CABC rule in prehospital care of the patient.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Trauma has become a leading cause of death among young adults in industrialized nations. In the United States in 2010, trauma was the cause of death in 63% of patients aged 1–24 years and 42% of the patients in the ages 25–44. Furthermore, trauma results with lowered patient’s productivity with high economic impact. A vascular trauma incidence is estimated between 1.6 and 2% in adults during peace and between 6 and 12% during war. Most of the civilian casualties are injured by penetrating objects like firearm bullets, blades, or machine parts. In Europe, where access to firearms is limited, most of the penetrating vascular injuries result from criminal acts (e.g., knife stabbing), traffic, and labor accidents [1, 2].
\nFast initial diagnosis, patient’s vital signs stabilization together with effective bleeding control, and quick transport to the hospital are crucial factors influencing future prognosis.
\nAfter the evaluation of the overall security condition on trauma site (traffic accident, disaster site, explosion area), it is important to predetermine a possible trauma mechanism in order to predict possible vascular injury as well as collateral damage of the adjacent tissues [2].
\nThe next step is the patient examination. After the initial evaluation of vital signs and recording the state of a victim’s consciousness (GCS), a CABC rule should be applied (Table 1).
\nC | \nControl bleeding—the bleeding controls a visible and life-threatening hemorrhage | \n
A | \nAirways—secure the airways and evaluate possible obturation causes | \n
B | \nBreathe—ventilation rate, volume, and effectiveness | \n
C | \nCirculation—central and peripheral circulation assessment, blood pressure, capillary flow, and skin perfusion | \n
CABC rule in prehospital care of the patient.
After CABC, a trauma extent assessment as well as medical examination are performed (SAMPLE) (Table 2). The medical examination should cover all body areas in direction from head to toe including the patient’s back and extremities. The aim of that procedure is to find any eventual collateral damage which can be life-threatening. The additional information from other victims or witnesses should be gathered, if possible [3].
\nS | \nSymptoms (bleeding, ischemia, shock, fractures, wounds, etc.) | \n
A | \nAllergies (drugs, food, chemicals (e.g., disinfectants), materials (plaster dressing, etc.)) | \n
M | \nMedicines—recently used or prescribed medicines | \n
P | \nPast—medical history and pregnancies | \n
L | \nLunch—last meal, time, and volume | \n
E | \nEvent—what has happened | \n
SAMPLE rule in the examination of the victim of an accident.
After the finishing of medical examination, the patient should be qualified to one of the following groups:
LOAD & GO—victim in extremely severe condition. Only a basic set of medical procedures is performed necessary to support life. The transport has a priority [4].
STAY & PLAY—all necessary procedures may be performed on-site. The transport follows the initial care.
During the transportation, especially with unstable patient in severe condition, the information to the admitting center (ATMIST scheme) should be sent (Table 3) [5].
\nA | \nAge | \n
T | \nTime of the event | \n
M | \nMechanism | \n
I | \nInjuries | \n
S | \nSymptoms | \n
T | \nTreatment (already performed) | \n
ATMIST algorithm.
The portable ultrasound devices are helpful in fast initial diagnosis of the injuries of large vessels of the chest or abdomen with the use of eFAST protocol (chest, pericardium, and abdomen) [6].
\nBelow we propose a procedure of prehospital care in vascular trauma:
Initial examination, CABC, SAMPLE
Control of the visible external bleeding
Evaluation of possible internal bleeding(s)
Intravenous access (intramedullar), fluid supply, hypovolemic shock treatment
Bleeding control specific to the vascular injury area
Medical transport and ATMIST
Direct wound compression.
Limb elevation.
Compression dressing.
Tourniquet: usually applied on arm or thigh, less often in distal areas (forearm, below the knee) usually 8 cm above the suspected vascular lesion. An effective modification of that technique is to apply two tourniquets, one high on the limb and the second 8 cm above the wound. Then the first one is released, while the second stays closed [3, 7].
Packing of the bottom of the wound with sterile gauze with continuous compression.
Hemostatic dressings and substances: in the form of dressing, powder or foam—usually a 3–5 min time is needed to initiate coagulation between a dressing and injury site [3, 8].
Direct compression.
Compression dressing.
Specific compression systems.
Direct compression.
Compression with contralateral hand.
Hemostatic media.
Direct compression.
Haemostatic suture of the skin vessels.
Direct compression.
Occlusive dressing.
Emergency thoracotomy.
Occlusive dressing.
Hemostatic foams
Pelvic belt.
Hemostatic foams.
