Hemoglobinopathy testing methods.
\r\n\tStatistical machine learning specifically poses some of the most challenging theoretical problems in modern statistics, the crucial among them being the general problem of understanding the link between inference and computation. This book intends to provide the reader with a comprehensive overview of linear method for regression, non linear method for regression, deep learning, unsupervised learning, artificial neural network, and support vector machine (SVM).
",isbn:null,printIsbn:null,doi:null,price:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a3fb79b0a4a302d6318df11534e1ec85",bookSignature:"Dr. Andino Maseleno",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8661.jpg",keywords:"Linear Method for Regression, Non Linear Method for Regression, Deep Learning, Unsupervised Learning, K-Means Clustering, Hierarchichal Clustering, Principal Component Analysis, Artificial Neural Network, Learning in Neural Network, Convolutional Neural Network, Support Vector Clustering, Multiclass SVM",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 3rd 2018",dateEndSecondStepPublish:"July 24th 2018",dateEndThirdStepPublish:"September 22nd 2018",dateEndFourthStepPublish:"December 11th 2018",dateEndFifthStepPublish:"February 9th 2019",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,editors:[{id:"219663",title:"Dr.",name:"Andino",middleName:null,surname:"Maseleno",slug:"andino-maseleno",fullName:"Andino Maseleno",profilePictureURL:"https://mts.intechopen.com/storage/users/219663/images/system/219663.jpg",biography:"Dr. Andino Maseleno is a research fellow at the Institute of Informatics and Computing Energy, Universiti Tenaga Nasional, Malaysia. He was a visiting fellow in Centre for lifelong learning, Universiti Brunei Darussalam, Brunei Darussalam, in July 2016 till March 2017. He received the B.S. in Informatics Engineering from UPN “Veteran” Yogyakarta, Indonesia in 2005, M.Eng. in Electrical Engineering from Gadjah Mada University, Indonesia in 2009, and Ph.D. in Computer Science from Universiti Brunei Darussalam, Brunei Darussalam in 2015.",institutionString:"Universiti Tenaga Nasional",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7311",title:"Electronic Versions of Traditional Media",subtitle:null,isOpenForSubmission:!0,hash:"b0f53a437e7aec5f7bd473de60f46e6e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7311.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7376",title:"Quantum Cryptography",subtitle:null,isOpenForSubmission:!1,hash:"2573ae2df9a0043aa7faca1ce4ed3fb7",slug:null,bookSignature:"Prof. Oleg Morozov",coverURL:"https://cdn.intechopen.com/books/images_new/7376.jpg",editedByType:null,editors:[{id:"69648",title:"Prof.",name:"Oleg",surname:"Morozov",slug:"oleg-morozov",fullName:"Oleg Morozov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7492",title:"Finite Element Method",subtitle:null,isOpenForSubmission:!1,hash:"547d37b1fc786c7aa0cdf478c9c7730b",slug:null,bookSignature:"Dr. Seifedine Kadry",coverURL:"https://cdn.intechopen.com/books/images_new/7492.jpg",editedByType:null,editors:[{id:"27144",title:"Dr.",name:"Seifedine",surname:"Kadry",slug:"seifedine-kadry",fullName:"Seifedine Kadry"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7607",title:"Artificial Neural Networks and its Impact on Metaheuristics and Engineering",subtitle:null,isOpenForSubmission:!0,hash:"b7f92b054dddc49df32d4f9c9e71507c",slug:null,bookSignature:"Dr. Ali Sadollah",coverURL:"https://cdn.intechopen.com/books/images_new/7607.jpg",editedByType:null,editors:[{id:"147215",title:"Dr.",name:"Ali",surname:"Sadollah",slug:"ali-sadollah",fullName:"Ali Sadollah"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7623",title:"Advanced Image and Video Coding",subtitle:null,isOpenForSubmission:!1,hash:"db1156342e3a1a46ff74cad035a3886b",slug:null,bookSignature:"Dr Sudhakar Radhakrishnan",coverURL:"https://cdn.intechopen.com/books/images_new/7623.jpg",editedByType:null,editors:[{id:"26327",title:"Dr",name:"Sudhakar",surname:"Radhakrishnan",slug:"sudhakar-radhakrishnan",fullName:"Sudhakar Radhakrishnan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7703",title:"Models of Concurrency",subtitle:null,isOpenForSubmission:!1,hash:"72513d370d5360c8f5886251e5063a3e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7703.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7711",title:"Brain-computer Interface",subtitle:null,isOpenForSubmission:!1,hash:"e62596fe51457df6f3eee38f678c6b62",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7711.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8223",title:"Processing and Analysis of Hyperspectral Data",subtitle:null,isOpenForSubmission:!0,hash:"02b920d9c266e28152227280ff18ebbe",slug:null,bookSignature:"Dr. Jie Chen",coverURL:"https://cdn.intechopen.com/books/images_new/8223.jpg",editedByType:null,editors:[{id:"218017",title:"Dr.",name:"Jie",surname:"Chen",slug:"jie-chen",fullName:"Jie Chen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8255",title:"Real-Time Systems",subtitle:null,isOpenForSubmission:!0,hash:"96fbe5e3a3b1ea46f627a3e0f30b8529",slug:null,bookSignature:"Dr. Sanath Alahakoon",coverURL:"https://cdn.intechopen.com/books/images_new/8255.jpg",editedByType:null,editors:[{id:"240351",title:"Dr.",name:"Sanath",surname:"Alahakoon",slug:"sanath-alahakoon",fullName:"Sanath Alahakoon"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8433",title:"Interactive Multimedia",subtitle:null,isOpenForSubmission:!1,hash:"10c60ae8cc995d9c76b2fba8dedc51e6",slug:null,bookSignature:"",coverURL:"//cdnintech.com/web/frontend/www/assets/cover.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52109",title:"Point‐of‐Care Testing in Sickle Cell Disease",doi:"10.5772/64862",slug:"point-of-care-testing-in-sickle-cell-disease",body:'\nApproximately 5% of the world\'s population carries traits for hemoglobin disorder (majority sickle cell disease, thalassemia). The global incidence of sickle cell disease (SCD) is 300,000 births/year of which 90% are estimated to occur in sub‐Saharan African and India, many of whom reside in low‐resource areas. In many of these areas, 50–80% of children die before five years of age [1]. In contrast, a small margin of affected individuals are born in the USA, England, France and other high‐resource countries where 98% of children are living >18 years of age. In these high‐resource countries, early diagnosis remains a key reason for the improved longevity [2, 3].
\nNewborn screening provides an early diagnosis of SCD which has demonstrated efficacy in reducing infant mortality through initiation of penicillin prophylaxis and delivery of care/education prior to the onset of clinical complications [4, 5]. However, current newborn screening programs are dependent on central laboratories with capabilities to perform cost‐efficient, high‐throughput screening [6]. In addition to high‐cost laboratory equipment, these programs require complex work‐flow including skilled individuals, sample transport and advanced systems of medical care. Additionally, most newborn screening samples are collected at outlying hospitals and are shipped to centralized laboratories where tests are batched and run on a scheduled basis and results are then sent to primary care providers or public health officials to communicate with affected families. Screening is two‐tiered starting with testing in the hospital and complementary, confirmatory testing performed at follow‐up to confirm the diagnosis (and validate the sample was sent on the correct patient). Thus, all individuals are tested while in the hospital during the newborn period, and the results are often not available for communication until several weeks after discharge. While systems of care exist in many developed countries for communicating these results, these options are not available in other, less resourced areas. Even in some high‐resource areas, it can also be difficult to find the newborn and bring them back to the provider for confirmatory testing.
