:"The Diversity of Parvovirus Telomeres",slug:"the-diversity-of-parvovirus-telomeres",totalDownloads:38,totalDimensionsCites:0,doi:"10.5772/intechopen.102684",abstract:"Parvoviridae are small viruses composed of a 4–6 kb linear single-stranded DNA protected by an icosahedral capsid. The viral genes coding non-structural (NS), capsid, and accessory proteins are flanked by intriguing sequences, namely the telomeres. Telomeres are essential for parvovirus genome replication, encapsidation, and integration. Similar (homotelomeric) or different (heterotelomeric) at the two ends, they all contain imperfect palindromes that fold into hairpin structures. Up to 550 nucleotides in length, they harbor a wide variety of motifs and structures known to be recognized by host cell factors. Our study aims to comprehensively analyze parvovirus ends to better understand the role of these particular sequences in the virus life cycle. Forty Parvoviridae terminal repeats (TR) were publicly available in databases. The folding and specific DNA secondary structures, such as G4 and triplex, were systematically analyzed. A principal component analysis was carried out from the prediction data to determine variables signing parvovirus groups. A special focus will be put on adeno-associated virus (AAV) inverted terminal repeats (ITR), a member of the genus Dependoparvovirus used as vectors for gene therapy. This chapter highlights the diversity of the Parvoviridae telomeres regarding shape and secondary structures, providing information that could be relevant for virus-host interactions studies.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Marianne Laugel, Emilie Lecomte, Eduard Ayuso, Oumeya Adjali, Mathieu Mével and Magalie Penaud-Budloo"},{id:"79209",title:"Virtual Physiology: A Tool for the 21st Century",slug:"virtual-physiology-a-tool-for-the-21st-century",totalDownloads:153,totalDimensionsCites:0,doi:"10.5772/intechopen.99671",abstract:"Veterinary physiology is a basic curricular unit for every course within the veterinary field. It is mandatory to understand how the animal body works, and what to expect of a healthy body, in order to recognize any misfunction, and to be able to treat it. Classic physiology teaching involves wet labs, much equipment, many reagents, some animals, and a lot of time. But times are changing. In the 21st century, it is expected that the teaching and learning process can be more active and attractive, motivating students to learn better. It is necessary to understand what students like, and to introduce novelties into the school routine. The use of a game-based learning, using “new” technologies, creating virtual experiences and labs, reducing the costs of reagents, equipment, and especially reducing the use of animals, will be the future for physiology teaching.",book:{id:"10665",title:"Updates on Veterinary Anatomy and Physiology",coverURL:"https://cdn.intechopen.com/books/images_new/10665.jpg"},signatures:"Carmen Nóbrega, Maria Aires Pereira, Catarina Coelho, Isabel Brás, Ana Cristina Mega, Carla Santos, Fernando Esteves, Rita Cruz, Ana I. Faustino-Rocha, Paula A. Oliveira, João Mesquita and Helena Vala"},{id:"78543",title:"Pulmonary Vein: Embryology, Anatomy, Function and Disease",slug:"pulmonary-vein-embryology-anatomy-function-and-disease",totalDownloads:183,totalDimensionsCites:0,doi:"10.5772/intechopen.100051",abstract:"Four pulmonary veins come from respective lung lobes drain oxygen-rich blood back to the left atrium. Failure of incorporation with the left atrium can lead to a condition, called Cor triatriatum sinister, that the left atrium is separated into two chambers by an abortive fibrous tissue. The venous system of lung and whole body communicate with each other in the earlier time and they will be disconnected in the following developmental process. Total or partial anomalous pulmonary venous connection refers to that there is/are some degree of the communication exists after birth, which can occur in different sites. In the veterinary field, retrospective studies and several case reports have been published to describe these rare congenital cardiovascular diseases in several species. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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