Patients in hypovolemic shock with controlled external bleeding should be administered with 500–1000 ml of crystalloids, with a constant blood pressure control. Blood pressure may be maintained near to normal values. In patients where there is no possibility to control the external or internal bleeding, crystalloids volume should allow to maintain the systolic blood pressure on the perfusion level (80–90 mmHg) to prevent anaerobic metabolism in supplied tissue. Exceptionally in patients with the traumatic lesion of the central nervous system, the systolic blood pressure should be maintained on higher levels of 100–110 mmHg, which secures cerebral perfusion pressure on the level of 60 mmHg [13].
\nIsolated vascular injury of the extremities is the most common vascular injury type during the peace in high-volume trauma center in Europe. The incidence rises in highly urbanized area due to traffic and labor accidents and varies between 1 and 2% of total number of traumatic patients admitted to the ER [14]. In our center, the incidence of the vascular trauma among all traumatic patients was 3% in a 5-year period (2014–2018). In the upper limbs, the regions of elevated risk are the armpit, the medial part of the arm, and the ulnar fossa due to a superficial position of the vascular structures. In the lower limb, attention should be focused on injuries of the groin, the medial thigh area, and the popliteal fossa. The ligation of the artery in vascular injury below the brachial bifurcation or knee trifurcation usually has no risk of the peripheral limb ischemia.
\nThe vascular damage may be caused by penetrating object (like knife blade, a part of a machinery, steel rod, etc.) or may have been an effect of the blunt trauma with the force acting directly on the vessel wall or by the surrounding tissues like bone fragments or luxated joints. Penetrating injuries, mostly with low energy character, constitute 70–90% of cases [15]. Blunt vascular trauma may be the effect of the vessel contusion and secondary thrombosis, which is often a result of the knee joint or upper arm luxation and dislocation of the humerus/tibia causing the blunt trauma.
\nAccording to an extent of the wound, in penetrating vascular injury, various clinical manifestations may occur, from puncture wound with minimal bleeding and minute signs of the peripheral ischemia to a large laceration of the skin with life-threatening hemorrhage.
\nThe on-site evaluation and diagnosis was described earlier in this chapter; in hospital, the physician after gathering information from the medical emergency service team should also try to obtain information from the patient especially about the traumatic mechanism and possible time of eventual ischemia. The mechanism of injury has a prognostic value. High-energy injuries (penetrating or blunt) have elevated risk of vascular damage, and the risk of amputation is higher in high-energy blunt trauma. Collateral damage of surrounding tissues and adjacent structures may require separate intervention (e.g., orthopedic surgery), or in the case of extensive polytrauma, complex interdisciplinary approach with advanced life support techniques.
\nIt is generally agreed that after 6 hours of the limb ischemia, irreversible changes occur in the nervous and musculatory systems, though it is important to precisely evaluate the onset time. The time may be counted from the injury time or if the ischemic process is iatrogenic (e.g., tourniquet, pressure dressing) from the time in which the blood flow was stopped.
\nConcomitant diseases and patient’s medical history are also important (arteriosclerosis, cardiac diseases, diabetes), as well as medications are prescribed, especially ASA and VKA.
\nThe decision of immediate surgery, especially when active bleeding is concerned, is crucial at the first minutes of examination, due to a high mortality rate in the case of misdiagnosis. A vast majority of victims presenting “hard signs” of vascular trauma require an immediate operation with sensitivity above 90%; on the other hand, if no “hard sign” is present (Table 4) (Figures 1 and 2), the vascular trauma probability is very low [16].
\nHard signs | \nSoft signs | \n
---|---|
Active pulsatile bleeding | \nPulse deficit | \n
Rapidly expanding hematoma | \nNeurological deficit | \n
Pulselessness | \nPaleness of the extremity | \n
Acute ischemia | \nNonexpanding hematoma | \n
Vascular thrill | \n— | \n
Bruit | \n— | \n
Hard and soft signs of vascular trauma.
A typical “hard sign” of the blunt vascular injury of the groin.
The algorithm of the management of the peripheral vascular injury patient.
“Soft signs” are not so specific in the prediction of the vascular injuries, and immediate open repair usually is not necessary. A single soft sign increases a chance of vascular injury in 10%, and two or more soft signs can have a vascular injury rate of 25% [17, 18] (Figure 1).
\nThe pulse and extremity blood supply should be evaluated in the first place. A physical examination and the pulse palpation of
The bleeding should be stopped as soon as possible by the use of compression dressing and tourniquet or if the situation allows temporary shunting of the damaged artery or vein. The vessel clamping or ligation can be done only in the last resort, when the patient’s life is directly at risk. If the damaged vessel is clearly visible and ischaemic symptoms occur, the patient should be referred to vascular surgery in order to perform emergency revascularization. After the bleeding control, the focus should be directed on the chances of the limb salvage. The MESS score is the most popular tool in assessment of the extremity salvage chance [cite mess]. Afterwards, if ischaemic signs are present, the limb condition should be rated according to TASC II categorization. Quite often there is no sign of active bleeding, especially in young patients where even a total intersection of femoral or brachial artery does not end with massive hemorrhage due to a vessel end contraction and thrombosis [18, 19, 20].