\nWhile newborn screening is limited in low‐resource areas, many high‐resource countries are unable to diagnose and confirm sickle cell disease at the point of care (POC). Similar to tests used during newborn screening, diagnostic tests for SCD are expensive and time consuming. As a result, the testing is often batched and run on specific days with limited availability for diagnosis at the point of care or when the patient presents. While this limitation does not affect most patients who have been previously identified within a health system, the inability to confirm the diagnosis at the point of care can lead to delays in treatment in outside hospitals (where the individual is not usually treated) or inappropriate treatment for an affected individual. Due to the painful nature of this disease, many patients face undue stigmatization for having sickle cell disease. Without “proof” of disease, patients may not be able to receive the care they need in a timely manner. Conversely, there are also anecdotal reports of individuals without SCD who falsely claim to be affected by the condition to receive opioid therapy in the emergency room setting. For those patients not established within a hospital system, a point‐of‐care test may enhance the ability of acute care physicians to provide appropriate therapy.
\nResearch has clearly demonstrated that the health burden of hemoglobin disorders can be reduced through screening and early diagnosis, prevention and management [5, 7, 8]. While these cost‐effective lifesaving strategies/therapies are already known, many are not universally available [9]. Thus, options for enhancing access to early diagnosis include the development of centralized laboratories in low‐resource areas and novel point‐of‐care testing method which remain in development.
\nThe diagnosis of a hemoglobin disorder is usually performed by confirmatory testing in hospital, private or academic laboratories. The majority of current labs in high‐resource areas utilize methods of protein chemistry methods such as isoelectric focusing (IEF) or high‐performance liquid chromatography (HPLC) and (Sebia) capillary electrophoresis (CE) [10]. Some additional laboratories utilize hemoglobin electrophoresis with either cellulose acetate or citrate agar. Specifically, acid citrate agar is used for conformation of hemoglobin SC disease. See Table 1 for a list of testing methods.
\n\nIsoelectric focusing utilizes agarose gels to separate hemoglobin (Hb) fractions and variants based on their isoelectric points [11]. Hb A and Hb F are clearly resolved by this method. Hb C can also be distinguished from Hb E and Hb O, and Hb S can be distinguished from Hb.
\nHigh‐performance liquid chromatography separates hemoglobin in sample by passing them through a column filled with a solid adsorbent material. Specifically, HPLC uses the principles of cation exchange for the separation and determination of the relative percentage of normal and abnormal hemoglobin. Each component in the sample interacts slightly differently with the adsorbent material, causing different flow rates for the different components and leading to the separation of the components as they flow out the column. This is the method used to identify and quantify relative fractions of Hb F, Hb A2, Hb S, Hb C, Hb Barts and other Hb variants. HPLC is also used to quantify Hb A2 and Hb F for carrier screening [12, 13].
\nHemoglobin electrophoresis at alkaline or acidic pH can be used as a primary or confirmatory method of identification. Electrophoresis separates molecules based on size and charge. Different hemoglobin has a different charge, and according to those charges and the amount, hemoglobin moves at different speeds in the gel whether in alkaline gel or acid gel. This method separates hemoglobin based on the relative mobility of the variant hemoglobin into characteristic bands [10, 14].
\nNovel diagnostic testing in hemoglobinopathies. A variety of novel methods of hemoglobinopathy testing are now available at select laboratories in high‐resource areas. These newer techniques expand the analysis and complexity of hemoglobinopathy testing and identification. Techniques include molecular methods of identification, such as the linear array assay, a multiplexed reverse dot blot genotyping method, used to simultaneously test for a panel of common beta‐globin variants (Hb S, C, E, D and O), as well as majority (>95%) of common beta‐thalassemia mutations[1] -. Another newer method uses multiplex gap PCR assays to detect common alpha thalassemia deletion mutations, alpha globin gene duplications and other globin gene deletions, such as Hb Lepore and HPFH. Finally, DNA sequence analysis of alpha, beta or gamma globin genes can also be performed to definitively identify unknown point mutations or sequence variation. At present, however, these more advanced techniques remain sequestered in advanced laboratories and are not universally available.
\nType of test | \nMethod | \nResults | \nPRO | \nCON | \n
---|---|---|---|---|
Traditional testing methods | \n||||
Isoelectric focusing | \nAgarose gels to separate hemoglobin based on isoelectric points | \nHb A, Hb F, Hb C, Hb S, Hb E and Hb OArab | \nReliable, able to distinguish most types of sickle cell disease including compound heterozygotes | \nExpensive, requires skilled technicians, often batched and run every few days | \n
High‐performance liquid chromotography | \nSeparates hemoglobin by principles of cation exchange | \nIdentify and quantify Hb F, Hb A, Hb A2, Hb S, Hb C, Hb Barts and others | \nReliable, able to distinguish most types of sickle cell disease, including compound heterozygotes | \nExpensive, requires skilled technicians, often batched and run | \n
Hemoglobin electrophoresis | \nSeparates Hb based on size and charge | \nIdentify and quantify HbF, Hb A, Hb A2, Hb S, Hb C, Hb Barts and others | \nReliable, able to distinguish most types of sickle cell disease including compound heterozygotes | \nExpensive, requires skilled technicians, often batched and run | \n
Novel diagnostic testing methods | \n||||
AMPS | \nDensity based test to separate Hb in different density fluids | \nIdentifies Hb S and Hb A | \nInexpensive, done at the point of care | \nInterpretation is more difficult, Less reliable results, difficult to distinguish HbSC disease | \n
Paper‐based Sickle test | \nMicrofluidic assessment | \nIdentifies Hb S and A and C and company has a separate test that can identify Hb F | \nInexpensive, done at the point of care, reliable diagnosis of HbSS disease, easily performed by non‐skilled personnel | \nRequires a scanner for final results, can be difficult to distinguish HbAS (trait) from HbSC, test could be altered in different humidities | \n
Sickle SCAN | \nLateral flow assay | \nDistinguishes Hb A, Hb S, Hb C | \nReliably identifies HbA, HbS, and HbC, easily performed by non‐skilled personnel, easily interpreted, rapid test at the point of care | \nMore expensive than the other point of care tests above. Does not identify hemoglobin F. Limit of detection of Hb A is 2% | \n
HemeChip | \nMicro‐elecrophoresis assay | \nDistinguishes Hb F, S, C, A, and D | \nReliable, able to distinguish most types of sickle cell disease including compound heterozygotes | \nRequires a skilled interpretation, web‐based image processing application for automated results | \n
Hemoglobinopathy testing methods.
In regions of the world where sickle cell trait and SCD are very prevalent, partnership between private and public organizations and researchers and local hospitals has resulted in impressive newborn screening/diagnostics for SCD. Examples of such efforts include Angola, Uganda and Jamaica.
\nAngola\'s newborn screening program for SCD was born out of the government mandated public health initiative for perinatal HIV screening and a partnership with Chevron. Chevron is one of the leading producers of petroleum in Angola. Thus, Chevron provides support for many Angola‐based health initiatives. This initiative was undertaken in partnership with a US academic hospital to assess whether a centralized newborn screening program for SCD was feasible in a low‐resource setting. Additional emphasis in this initiative was placed on local training and capacity building for the region. The laboratory was set up in the only pediatric hospital in Angola, and the program was designed to send all collected samples to this location for analysis [15].
\nFor the pilot program in Angola, researchers selected two large maternity hospitals in Luanda as initial sites of blood collection from newborn infants. To enhance local capacity building, obstetrical nurses were trained in the techniques of blood collection and then retrained monthly, and then retrained approximately once a month. All samples were drawn using a heel stick procedure to fill bloodspots on a custom‐designed Whatman screening card. Individual cards were distinguished by unique barcodes linked to a database containing necessary demographic information. Additionally, a detachable portion of the card was provided to the mother. Bloodspots were dried and placed in a plastic bag for storage until specimen pickup, as all testing was performed at the central laboratory.