\nAnkle-brachial index (ABI) or arterial pressure index (API) is a useful adjunct to physical examination. ABI value <0.9 has 87% sensitivity and 97% specificity in the assessment of vascular trauma, reaching 95% of sensitivity when focused on big arterial trunks. ABI value below 0.9 is an direct indication for further imaging as US, CT angiography, or MRI. On the other hand, ABI value >0.9 with no signs of the orthopedic injury allows to release the patient from ER, with the further referral to outpatient clinic in the next few days for reassessment of eventual delayed presentation of vascular injury [21].
\nIn the first option of treatment, especially in patients presenting with TASC II and III category, the treatment of choice is an open repair. Both stumps of the damaged vessels should be identified and clamped.
\nAfter the thrombectomy and vessel stump preparation, an anastomosis is performed. The best option is end-to-end anastomosis without any conduit; however that option is only possible in directly cut vessels where the surgeon is able to mobilize vessel stumps from the surrounding tissue very often soaked with the blood and tissue liquids. If there is any tension between arterial or venous stumps, the better option is to make a conduit, preferably from autologous vein. Reversed great saphenous vein (GSV) graft is the most popular choice; however, there are other possibilities like small saphenous vein and basilic or radio-cephalic vein. However, SSV and other peripheral veins are more difficult to harvest and may have insufficient diameter.
\nIf the vein is not available, the surgeon faces a decision whether to use a homologous material (if available) like frozen bovine graft or frozen homograft or to use synthetic prosthesis. If the synthetic prosthesis has to be used as a conduit, the most infection-resistant option available on shelf should be utilized (Table 5).
\nSurgical material | \n
---|
Autologous vein GSV, SSV, RCV, BV | \n
Frozen bovine graft | \n
Homograft | \n
Silver-coated prosthesis (Braun, Intergard) | \n
PTFE | \n
Rifampin-soaked Dacron | \n
Material for grafting in vascular injury.
The endovascular modality is limited only to cases with preserved continuity of the vessel, which can be visualized only in CT angiography, and we recommend that option to patients with TASC I category (viable limb). Usually endovascular approach is effective in arterial puncture with pseudoaneurysm formation or arterial thrombosis in cases of isolated blunt trauma mostly in popliteal and axial region or in cases of arm luxation (Figures 3, 4, 5).
\nBlunt trauma of the popliteal fossa resolved by the endovascular approach. (a) thrombosis of the popliteal artery, (b) restored flow in the vessel.
The pseudoaneurysm sac successfully closed by biothrombin injection (arrow) [
The pseudoaneurysm of the right axillary artery successfully resolved by trans-catheter thrombin injection. (a) a CT scan of the lesion, (b) arteriography image of the lesion before the injection, (c) a balloon catheter occluding the aneurysm “jet”, (d) angiographic image of the axillary artery after the treatment [
The traumatic damage of the thoracic aorta is usually an effect of traffic accidents or sudden fall resulting from acceleration-deceleration mechanisms. Less often it is a result of the penetrating injury like knife stabbing or gunshot. In that case the damage of the aortic wall is usually complete with massive hemorrhage into mediastinum or pleural cavity, which is in most cases fatal. In blunt trauma, the most common site of injury is the descending aorta left from subclavian artery ostium and below the aortic ligament. In most cases, the intimal tear occurs resulting in acute dissection progressing downwards to the visceral arteries and to the aortic bifurcation. Sometimes we can observe almost complete aortic wall tear, pseudoaneurysm formation in the chest and progressing dissection.
\nThe computed angiotomography is a routine examination which allows to diagnose the thoracic aorta injury with high accuracy and has become a standard procedure in chest injuries. If there is no possibility of CT scanning, a transesophageal ultrasound can be used however in a very limited fashion.
\nFrom the beginning of the century, a thoracic endovascular stent-graft implantation (TEVAR) has become a routine procedure in salvaging patients with aortic injury, decreasing a perioperative mortality from 70% to 15–30%. If open surgical procedure has to be performed, a chance of survival drops dramatically to 15–20%. The open repair usually requires high aortic clamping, and the risk of the neurological deficit resulting from spinal cord ischemia is significantly higher than during the TEVAR. In TEVAR, however, the risk of spinal cord ischemia is also significant (23%), especially in cases when the graft fabric covers the ostium of the left subclavian artery (LSA) and suppresses the collateral circulation from internal mammary artery (LIMA) to the intercostals. If the patient is in stable condition, a surgeon can bypass the left subclavian ostium, by performing a carotid-subclavian conduit preserving the flow in LSA and LIMA. Another popular neuroprotective option is the drainage of the cerebrospinal fluid to reduce the pressure from eventual spine edema. In many centers that procedure is performed routinely during TEVAR or open repair when LSA closure is necessary [4, 23, 24].