\nIsoelectric focusing (IEF, RESOLVE® neonatal hemoglobin system, PerkinElmer, Inc.) was used to perform testing of the dried bloodspot samples within one to two days of arrival in the NBS laboratory. Samples were batched for testing (as done in the USA). Once resulted, the samples were scored first by the laboratory technician and the laboratory supervisor subsequently scored each gel independently to ensure accuracy of results. All IEF results with an FAS, FS or other abnormal hemoglobin patterns, or in the rare instance of an indeterminate result, were selected for repeat analysis by capillary electrophoresis (CE).
\nAttempts were made to contact all families of all newborns with HbSC or HbSS results between 6 and 8 weeks of age. Attempted contact was made by telephone. If the family could be reached, infants had repeat samples drawn for confirmatory testing and enrollment in the local sickle cell clinic. However, due to the low‐resource area and limited telephone access, 46% of families of infants (with +tests) could not be contacted highlighting the difficulties of centralized laboratory testing in low‐resource areas [15, 16].
\nSimilar to Angola, the Ugandan Ministry of Health already had an active program for prevention of mother‐to‐child transmission of HIV based on identifying and treated infected mother and exposed newborns. It identifies and treats infected mothers and their exposed infants. For this program, dried blood spots are collected from exposed infants at health‐care facilities across the country, carried by motorcycle to laboratory hubs at the subdistrict level, and shipped by courier to the Central Public Health Laboratories in the capital. A sickle cell laboratory was initiated within the same central public health laboratories to test for normal and abnormal hemoglobin. Also like Angola, the initiation of the sickle cell NBS program was initiated through a partnership between a US academic center and the local hospital and ministry of health [17–19].
\nThe laboratory methods for sickle cell disease in Uganda were the same as those discussed in Angola. Again, local staff at the Central Public Health Laboratories received on‐site training by a technical, US‐based team on the study protocol, isoelectric focusing procedures and interpretation of results. Additional sessions and re‐teaching sessions were also provided as well as ongoing laboratory support. The system for reporting positive results in Uganda was more advanced than that of Angola. Here, the hemoglobin results were communicated to the collection sites with the existing HIV notification system [20].
\nJamaica initiated newborn screening in 1973 with the development of the well‐described Jamaican Sickle Cell Cohort Study. In this initial effort, 100,000 consecutive live births were screened at the main Government Maternity Hospital (Victoria Jubilee Hospital, Kingston). Obstetric and labor nurses were trained to collect cord blood specimens, and self‐adhesive labels were provided in every labor ward. These labels were duplicated and consecutively numbered so that identical labels were applied to the blood tube and a data card for each patient. The blood tubes were stored at room temperature, collected each morning. These were utilized to form hemolysates which were then used for hemoglobin electrophoresis [21, 22].
\nFollowing this initial work, Jamaica initiated a second centralized screening program in 1995 including both the main Government Maternity Hospital in Kingston (Victoria Jubilee Hospital) as well as both the University Hospital of the West Indies, Kingston (added in 1997) and the Spanish Town Hospital (added in 1998) to include 43% of births in Jamaica. Cord blood samples were collected at birth on a Guthrie card instead of in tubes as done in the initial study. All hemoglobin electrophoresis testing was performed by the newborn screening program at the Sickle Cell Unit (SCU), Tropical Medicine Research Institute, Jamaica. Patient demographics were collected with the Guthrie card and recorded in the newborn screening database. After testing was completed, infants with positive screening results suggestive of a hemoglobinopathy or with an inappropriate specimen or unclear results were notified by letter to come in for confirmatory testing. For those babies who fail to come in, a research nurse found them to encourage parents to bring their infant to the SCU for further testing.
\nFrom 1995 to 2006, 150,803 infants had undergone cord blood screening and approximately 889 infants had phenotype results suggestive of possible SCD in the initial testing [3].
\nWhile the efforts described above are successful, they rely on a significant amount of government or partnership support to establish the infrastructure needed for testing patients, confirming the diagnosis and re‐identifying/contacting the affected families. Additionally, a large enough patient population is needed within specific areas to justify the cost of this type of infrastructure. Thus, it remains a priority to validate a POC testing device for the diagnosis of SCD.
\nTo be an effective diagnostic test at the point of care (POC), all testing methods/devices must contain some similar properties. By definition, POC testing requires that testing must occur at or near the site of patient care. The goal of POC is to improve medical and economic outcomes by promoting rapid response and faster therapeutic turnaround time which requires rapid testing in close proximity to the patient. POC tests should also be simple. “Simple” means that the device/test uses unprocessed samples, is easy to read and interpret, does not require medical personnel for testing and includes instructions for confirmatory testing when needed. The test must demonstrate “insignificant risk of erroneous result” through risk analysis which can be overcome for hemoglobinopathy testing through the obligation to perform confirmatory testing. Finally, one of the advantages of diagnostic POC testing is the opportunity for immediate feedback for the patient [23, 24]. A POC gives the tester (or clinician) the capability to interact at the time of testing, taking advantage of the counseling and educational opportunity.
\nThese devices must have high specificity to detect HbS (including in the presence of hemoglobin F), the capacity to distinguish sickle cell trait (HbAS) from samples with SCD. These point‐of‐care testing methods for SCD and sickle cell trait must be scalable, portable and easy to use. Results must be available within the same visit/time period for the affected patient (no follow‐up required to receive tests results). For low‐resource areas, devices need to be low cost, compact, and light weight to enhance portability. Finally, testing must be easy to perform with a simple design and rapid interpretation that does not require complex evaluation (i.e., does not require a medical professional) [25, 26].
\nThere are several testing methods and devices currently in development to achieve the aims above. These tests rely in different ways on the pathophysiologic properties of the sickle hemoglobin that differentiate it from other hemoglobin. While this list likely not exhaustive, it includes the current published tests in development. The testing methods are in various stages of evaluation and validation, and many companies and individuals are seeking device agency approvals. Current testing methodologies are listed in Table 1 and include in the following.
\nOne of the main properties of cells containing hemoglobin S is that these cells sickle upon deoxygenation. The degree of sickling is relative to the quantitative amount of S hemoglobin within the red cell. As cells sickle, this increases their density which allows red blood cells (RBCs) containing hemoglobin to be separated by cell density. Red blood cells in SCD have a specific distribution of cell densities which can be distinguished using Aqueous Multiphase Systems (AMPS). This system includes a combination of polymers and/or surfactants in water than form distinct, immiscible phases which allows the separation of cells based on density. For this testing device, whole blood must be centrifuged and separated into components prior to the red cells being placed in the AMPS solution. To allow for centrifugation in low‐resource areas, investigators have identified battery operated mini‐centrifuges capable of successfully separating the red cell fragment and allowing for testing. Devices are stable and densities can be tuned to distinguish very small differences (Δρ ∼0.0005 g/cm3). However, potential negatives include difficult in interpretation in the field and inability to successfully distinguish hemoglobin SC disease (Figure 1) [27, 28].
\nAMPS‐based sickle cell disease POC test [27].
Paper‐based testing utilizes similar methodology to conventional hemoglobin solubility assays (e.g. SickleDex™, SA and ASI test), which have been used routinely by blood banks and clinical laboratories to verify the presence of HbS in blood samples for many years [10]. When deoxygenated, sickle hemoglobin forms polymers, which are more soluble in solution. Specific solubility buffers contain:
Saponin irreversibly lyses red blood cells (RBCs) by creating holes in the lipid bilayer that releases hemoglobin into the buffer.
Sodium hydrosulfite converts the released hemoglobin into deoxy‐Hb that is either soluble (HbA, HbE, HbF or HbC) or insoluble (HbS) in the phosphate buffer.
When these solutions of hemolyzed samples are placed on paper, the delay in transit time caused by the sickle polymers results in a characteristic blood stain pattern which distinguishes normal, sickle cell trait and SCD samples. In other words, paper‐based assay identifies the presence of HbS by measuring the separation of HbS from non‐HbS by differential wicking/transit of insoluble Hb S vs. soluble Hb in a paper matrix. Blood stain patterns are produced on the chromatography paper based on solubility. However, instead of measuring turbidity (as in Sickledex test), the paper blood stain reflects the amount of polymerized HbS trapped within the paper fibers while the soluble (non‐polymerized) hemoglobin continues to spread on the paper. Because hemoglobin is naturally colored, the assay read out uses the red color count in the region of the polymerized hemoglobin and soluble hemoglobin [29].
\nTesting results (the blood stain) can then be scanned using portable scanners (on a cell phone) to quantify the density of the blood stain and differentiate SCD vs SC trait vs. sickle SC disease. However, this test remains dependent on a low percent of fetal hemoglobin which makes it less ideal in newborn screening. A newer version of the test in development may resolve this complication but results are pending at this time. This device successfully reduces the required blood sample volume, lowering the per‐test cost and significantly simplifying the interpretation of results. Sickle cell anemia can be distinguished easily but scanning is required for further hemoglobin differentiating. Scanned results are easy to interpret which makes the test highly adaptable in the non‐medical population (Figure 2) [30].
\nCharacteristic blood stain patterns produced by paper‐based SCD assay.
Lateral flow assays are simple devices intended to detect the presence (or absence) of a target analyte. For this type of test, the analyte is hemoglobin. Antibodies are utilized to bind to the human alpha globin chain and are conjugated to colored nanoparticles. These antibodies are conjugated to yellow‐colored nanoparticles bind the antigen (Hb) as they migrate toward the test lines. Conjugated antibodies with bound Hb (antigen) bind to capture antibodies (polyclonal antibodies for specific hemoglobin S, C, A) on each of three test lines (producing positive result). Nanoparticles without antigens bind to the control line (proof of validity of the testing device) (Figure 3) [32].
\n(a–d) Lateral testing method [31].
Current tests in development utilize polyclonal antibodies that can bind to hemoglobin S, C, A and F. The result is a single test line for each specific hemoglobin (identifying the presence of that particular hemoglobin). Importantly, this type of test is electricity/battery free, can be performed with capillary whole blood that does not require centrifugation and produces rapid results. Because lateral flow tests can demonstrate the result of more than one hemoglobin at a time, these devices can also detect heterozygotes (patients carrying two or more distinctive hemoglobin or patients who have been transfused with a differing hemoglobin).
\nThe newest published device for point‐of‐care testing in SCD is a small version of a hemoglobin electrophoresis. Minimal amount of blood (from a capillary stick) is required and placed on a piece of cellulose paper in alkaline buffer. The paper is then inserted into a device (Figure 4) that houses a micro‐engineered plastic chip for cellulose acetate electrophoresis and uses a battery powered electric field to separate hemoglobin based on charge as described in standard hemoglobin electrophoresis. The result requires image quantitation using an intensity‐based application on a mobile phone image. Results validated against standard EP and HPLC with correlation >0.96 for all hemoglobin tested including the ability to distinguish Hb F, S, C, A, D. This test utilizes the principles of electrophoresis to detect and distinguish hemoglobin based on the traveling distance from the sample application point and displays quantitative % hemoglobin fractions. A web‐based image processing application for automated and objective quantification of HemeChip results at the POC using cloud computing resources [33].
\n(a–c) Hemechip [33].
Multiple point‐of‐care tests are currently in development for the identification of sickle cell disease at the point of care. It is important for confirmatory hematology testing, a multiplex device should be available for clinicians to make proper clinical assessments. As discussed, the device and method must distinguish target hemoglobin from interfering substances in blood that cause false‐positive or negative results. It is clear that the pathophysiology of SCD, specifically the point mutations in the genome leading to the hemoglobin expression and the polymer formation that occurs upon cellular dehydration have been well utilized in the design of these testing devices. The optimal testing method will be the device that can produce at the lowest cost, easily utilized in a low‐resource setting, with easy‐to‐interpret results and low false‐negative results.
\nBased on the testing method described above, the lateral flow test is currently the most easily utilized in the field without requiring specialists for interpretation. This test has the capacity to clearly distinguish the majority of hemoglobin within a rapid period of time. However, it is unclear whether lateral flow tests will be cost prohibitive for widespread use. Alternatively, the Hemechip provides an excellent method for sickle cell disease confirmation also easily utilized in point‐of‐care settings although the interpretation requires additional skill as well as the use of mobile phone and internet access.
\nThere are significant therapeutic and diagnostic health disparities that exist between SCD and other, inherited and acquired health conditions. Recent literature demonstrates that point‐of‐care diagnostics for sickle cell disease are feasible and accurate. Thus, it is hopeful that novel point‐of‐care diagnostics will change the screening paradigm for some areas in which central lab testing is not available.
\nIn the old Talmud, an imbecile, deaf-mute, and a minor were included in the same category related to religious obligations (Baba Kama 55 page B). This approach was explained as probably the earliest expression of the significance and power of early intervention—for babies and for disabled people.
In recent decades, we return to this approach and look for suitable and efficient early intervention models in order to successfully cope with developmental insults.
Training with babies in an aquatic setting has been found to benefit and promote infant health and development [1, 2, 3], being based on the physical properties of water and their physiological outcomes on the neuromotor [4, 5, 6], cardiovascular [7, 8], and respiratory functions [3]. Specifically, training with babies in an aquatic setting adapted for young babies with developmental risk may strengthen the function of autonomic parasympathetic nervous system and improve the development of neural circuits through better brain perfusion and sensory-motor training [1, 2, 9, 10].
In warm water, increased environmental pressure advances deep lung ventilation and higher lymphatic and venous return from the periphery; higher levels of blood and lymph entering the heart’s right atrium cause slight bradycardia, producing a calming effect; most important for these infants, the water buoyant force causes the proprioceptors to cease registration of gravity; and an automatic reduction of muscle tone ensues. The benefits of reduced muscle tone linger for some hours following immersion. In these beneficial conditions, training is most effective both for sensory, emotional, and neuromotor purposes, and active parent role in this process is an additional advantage.
Training with young babies at risk, in an aquatic setting, may not cure severe brain lesions such as cerebral palsy; however, implying specific training approaches in specific developmental time windows may allow early effective intervention [11, 12, 13, 14, 15] which may eventually improve brain development.
This was our basic concept when we started our journey into the project, yet our findings showed us that our training protocol may have a deep neuro-power, more than we could foresee.
Neurodevelopmental syndromes are a continuously growing issue. These are impairments in the growth and development of the brain and CNS which appear in a variety of emotional, cognitive, motor, and social skills. One most important question when diagnosing and treating young children concerns the critical developmental time window through which chances for improvement would be strongest. Considering the fragility of young babies who are at developmental risk and the general tendency to postpone definite developmental diagnosis, the consideration of intervention should include neurological background of developmental mile stones.