\nThe rupture of the large veins in the chest is usually fatal, and patients do no reach the hospital. However, if the patient’s condition allows for medial thoracotomy with sternotomy to expose superior vena cava, there is a chance to control the bleeding and after the patient stabilization to reconstruct the damaged vessel. There are some reports of successful endovascular treatment of vena cava injury [25, 26, 27]; however all concern iatrogenic injuries.
\nAbdominal aorta injuries result more often from penetrating mechanism than from blunt trauma. The location of the vessel makes it relatively resistant for blunt injury. If blunt aortic injury occurs, it is usually a part of extensive polytrauma with spine fracture and multiple adjacent organ damage. An exception may be an abdominal aortic rupture during blunt trauma of the abdomen without any collateral damage, which can occur during a car accident or a fall. More frequent are penetrating injures being a result of a criminal act or labor accident. The patient usually presents symptoms of hypovolemic shock, and the first steps should be done to stabilize the vital signs and blood pressure and secure the adequate volume of blood and plasma. The CT scan is a standard procedure confirming an initial diagnosis with visible hematoma in retroperitoneal space. The REBOA procedure (Figure 6) is useful during patient stabilization and preparation to surgery or endovascular repair. In open repair a medial abdominal access is used to expose the aorta for clamping and vascular reconstruction usually by the use of polyester or PTFE graft [28]. Less often a simple suture of patch from polyester or autologous vein is used. If there is additional collateral damage like intestine tear, hepatic or renal injury or pelvic fracture, it can be done simultaneously. In cases of isolated aortic damage, usually resulting from penetrating mechanism, an endovascular stent-graft implantation (EVAR) is an effective option.
\nREBOA technique in salvaging the patient with an aortic rupture.
Blunt iliac artery injuries usually result in pelvic polytrauma with multiple fractures of the pelvis and possible damage of the bladder, uterus, intestines and ureter. In most cases an interdisciplinary approach of specialized trauma team is necessary, and a vascular surgeon’s job is to restore the blood flow stopped by thrombosis of the iliac artery or to stop the bleeding and to perform the vascular reconstruction. In cases of hypogastric artery injury, the vessel ligation is the most common solution. In common iliac artery or external iliac artery injury, a reconstruction with the use of artificial bypass is the first choice. The venous grafting has a limited application due to not sufficient diameters of available veins. In cases in which an infection risk is elevated, silver knitted grafts are the most popular option. The isolated blunt external iliac artery above the inguinal ligament resulting in its thrombosis and chronic limb ischemia in young patients resulting from a bike accident were reported [29].
\nPenetrating external iliac artery injuries especially in the region of inguinal ligament, known as death triangle injury, are challenging cases where fast decision of surgery is life-saving. The bleeding control in that region is difficult and possible only by direct compression or by modified REBOA procedure when the balloon is opened in the common iliac artery. The open repair is a gold standard because most of the injuries result from a knife stabbing or gunshot, and endovascular endografting has a limited application.
\nA penetrating injury of the inferior vena cava usually produces a large retroperitoneal hematoma having a tendency to self-cease with the drop of the blood pressure and compression produced by the hematoma. That condition is however unstable, and the patient may die suddenly among the symptoms of irreversible hypovolemic shock. Urgent surgical exploration is necessary to seal the rupture in the vein wall. As much as possible the VCI should be exposed to find the rupture, and after the compression of the inflow and outflow site, suture it or reconstruct by the use of artificial graft (usually PTFE). Recently, there have been reports of successful treatment of the VCI ruptures by the use of covered stents or stent grafts however in majority concerning iatrogenic damage [14, 30, 31, 32, 33].
\nThe blunt injury of IVC is a very rare condition, with a prevalence of 1% of all blunt abdominal traumas resulting in dissection, pseudoaneurysm formation, or IVC thrombosis. In the literature there are single reports in the management of IVS blunt injuries usually catheter-directed techniques [16, 34, 35].
\nThe penetrating injuries of the carotid arteries and jugular veins are mostly resulting in a stabbing effect or an effect of the gunshot. The bleeding control in the case of open wound of the neck is a crucial element of the further success. In the case of the venous injury, a direct compression on the ruptured vessel is usually sufficient to transport the patient to the operation room and to perform exploration and vessel reconstruction. The problem occurs in the case of arterial damage with high-volume blood outflow. Too much compression may lead to severe neurological deficits so pressure should be administered only to stop the bleeding. Additional wound packing may also be helpful. In our opinion every penetrating vascular injury of the neck should be surgically explored in order to prevent a secondary damage as uncontrolled hematoma expansion leading to neurological and respiratory deficits which is supported by the data from the literature [36, 37]. The unstable patients are qualified to immediate surgery, while the stable ones after fast-track imaging in order to localize the exact lesion location should also undergo surgical exploration (Figure 7).