During fetal development, a temporary assembly progresses in the subcortical future white matter, situated between the intermediate zone and the developing cortical plate, named cortical subplate [16]. As widely described in our recent paper [17], the subplate is thickest around the time of high production of oligodendrocyte father cells (29 weeks PMA), and is absorbed gradually until around 4 months post-term, with relocation of fiber terminals into the cortex [18, 19]. Most of its networks run through the (future) periventricular white matter. The size and duration of the subplate visibility correspond with cortical fiber complexity, being considered a recent phylogenetic structure that enables the increasing complexity of cortical circuitry [20].
The cortical subplate is a transmission complex for the neural projections of the developing cortical circuits and a regulating component that orchestrates neural network activity [21, 22]. Hence, subplate neurons are important for precise wiring and functionality of the cerebral cortex—they make initial temporary synapses between thalamic axons and their destinations in the early C4 layer [23].
SCP neurons, with their numerous synaptic contacts, are important factors that influence cortical development and ripening [24, 25, 26]. In the time gap of their presence, the SCP neural circuits are prone to hypoxic insult [27], which may cause long-term influence on brain development and functional deficits in various aspects. The time window of SCP circuits’ high action is also the time window when young infants born premature make their first surviving out of utero.
Neurodevelopmental impairments range from MND (minimal brain deficit) to ASD (autism spectrum disorder) and CP (cerebral palsy) [28, 29, 30, 31, 32, 33, 34]. Despite recent technological and scientific advance, there is currently no cure for severe neurodevelopmental impairments. However, various therapies may reduce the traumatic effect of brain lesions when diagnosed and treated during specific time windows in early infancy. Hence, the first weeks of baby’s life may be critical for brain development through early and effective intervention.
The babies participating in our study were born premature and participated in this research during cortical subplate activity time window. Average birth percentage of preterm babies is around 10% and it is continuously rising. Prematurity is the global second frequent cause of death among babies. Although new medical tools enable more premature babies to live, many are at high risk for brain damage [29, 33, 35, 36] and neurodevelopmental insults [30, 34].
For example, cerebral palsy in premature neonates is caused mainly by developmental brain injury at the white matter of the brain—periventricular leucomalacia (PVL), due to bleeding in the brain (IVH, ICH), oxygen or blood deprivation (hypoxia, anoxia) in the brain [29, 32, 33]. Periventricular leucomalacia may cause severe, long-term damage to brain tissue [37, 38, 39, 40]. Common symptoms of CP include lack of muscle coordination while performing voluntary movements (ataxia), and stiff or tight muscles and exaggerated reflexes (spasticity) with associated cognitive impairments.
Autism spectrum disorder (ASD) is the joint name for neurodevelopmental impairments characterized by abnormal social interaction, communication, limited range of activities and areas of interest [41], and typical motor impairments [42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. Being considered as sharing a similar mechanistic basis [54], previous ASD subcategories were unified under DSM5 (2013), and the classification today is based on severity of symptoms and level of disability.
There is a remarkable increase in the number of children diagnosed with ASD over the past 30 years, from less than 0.1% [55, 56] to ∼1% [57] and more. Among infants at risk, premature infants have a five times higher risk of developing ASD, and a significantly high incidence of autistic symptoms was identified in premature infants [58, 59]. Changes in diagnostic criteria, different assessment tools, and increased public awareness may be only partially responsible for the increase in ASD epidemiology [60]. Studies indicate that genetic, neurological [59, 61, 62, 63, 64, 65, 66], and environmental [67, 68, 69, 70, 71, 72] factors are involved in the emergence of autism spectrum disorder (ASD).
Prenatal exposure to particulate matter solid fuels and traffic-related air pollutants, especially in the third trimester of prenatal development [67], link the ambient epigenetic aspects with internal genetic vulnerability due to lower, enzymatically based, removal ability of harmful remnants from infant’s body. Indeed, these findings are in agreement with recent neurological understanding about the developmental time window of subcortical plate (SCP) during late prenatal and early postnatal period.
Early and effective intervention, through the important developmental time window of cortical subplate activity, may minimize neurological and functional deficits.
We have developed a unique training model for water—INA (Infant Neural Aquatics). The model consists of repetitive bilateral motor training and sustained moderate aerobic activity and their influence on desensitization and reprocessing of adverse events in utero and after birth.
After parents signed informed consent, INA was conducted in the hydrotherapy pool— babies were placed in warm water in vertical and horizontal positions, supported by the buoyancy of water and the caring hands of parent or therapist. Training started with a set of pre-structured movements through which parents practice handling of the infant in the water, in a way that enables free and integrated movement, eye contact, vocal communication, and increased confidence.
Working technique employed was modified for young and prematurely born Infants, including: passive mobilization, various rotations, relaxed floating, 8 shape delicate mobilization when the infant is supported under occiput and rib cage. Infants were video recorded during water sessions, under water and above water, once a week along 14 consecutive weeks (Figures 1–4).
INA (Infant Neural Aquatics) approach at work: Encouraging eye contact.
INA (Infant Neural Aquatics) approach at work: Relaxed floating.
INA (Infant Neural Aquatics) approach at work: 8 shape delicate mobilization.
INA (Infant Neural Aquatics) approach at work: Passive mobilizatio.
Developmental track of the babies with early intervention employing the INA approach was conducted at fixed time points using the non-intrusive General Movements (GM) tool [73, 74, 75]. The babies showed about 70% delta in developmental improvement comparing w/wo INA when the babies were around 55 wPMA.
Using the developmental tool ABAS (Adaptive Behavioral Assessment Scale) [76], the children showed about 40% delta in developmental improvement comparing w/wo INA, when the babies were around 1.5 years old (Graphs 1, 2).
Difference in developmental tracks between before and after early intervention period (delta), in group with INA (blue) compared to group without INA (red), at the age of 55 wPMA (delta1) and at the age of 1.5 years (delta2).
Developmental grades before, immediately after, and 1 year after early intervention period.
Intervention group. 78.27% of the subjects got the same results in delta1 and delta2 (for 8.70% both delta are equal 0 and for 69.57% both delta were equal 1), 21.74% of the subjects did not get the same results in delta1 and delta2—delta1 = 1 and delta2 = 0 (no opposite cases). We calculated the kappa coefficient (system consistency) = 0.3575 (confidence limit 95% is −0.0242 till 0.7393). We conducted McNemar’s Test (significance of results), P = 0.0625.
Control group. 87.50% of the subjects got the same results in delta1 and delta2 (for 66.67% both delta were equal 0 and for 20.83% both delta are equal 1), 12.50% of the subjects did not get the same results in delta1 and delta2—delta1 = 0 and delta2 = 1 (no opposite cases). We calculated kappa coefficient (system consistency) = 0.6897 (confidence limit 95% is 0.3774 till 1.000). We conducted McNemar’s Test (significance of results), P = 0.2500.
In order to test if group (w/wo early intervention) and the babies’ preliminary grades were dependent, we used Fisher Exact test and got non-significant result (P = 0.5806), which proves no link between group (w/wo early intervention) and babies’ developmental grade. In order to test if group (intervention/control) and the babies’ grades at 55 wPMA were dependent, we used Fisher Exact test and got significant result (P = 0.0016), which proves a link between intervention and infant early developmental grade.
In order to test if group’s grade (intervention/control) and delta1 were dependent, we used Fisher Exact test and got significant result (P < 0.0001). In the intervention group. 8.70% got delta = 0, and in the control group. 79.17% got delta = 0. In order to test if group’s grade (intervention/control) and delta2 were dependent, we used Fisher Exact test and got significant result (P = 0.0199). In the intervention group. 30.43% of delta = 0, and in the control group. 66.67% got delta = 0.
Our results show significant improvement in developmental tracks of babies receiving INA compared to babies who did not, that is, delta in developmental tracks, between before and after early intervention, is ∼40% higher when babies receive INA as observed without INA.
Screening of our videos, recording INA practice with the babies, we interpret that in addition to the significant benefits of the water’s physical environment (described above), INA model functions as a therapeutic tool for the babies who experienced a trauma, much like the modern variants of EMDR (Eye Movement Desensitization and Reprocessing) model [77]. The bilateral passive and active stimulation and movement during INA training cause a scheduled activation of both right and left cortical hemispheres, unlock the traumatic experience in the right hemisphere, promote new connections in interhemispheric neural cycles, contributing to the high delta scores in the participants who received INA compared with those who did not.
We assume that longer intervention periods would keep the high delta scores to older age, allowing the brain more training and a longer period of enhanced conditions.
In the next stage of the project, we define the correlation between concentration curves of biomarkers related to brain injury in the participants’ body fluids, and neuro-developmental track.
Indeed, the research described here directs the light on a certain vulnerable group of babies. However, the scientific and clinical products of this project, when properly tuned, may be successfully applied to various groups who are at developmental risk—children and youth diagnosed with post-trauma, or under extreme/acute emotional load, etc.
This scientific work is dedicated to my dear parents for their unlimited love and care.
We wish to thank:
The parents of the babies for their trust and cooperation.
The hydro therapists at Sheba MC Rehabilitation Pool for their collaboration.
The Haifa University Research Dean Fund for their generous support.
The Magi-Adelis Research Fund for their generous support.
The National Institute for Psychobiology in Israel, for their generous support.
IntechOpen's Authorship Policy is based on ICMJE criteria for authorship. In order to be identified as an Author, one must:
',metaTitle:"Authorship Policy",metaDescription:"IN TECH's Authorship Policy is based on ICMJE criteria for authorship. In order to be identified as an Author, one must:",metaKeywords:null,canonicalURL:"/page/authorship-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"All contributors who meet the three criteria should be listed as Authors. Their exact contributions should be described in the manuscript at the time of submission.
\\n\\nConversely, all contributors who don't meet the three criteria should be listed in the acknowledgments section of the manuscript, along with a short description of their contributions.
\\n\\nCHANGES IN AUTHORSHIP
\\n\\nIf it is necessary to make changes to the Authors' list after a manuscript has been submitted or published, the corresponding Author must provide a valid reason to amend the list of Authors. All listed Authors must verify and approve the proposed changes in order for them to be made.
\\n\\nAFFILIATION
\\n\\nAuthors are responsible for ensuring all addresses and emails provided are correct. The affiliation(s) of all authors should be the affiliation(s) where the research was conducted. No changes to the affiliation(s) can be made after the chapter is published.
\\n\\nPolicy last updated: 2017-05-29
\\n"}]'},components:[{type:"htmlEditorComponent",content:"All contributors who meet the three criteria should be listed as Authors. Their exact contributions should be described in the manuscript at the time of submission.
\n\nConversely, all contributors who don't meet the three criteria should be listed in the acknowledgments section of the manuscript, along with a short description of their contributions.
\n\nCHANGES IN AUTHORSHIP
\n\nIf it is necessary to make changes to the Authors' list after a manuscript has been submitted or published, the corresponding Author must provide a valid reason to amend the list of Authors. All listed Authors must verify and approve the proposed changes in order for them to be made.
\n\nAFFILIATION
\n\nAuthors are responsible for ensuring all addresses and emails provided are correct. The affiliation(s) of all authors should be the affiliation(s) where the research was conducted. No changes to the affiliation(s) can be made after the chapter is published.
\n\nPolicy last updated: 2017-05-29
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[],filtersByRegion:[],offset:0,limit:12,total:null},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"7543",title:"Physical Therapy Effectiveness",subtitle:null,isOpenForSubmission:!0,hash:"93377540da309c7e9bf2a7dc286b6c77",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7543.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7713",title:"Generation Model (GM) of Particle Physics",subtitle:null,isOpenForSubmission:!0,hash:"4e2b2661c169cbb14574be95f1d01e38",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7713.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7730",title:"Atomic Energy Science And Technology",subtitle:null,isOpenForSubmission:!0,hash:"40a7b7327b1f8c3e5392ea8641a70797",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7730.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7793",title:"Ambient Intelligence",subtitle:null,isOpenForSubmission:!0,hash:"097d9965fafdf203ddab26168df32387",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7793.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7816",title:"Crowdfunding",subtitle:null,isOpenForSubmission:!0,hash:"fd90ad45b7f8647a5ba518d18cc97b3e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7816.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7817",title:"Music Therapy",subtitle:null,isOpenForSubmission:!0,hash:"95ca321c0dbae6b9883fe7c84f4ac727",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7817.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7844",title:"Management of Dysphagia",subtitle:null,isOpenForSubmission:!0,hash:"b780818606f915bd0c5adc01c5ba6ae3",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7844.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7845",title:"Platelet Aggregation Inhibitors",subtitle:null,isOpenForSubmission:!0,hash:"dd19b595b164bfa1a5d25bab59506203",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7845.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!0,hash:"bd3c45092cf87145bda8c4585c0d6799",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7851",title:"Hypoactive Sexual Desire Disorder",subtitle:null,isOpenForSubmission:!0,hash:"665f7c67bc3facc09f09e0b70afea5ca",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7851.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7852",title:"Pathologic Angiogenesis",subtitle:null,isOpenForSubmission:!0,hash:"2e2e79aa033b6f1c096eb1fb9be03d1c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7852.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7599",title:"Radio Detection of Cosmic Neutrinos",subtitle:null,isOpenForSubmission:!0,hash:"9ff942a0b2410b41b054027a538b0c3c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7599.