\nLeft carotid artery injury with the compressing hematoma (arrow).
Blunt injury of the cervical vessels is a relatively rare condition with prevalence <0.1% and however related to increased mortality and morbidity due to a cerebral infarction. The symptoms of the cerebral ischemia may occur up to 72 h after an accident due to an embolisation from the local vessel thrombosis or dissection. The CT angiography scans should be performed in all patients suffering the injury of the neck in stable condition without signs of rapidly developing hematoma in order to exclude a sub-intimal dissection or thrombosis which can be a source of embolic material. In these patients an endovascular option is a good solution for covering a damaged area with a closed cell stent or stent-graft.
\nIn the recent years, in the development of mini-invasive and endovascular techniques, an increase of iatrogenic vascular injuries is observed. A most common complication of the vascular access in endovascular approach is hematoma and pseudoaneurysm in the access site [22, 38]. The rate of these incidents varies between 0.5 and 1.0% and recently was decreased by the use of various vascular sealing systems. A perforation or tear of the arterial wall not in the access site is the second very frequent complication of the endovascular procedure. The typical location of the perforation is iliac arteries, when during the approach to the target lesion (coronary arteries, carotid arteries, abdominal aorta) a hydrophilic guidewire perforates the vessel typically in the location of arteriosclerotic plaque [5, 39]. If the guidewire perforation is noticed quickly, usually it has no consequences besides small extravasation which may require a low-pressure balloon inflation to seal the leak. Sometimes, however, the perforation is not noticed, and some larger bore devices (balloons, stent-graft parts) may be pushed outside the arteries producing a large diameter tear in the arterial wall. If there is no possibility to seal the leak by the use of stent-graft, the only solution is to open the low-pressure balloon inside the vessel and urgent laparotomy or thoracotomy.
\nIn open repair, the iatrogenic traumatic vascular trauma has been observed mostly during orthopedic repositions, general surgery procedures, gynecology, and neurosurgery. After an introduction of the laparoscopic techniques at the beginning of the last decade of the XX century, an incidence of unintentional rupture of the large vessels in abdominal and pelvic region during the introduction of the trocars increased. That type of the injury may have very dramatic outcome, with massive and rapidly increasing hematoma especially when the abdominal part of vena cava or iliac veins are concerned. In that case only an instant conversion and pressure packing may stop the bleeding and save the patient. After a bleeding control is achieved, the vascular reconstruction may take place which is very often limited to pacing a vascular suture on the vein; less frequently the patch, bypass or ligation is needed [40, 41, 42].
\nWhen arterial vessels are damaged, a massive bleeding is not so often; in some cases, one can observe a pseudoaneurysm formation, vessel thrombosis, or retroperitoneal hematoma which also requires an urgent surgery; however, the symptoms are not so dramatic and chances are better. In that case, a vascular reconstruction usually ends with suturing the damaged artery. Sometimes, a thrombectomy is performed, with more extensive reconstructions with patches or bypasses. In the pelvic region, when hypogastric artery is damaged, very often a ligation of the vessel is one of the options.
\nInjuries of the hepatic arteries or vascular structures of hepatic ligament are less frequent and cause mostly by thermal mechanism during electrocoagulation [43].
\nVascular injury during the orthopedic surgery is not a frequent complication with an incidence of 0.05–0.1%. However due to a large number of procedures performed, it concerns patients in almost every hospital in which total hip and knee arthroplasty is performed, as well as urgent repositions of the spine and long bones of the extremities with stabilization by the use of external or internal material [44, 45]. During the hip or knee replacement, the mechanism of injury is usually indirect, resulting from torsion and elongation forces resulting in intimal tear and vessel thrombosis. In rare cases the misplaced fixation screws of the acetabulum caused active bleeding or thrombosis of external iliac artery. During the open repositions, the mechanism is usually directly caused by a stabilization material and fixation screws resulting in arterial damage. In that case, the time of diagnosis is crucial, especially when iliac, femoral, or brachial arteries are involved. In some cases like popliteal artery thrombosis after a total knee replacement, an endovascular option is possible. However, in most cases, an arterial reconstruction is the only possible solution. Repositions of the bones of forearm and below the knee have a significantly lower risk of ischaemic complication due to the anatomic reasons, but an active bleeding or pseudoaneurysms may occur. In that area, however, a ligation of the single main arterial trunk like radial or tibial artery usually has no ischaemic consequences.