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:27},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:31},{group:"topic",caption:"Business, Management and Economics",value:7,count:7},{group:"topic",caption:"Chemistry",value:8,count:31},{group:"topic",caption:"Computer and Information Science",value:9,count:20},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:9},{group:"topic",caption:"Engineering",value:11,count:90},{group:"topic",caption:"Environmental Sciences",value:12,count:12},{group:"topic",caption:"Immunology and Microbiology",value:13,count:10},{group:"topic",caption:"Materials Science",value:14,count:20},{group:"topic",caption:"Mathematics",value:15,count:6},{group:"topic",caption:"Medicine",value:16,count:104},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:7},{group:"topic",caption:"Neuroscience",value:18,count:4},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:2},{group:"topic",caption:"Physics",value:20,count:17},{group:"topic",caption:"Psychology",value:21,count:1},{group:"topic",caption:"Robotics",value:22,count:3},{group:"topic",caption:"Social Sciences",value:23,count:15},{group:"topic",caption:"Technology",value:24,count:8},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:1108},popularBooks:{featuredBooks:[],offset:0,limit:12,total:null},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"7452",title:"Microbiology of Urinary Tract Infections",subtitle:"Microbial Agents and Predisposing Factors",isOpenForSubmission:!1,hash:"e99363f3cb1fe89c406f4934a23033d0",slug:"microbiology-of-urinary-tract-infections-microbial-agents-and-predisposing-factors",bookSignature:"Payam Behzadi",coverURL:"https://cdn.intechopen.com/books/images_new/7452.jpg",editors:[{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7437",title:"Nanomedicines",subtitle:null,isOpenForSubmission:!1,hash:"0e1f5f6258f074c533976c4f4d248568",slug:"nanomedicines",bookSignature:"Muhammad Akhyar Farrukh",coverURL:"https://cdn.intechopen.com/books/images_new/7437.jpg",editors:[{id:"63182",title:"Dr.",name:"Muhammad Akhyar",middleName:null,surname:"Farrukh",slug:"muhammad-akhyar-farrukh",fullName:"Muhammad Akhyar Farrukh"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7519",title:"Sol-Gel Method",subtitle:"Design and Synthesis of New Materials with Interesting Physical, Chemical and Biological Properties",isOpenForSubmission:!1,hash:"cf094d22ebcb3083749e5f96e47f7769",slug:"sol-gel-method-design-and-synthesis-of-new-materials-with-interesting-physical-chemical-and-biological-properties",bookSignature:"Guadalupe Valverde Aguilar",coverURL:"https://cdn.intechopen.com/books/images_new/7519.jpg",editors:[{id:"186652",title:"Dr.",name:"Guadalupe",middleName:null,surname:"Valverde Aguilar",slug:"guadalupe-valverde-aguilar",fullName:"Guadalupe Valverde Aguilar"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3568",title:"Recent Advances in Plant in vitro Culture",subtitle:null,isOpenForSubmission:!1,hash:"830bbb601742c85a3fb0eeafe1454c43",slug:"recent-advances-in-plant-in-vitro-culture",bookSignature:"Annarita Leva and Laura M. R. Rinaldi",coverURL:"https://cdn.intechopen.com/books/images_new/3568.jpg",editors:[{id:"142145",title:"Dr.",name:"Annarita",middleName:null,surname:"Leva",slug:"annarita-leva",fullName:"Annarita Leva"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"1770",title:"Gel Electrophoresis",subtitle:"Principles and Basics",isOpenForSubmission:!1,hash:"279701f6c802cf02deef45103e0611ff",slug:"gel-electrophoresis-principles-and-basics",bookSignature:"Sameh Magdeldin",coverURL:"https://cdn.intechopen.com/books/images_new/1770.jpg",editors:[{id:"123648",title:"Dr.",name:"Sameh",middleName:null,surname:"Magdeldin",slug:"sameh-magdeldin",fullName:"Sameh Magdeldin"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"6679",title:"Serotonin",subtitle:null,isOpenForSubmission:!1,hash:"9c833c86546ec9d3c38fb24a1072dbd0",slug:"serotonin",bookSignature:"Ying Qu",coverURL:"https://cdn.intechopen.com/books/images_new/6679.jpg",editors:[{id:"94028",title:"Dr.",name:"Ying",middleName:null,surname:"Qu",slug:"ying-qu",fullName:"Ying Qu"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"6856",title:"Gold Nanoparticles",subtitle:"Reaching New Heights",isOpenForSubmission:!1,hash:"23e172496e46e18712a901308d074cfb",slug:"gold-nanoparticles-reaching-new-heights",bookSignature:"Mohammed Rahman and Abdullah Mohammed Asiri",coverURL:"https://cdn.intechopen.com/books/images_new/6856.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed",middleName:"Muzibur",surname:"Rahman",slug:"mohammed-rahman",fullName:"Mohammed Rahman"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"632",title:"Wide Spectra of Quality Control",subtitle:null,isOpenForSubmission:!1,hash:"9f7ce64f86daee44a8c5604e8924de1c",slug:"wide-spectra-of-quality-control",bookSignature:"Isin Akyar",coverURL:"https://cdn.intechopen.com/books/images_new/632.jpg",editors:[{id:"36323",title:"Dr.",name:"Isin",middleName:null,surname:"Akyar",slug:"isin-akyar",fullName:"Isin Akyar"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3037",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 3",isOpenForSubmission:!1,hash:"1de63ac4f2c398a1304a7c08ee883655",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-3",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/3037.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"6151",title:"Noninvasive Ventilation in Medicine",subtitle:"Recent Updates",isOpenForSubmission:!1,hash:"77e2fc8d909ac2458e0087490ea02a6d",slug:"noninvasive-ventilation-in-medicine-recent-updates",bookSignature:"Mayank Vats",coverURL:"https://cdn.intechopen.com/books/images_new/6151.jpg",editedByType:"Edited by",editors:[{id:"148941",title:"Dr.",name:"Mayank",middleName:"Gyan",surname:"Vats",slug:"mayank-vats",fullName:"Mayank Vats"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7437",title:"Nanomedicines",subtitle:null,isOpenForSubmission:!1,hash:"0e1f5f6258f074c533976c4f4d248568",slug:"nanomedicines",bookSignature:"Muhammad Akhyar Farrukh",coverURL:"https://cdn.intechopen.com/books/images_new/7437.jpg",editedByType:"Edited by",editors:[{id:"63182",title:"Dr.",name:"Muhammad Akhyar",middleName:null,surname:"Farrukh",slug:"muhammad-akhyar-farrukh",fullName:"Muhammad Akhyar Farrukh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6679",title:"Serotonin",subtitle:null,isOpenForSubmission:!1,hash:"9c833c86546ec9d3c38fb24a1072dbd0",slug:"serotonin",bookSignature:"Ying Qu",coverURL:"https://cdn.intechopen.com/books/images_new/6679.jpg",editedByType:"Edited by",editors:[{id:"94028",title:"Dr.",name:"Ying",middleName:null,surname:"Qu",slug:"ying-qu",fullName:"Ying Qu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7452",title:"Microbiology of Urinary Tract Infections",subtitle:"Microbial Agents and Predisposing Factors",isOpenForSubmission:!1,hash:"e99363f3cb1fe89c406f4934a23033d0",slug:"microbiology-of-urinary-tract-infections-microbial-agents-and-predisposing-factors",bookSignature:"Payam Behzadi",coverURL:"https://cdn.intechopen.com/books/images_new/7452.jpg",editedByType:"Edited by",editors:[{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7215",title:"Recent Developments in Photovoltaic Materials and Devices",subtitle:null,isOpenForSubmission:!1,hash:"2f824828c2212e79b75fa65b194c5007",slug:"recent-developments-in-photovoltaic-materials-and-devices",bookSignature:"Natarajan Prabaharan, Marc A. Rosen and Pietro Elia Campana",coverURL:"https://cdn.intechopen.com/books/images_new/7215.jpg",editedByType:"Edited by",editors:[{id:"199317",title:"Dr.",name:"Natarajan",middleName:null,surname:"Prabaharan",slug:"natarajan-prabaharan",fullName:"Natarajan Prabaharan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7485",title:"Applied Modern Control",subtitle:null,isOpenForSubmission:!1,hash:"c7a7be73f7232e08867ed81bdf9850c6",slug:"applied-modern-control",bookSignature:"Le Anh Tuan",coverURL:"https://cdn.intechopen.com/books/images_new/7485.jpg",editedByType:"Edited by",editors:[{id:"180550",title:"Dr.",name:"Le",middleName:null,surname:"Anh Tuan",slug:"le-anh-tuan",fullName:"Le Anh Tuan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7488",title:"Analytical Pyrolysis",subtitle:null,isOpenForSubmission:!1,hash:"30a667792c3a70b53d30fb6e9e1e7b4d",slug:"analytical-pyrolysis",bookSignature:"Peter Kusch",coverURL:"https://cdn.intechopen.com/books/images_new/7488.jpg",editedByType:"Edited by",editors:[{id:"254714",title:"Dr.",name:"Peter",middleName:null,surname:"Kusch",slug:"peter-kusch",fullName:"Peter Kusch"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7242",title:"Engineered