\nVascular injuries are not a frequent condition; however, they are one of the most dangerous and challenging cases for medical personnel in the field of proper diagnostics and therapy. In the vast majority of cases, regardless of whether they concern civilian or warfare victims, there are penetrating injuries resulting in massive bleeding or limb-threatening ischemia. The implementation of proper treatment already at the prehospital stage is an essential factor for the patient survival and the limb salvage.
\nFast initial assessment of the patient’s condition based on the CABC algorithm, adopting an appropriate transport strategy (Load & Go or Stay & Play), application of bleeding control techniques adequate to the area of injury, and early prevention of hypovolemic shock are the key factors for prehospital treatment.
\nDue to the rapid development of minimally invasive techniques in various fields of medicine (cardiology, neurology, abdominal surgery, urology), the number of iatrogenic vascular injuries increased. Despite the low incidence of such events, iatrogenic injuries are quite common due to high volumes of minimally invasive procedures performed and require the involvement of a vascular surgeon.
\nThe vascular trauma is very often a part of polytrauma requiring the interdisciplinary trauma team of various specialists to perform a wide range of operations in one time such as vascular reconstructions together with reconstructive orthopedics or reconstruction of the urinary tract. The vascular trauma patients and especially patients with polytrauma should be transported to specialized trauma centers with the high reference level.
\nThe development of a new drug is an extensive, intricate, highly risky and expensive process. According to the study of 12,728 transitions over the last decade (2011–2020), the success rates of clinical drug development were 52.0% (Phase I), 28.9% (Phase II) and 57.8% (Phase III) separately [1]. Most of the candidates failed in the early drug development process for reasons of efficacy and safety concerns [2]. This causes a huge cost in drug development, ranging from tens of millions to billions. In addition, it typically takes at least 10 years from initial laboratory evaluation for a new drug to be approved. All these factors lead to low output disproportionately to the high input and make it challenging for the pharmaceutical industry to respond to emergent infectious diseases within a time frame that is able to impact the course of an outbreak. As a result, the development of vaccine candidates will likely remain to be the optimal mechanism to address outbreaks in the immediate future. Notwithstanding the extraordinary developments in vaccine technology—exemplified by recent events [3, 4]—there still remains a need for therapeutics as a sufficiently successful virus will rapidly become pan/endemic, creating a constant need for treatment of those unfortunate enough to not have access to a vaccine due to socioeconomic, age or immunostatus issues. Indeed, in the case of a pandemic, there is likely to be constant strain on health systems to treat patients, which will significantly enhanced in the absence of an effective therapy as it will instead rely heavily on patient support technologies such as ventilation or oxygen therapy.
A potential solution to this conundrum is the examination of already proposed (ideally approved) medications—repurposing—to assess their potential in the treatment of an emergent diseases. Drug repurposing as a strategy to identify potential new indication areas of approved/old drugs has many advantages. Firstly, low risk. Most repurposed drugs have at least been tested in early clinical trials. Hence, the failure rate of repurposing candidates caused by safety is very low. Secondly, low cost. Most old or approved drugs have clear safety, pharmacokinetics and pharmacodynamics data, which reduces the studies that need to be performed before the drugs extension to a novel indication. Thirdly, a higher success rate. The drugs used for repurposing are enriched from previous studies. This means less promising compounds are filtered out, allowing for a higher success rate [5]. Finally, while the molecular complexity of the protein targets of diseases is extremely broad, areas of essential molecular function can be identified as conserved in many diseases. For example, tyrosine kinase activity is a frequent target for the development of cancers from highly diverse tissues. A common feature of all kinases is the presence of an ATP-binding site, which has resulted in a large number of targeted cancer therapies (tyrosine kinase inhibitors, TKIs) which have a strong resemblance to ATP on the molecular level. This has further resulted in the clinical testing of TKIs for cancers distinct to those for which they were developed, as the evolutionary pressure to retain a function ATP-binding site provides a precondition for potential TKI cross-reactivity [6].
In the past decades, the successful application of drug repurposing shows a promising direction for drug development. For example, Thalidomide was firstly synthesized by Ciba in 1953 and came on to the market to relieve morning sickness in 1957. In 1961, Thalidomide was taken off the market due to the severe teratogenic effect on the developing fetus. In the following years, an Israeli researcher found that thalidomide could be used as a treatment against autoimmune diseases. In 1998 it was approved by FDA for the repurposed use in the treatment of ENL [7, 8, 9]. In this chapter, we present an overview of the benefits and drawbacks of drug repurposing in viral disease, including approaches, applications and outlook.
Drug repurposing is the process of identifying new indications and uses for approved/existing drugs [10]. It mostly involves approved drugs or compounds under study, which have clear pharmacokinetics and pharmacodynamics that provide data on metabolic stability, tissue distribution and clearance rates. In the past decades, a large quantity of new molecular entity drugs was approved or studied, meaning that not only the ~2000 FDA approved compounds can be screened [11, 12], but also a much larger potential library of compounds that have been developed to have appropriate physico-chemical properties for their use as drugs, but that may have failed clinical trials due to lack of action in their original disease class. This, perhaps, is the key benefit of repurposing—as all potential repurposing candidates possess “drug-like” properties. However, these properties should be borne in mind by the researcher as they strongly impact the potential of repurposed compounds in clinical use.
The classic description of “drug-like” properties has grown significantly since the original introduction of the “Rule of 5” by Lipinski (Ro5) [13]. This initial classification arose from the observation that successful drugs shared common properties: low molecular weight (Mw), a relative scarcity of potential electrostatic interactions (H-bond donors and acceptors) and a partition coefficient (logP) that indicated the molecules would be able to passively diffuse across cell membranes. While, the most important descriptors remain unchanged a summary of Lipinski’s and others rules is provided in Table 1 [13, 14, 15, 16, 17]. As repurposing candidates will be drawn from compounds that are likely to be enriched for these properties and therefore the potential route of administration for the repurposed disease should be compatible with these. For instance, compounds that are a good fit to Ro5 would be relatively poorly applied to diseases for which administration would be via inhalation [18]. Thus, the availability of this pharmacological information and likely route of administration is of key importance in deciding on which compounds should be assessed for repurposing.
RO5 | RO3 | Ghose rules | Veber’s Rules | MDDR-like rules |
---|---|---|---|---|
MW ≤ 500 HBD ≤ 5 HBA ≤ 10 LogP ≤ 5 | MW < 300 Da HBD ≤ 3 HBA ≤ 3 cLogP ≤3 NRTB ≤3 | 160 ≤ MW ≤ 480 −0.4 ≤ logP ≤5.6 30 ≤ AMR ≤ 130 20 ≤ NA ≤ 70 | NRTB < 10 PSA < 140 Å | RNG ≥ 3 RGB ≥ 18 NRTB ≥6 |
Summary of ‘druglikeness’ rules applied in drug development.
In summary, these studies provide a wealth of information about the clinical application and mechanism of action, aiding the rapid development of the drug repurposing. When compared with
At its broadest level drug repurposing approaches can be divided into two geneal types: computer-based and experimental techniques [20, 21]. Within both these approaches there are three main angles of attack, drug-centric, target-centric and disease-centric methods [22]. As indicated by its name, drug-centric approaches start from the point of view of a drug, with the aim to find efficacy against diseases other than the initial indication. In the case of a disease-centric approach the disease is the focus, with the purpose being to identify and repurpose a drug specifically against that disease. Target-centric methods utilize drugs that bind to well-characterized targets that are known to be, or at least suspected to be, involved in other diseases besides the drugs’ original indication. What they have in common is that at the core these strategies often employ similarity assessment to identify drugs that can potentially be repurposed.
Traditional drug repurposing often relies on the in vitro/in vivo identification of active drugs or alternative targets. Whilst this can provide promising compounds with reliable, desired activity, it can be expensive, involves physical access to the drug libraries and requires setup and optimization of the assays [23]. With the rapid development of bioinformatics and the accumulation of vast amounts of experimental data, the development of drug repurposing, especially the initial stage, has moved from traditional biological experiments towards an increasing diversity of computational screening approaches, partially due to the lower cost and lower barrier to entry [24].
Virtual screening is an essential computational approach in drug discovery, and particularly in drug repurposing. It involves the use of computer programs to evaluate compound libraries on a specified criterion, usually similarity or calculated binding energy. Virtual screening can be classified into two categories: ligand-based and structure-based virtual screening [25, 26].
Ligand-based screening focuses on analyzing the structure-activity information of known active ligands against a certain indication to identify other potentially effective drugs. This analysis relies on similarity in the form of pharmacophores and geometric shape which can be informed by structural knowledge of the ligand-target complex to identify key pharmacophores or without structural information, relying on the structure-activity relationship information from experimental approaches to identify the pharmacophores [27]. Pharmacophores are the chemical moieties of drugs that play essential roles in the interaction with their targets. Pharmacophore features—including features such as hydrogen bond donors, hydrogen bonds acceptors, charge groups, aromatic rings and hydrophobic centroids are then identified together with their spatial characteristics and mapped into a string [28]. This string can serve as a fingerprint, which can be used for easy similarity matching between different drugs, potentially identifying drugs that are also active against the disease.
This approach can be successful for small molecules as they are relatively simple molecules from a chemical perspective. Their pharmacophoric features are limited and usually rely on a few strong, deeply buried interactions with the target, making it easy to map and identify drugs with similar characteristics [29]. In contrast, biologics, such as peptides and antibodies, are far less suitable to these techniques as their method of actions typically dependent on mimicking protein-protein interactions, which are characterized by large, flat interaction surfaces [30, 31]. This makes them highly specific for their target, allowing for targeted therapies with typically less side-effects, but that specificity also prevents them from being repurposed for a different target.