Fabrics",subtitle:null,isOpenForSubmission:!1,hash:"757cc326df7bcca72c8c850d9f4f71d1",slug:"engineered-fabrics",bookSignature:"Mukesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/7242.jpg",editedByType:"Edited by",editors:[{id:"36895",title:"Dr.",name:"Mukesh Kumar",middleName:null,surname:"Singh",slug:"mukesh-kumar-singh",fullName:"Mukesh Kumar Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7245",title:"Challenging Issues on Paranasal Sinuses",subtitle:null,isOpenForSubmission:!1,hash:"67a331ebb2dd2b8f73228fa4daa7382f",slug:"challenging-issues-on-paranasal-sinuses",bookSignature:"Tang-Chuan Wang",coverURL:"https://cdn.intechopen.com/books/images_new/7245.jpg",editedByType:"Edited by",editors:[{id:"201262",title:"Dr.",name:"Tang-Chuan",middleName:null,surname:"Wang",slug:"tang-chuan-wang",fullName:"Tang-Chuan Wang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7519",title:"Sol-Gel Method",subtitle:"Design and Synthesis of New Materials with Interesting Physical, Chemical and Biological Properties",isOpenForSubmission:!1,hash:"cf094d22ebcb3083749e5f96e47f7769",slug:"sol-gel-method-design-and-synthesis-of-new-materials-with-interesting-physical-chemical-and-biological-properties",bookSignature:"Guadalupe Valverde Aguilar",coverURL:"https://cdn.intechopen.com/books/images_new/7519.jpg",editedByType:"Edited by",editors:[{id:"186652",title:"Dr.",name:"Guadalupe",middleName:null,surname:"Valverde Aguilar",slug:"guadalupe-valverde-aguilar",fullName:"Guadalupe Valverde Aguilar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"248",title:"Autonomous Research Robotics",slug:"autonomous-research-robotics",parent:{title:"Robotics",slug:"physical-sciences-engineering-and-technology-robotics"},numberOfBooks:1,numberOfAuthorsAndEditors:2,numberOfWosCitations:25,numberOfCrossrefCitations:35,numberOfDimensionsCitations:58},booksByTopicFilter:{topicSlug:"autonomous-research-robotics",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"3792",title:"Robotics 2010",subtitle:"Current and Future Challenges",isOpenForSubmission:!1,hash:"b266dc4d99301e4ddf0dd05915a81bda",slug:"robotics-2010-current-and-future-challenges",bookSignature:"Houssem Abdellatif",coverURL:"https://cdn.intechopen.com/books/images_new/3792.jpg",editedByType:"Edited by",editors:[{id:"2524",title:"Dr.",name:"Houssem",middleName:null,surname:"Abdellatif",slug:"houssem-abdellatif",fullName:"Houssem Abdellatif"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"9370",doi:"10.5772/7327",title:"Screw and Cable Acutators (SCS) and Their Applications to Force Feedback Teleoperation, Exoskeleton and Anthropomorphic Robotics",slug:"screw-and-cable-acutators-scs-and-their-applications-to-force-feedback",totalDownloads:2432,totalCrossrefCites:6,totalDimensionsCites:13,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Phillipe Garrec",authors:null},{id:"9376",doi:"10.5772/7323",title:"Development of Mobile Robots Based on Peristaltic Crawling of an Earthworm",slug:"development-of-mobile-robots-based-on-peristaltic-crawling-of-an-earthworm",totalDownloads:1836,totalCrossrefCites:7,totalDimensionsCites:11,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Hayato Omori, Taro Nakamura, Tomohide Iwanaga and Takeshi Hayakawa",authors:null},{id:"9372",doi:"10.5772/7329",title:"Human Machine Interface in Assistive Robotics: Application to a Force Controlled Upper-Limb Powered Exoskeleton",slug:"human-machine-interface-in-assistive-robotics-application-to-a-force-controlled-upper-limb-powered-e",totalDownloads:2537,totalCrossrefCites:5,totalDimensionsCites:7,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Malek Baklouti, Jamil AbouSaleh, Eric Monacelli and Serge Couvet",authors:null}],mostDownloadedChaptersLast30Days:[{id:"9362",title:"Operational Space Dynamics of a Space Robot and Computational Efficient Algorithm",slug:"operational-space-dynamics-of-a-space-robot-and-computational-efficient-algorithm",totalDownloads:1910,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Satoko Abiko and Gerd Hirzinger",authors:null},{id:"9383",title:"The Memory Game: Creating Reactive, Interruptible, Turn-Taking, Human-Eobot Interaction for ASIMO",slug:"the-memory-game-creating-reactive-interruptible-turn-taking-human-robot-interaction-for-asimo",totalDownloads:1403,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Victor Ng-Thow-Hing , Jongwoo Lim, Joel Wormer, Ravi Kiran Sarvadevabhatla, Carlos Rocha, Kikuo Fujimura and Yoshiaki Sakagami",authors:null},{id:"9379",title:"Towards Multimodal Interface for Interactive Robots: Challenges and Robotic Systems Description",slug:"towards-multimodal-interface-for-interactive-robots-challenges-and-robotic-systems-description",totalDownloads:1481,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Burger Brice, Ferrane Isabelle and Lerasle Frederic",authors:null},{id:"9378",title:"A Model-Based Synthetic Approach to the Dynamics, Guidance, and Control of AUVs",slug:"a-model-based-synthetic-approach-to-the-dynamics-guidance-and-control-of-auvs",totalDownloads:1200,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Kangsoo Kim and Tamaki Ura",authors:null},{id:"9367",title:"Shape Classification using Tactile Information in Rotation Manipulation by Universal Robot Hand",slug:"shape-classification-using-tactile-information-in-rotation-manipulation-by-universal-robot-hand",totalDownloads:1388,totalCrossrefCites:5,totalDimensionsCites:6,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Hiroyuki Nakamoto, Futoshi Kobayashi and Fumio Kojima",authors:null},{id:"9370",title:"Screw and Cable Acutators (SCS) and Their Applications to Force Feedback Teleoperation, Exoskeleton and Anthropomorphic Robotics",slug:"screw-and-cable-acutators-scs-and-their-applications-to-force-feedback",totalDownloads:2432,totalCrossrefCites:6,totalDimensionsCites:13,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Phillipe Garrec",authors:null},{id:"9375",title:"Design, Development, Dynamic Analysis, and Control of a Pipe Crawling Robot",slug:"design-development-dynamic-analysis-and-control-of-a-pipe-crawling-robot",totalDownloads:3555,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Amir H. Heidari, Mehran Mehrandezh, Homayoun Najjaran and Raman Paranjape",authors:null},{id:"9363",title:"Modeling and Control of Mechanical Systems in Terms of Quasi-Velocities",slug:"modeling-and-control-of-mechanical-systems-in-terms-of-quasi-velocities",totalDownloads:2107,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Farhad Aghili",authors:null},{id:"9376",title:"Development of Mobile Robots Based on Peristaltic Crawling of an Earthworm",slug:"development-of-mobile-robots-based-on-peristaltic-crawling-of-an-earthworm",totalDownloads:1836,totalCrossrefCites:7,totalDimensionsCites:11,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Hayato Omori, Taro Nakamura, Tomohide Iwanaga and Takeshi Hayakawa",authors:null},{id:"9372",title:"Human Machine Interface in Assistive Robotics: Application to a Force Controlled Upper-Limb Powered Exoskeleton",slug:"human-machine-interface-in-assistive-robotics-application-to-a-force-controlled-upper-limb-powered-e",totalDownloads:2537,totalCrossrefCites:5,totalDimensionsCites:7,book:{slug:"robotics-2010-current-and-future-challenges",title:"Robotics 2010",fullTitle:"Robotics 2010 Current and Future Challenges"},signatures:"Malek Baklouti, Jamil AbouSaleh, Eric Monacelli and Serge Couvet",authors:null}],onlineFirstChaptersFilter:{topicSlug:"autonomous-research-robotics",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},privacyPolicy:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},humansInSpaceProgram:{},route:{name:"book.detail",path:"/books/contemporary-pediatrics",hash:"",query:{},params:{book:"contemporary-pediatrics"},fullPath:"/books/contemporary-pediatrics",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()