In contrast, structure-based virtual screening uses the three-dimensional structure of a target of therapeutic interest [32, 33], which is screened against a virtual library of approved drugs in order to identify those that show interactions with this novel target. Drugs are docked against the target and interaction analysis is performed based on binding energy and binding geometry. Many different docking software packages have been developed with the key differences being in the docking methodologies and the scoring functions used to rank the drugs [34]. Classical scoring functions usually rely on experimental data or prior information to rank the drugs. However, these have been consistently getting outperformed by machine learning based scoring functions, especially when specific target data is available to train on [35, 36].
Developments in computational power have made virtual screening approaches highly accessible to labs all over the world as they do not require nearly the amount of financial resources compared to wet-lab experiments. In addition, due to the speed at which the screenings can be performed nowadays, huge libraries containing 100’s of millions of compounds can be screened against a target rapidly massively increasing the chemical space explored [37]. Though these advances are very useful in early drug discovery, where it can be used to screen fragment and compound libraries that cover a diversity in chemical space, they are less impactful when it comes to drug repurposing since the amount of approved drugs is limited and does not comprise wide chemical space. A downside of structure-based screening is the need for the actual structural information, which can be difficult to obtain for novel targets. Fortunately the number of entries available in the PDB has been growing at an exceptional rate, more than doubling in the last decade [38], meaning more and more targets have structural information available. In addition, the recent achievements of AlphaFold [39], including the prediction of the 3-dimensional structures of the entire human proteome, might alleviate this issue [40]. Overall this still has a positive impact on drug repurposing strategies as the more structural information is available the better scoring functions can be become, aiding both ligand-based and structure-based methods in identifying drugs that can be repurposed.
Machine learning is an overarching term used to describe diverse algorithms that use data sets to perform intelligent predictions [41]. The algorithms can be trained on large datasets to identify patterns and interactions. The trained algorithm can then be applied to novel data to identify or predict outcomes or interactions.
Computer based drug repurposing techniques utilizing machine learning have been gaining a lot of traction due to a large increase in available omics data in a variety of databases and the development of sophisticated algorithms that can utilize this data [42, 43, 44]. It is carried out using computational biology, bioinformatics and database tools, which allows for economical and high efficiency drug discovery [45]. Machine learning techniques used for drug repurposing include: k-nearest neighbor algorithms, decision tree, random forest, artificial neural networks, k-means clustering and principal component analysis [20, 46, 47].
In recent years researchers have not been able to keep up with the amount of information being generated by omics experiments, creating a need for different data analysis methods. Where previously they would manually comb through the data looking for patterns and connections, there has been a shift towards big data analysis utilizing machine learning approaches, which have shown several specific applications in drug repurposing [48].
Signature matching is an approach where complex patterns and profiles—signatures—are generated for diseases and drugs by machine learning algorithms from large omics datasets. By looking for negative correlations between differential signatures resulting from diseases and from drug treatments, drugs can be identified that can serve as treatments for those diseases outside of their original indication [5, 20]. Simultaneously, drug signatures can also be compared with the signatures of structurally dissimilar drugs, with the idea being that if drugs show a similar signature they can share a therapeutic application irrespective of chemical similarity. For both these applications there is an alternative signature that can be compared, the clinical phenotype signature. Even though some diseases or drugs might show little to no similarities in direct transcriptomic, metabolomics or proteomic patterns, they could still have similar clinical phenotypic outcomes, which can also allow for the identification of repurposing uses of drugs [49].
Another use of signature matching is in finding similar chemical features of drugs and mapping a network based on shared features. This allows for the identification of drugs that may potentially be repurposed—as similarity in pharmacophores tends to correlate with a similarity in biological activity.
Related to signature-based methods, application of genome-wide association studies (GWAS) have also shown to be valuable within the field of drug repurposing [50]. GWAS data can be analyzed using machine learning approaches to identify interaction and association patterns of genes linked to diseases [51]. Genes identified by GWAS to associate with a disease tend to be enriched with druggable targets. By cross-referencing the disease enriched genes with databases containing drug-target information drugs can be found that inhibit specific genes that are involved in other indications but also seemingly play a role in the GWAS investigated disease, potentially being able to reuse that drug. In addition if a gene is shown to be associated with a disease it could become a novel drug target, which can be screened against using approved drug libraries.
Even though GWAS identified genes can be associated with a disease that does not mean that the target is druggable. Pathway mapping could be a potential tool to leverage the information gained with GWAS and expand upon it [52]. By analyzing the pathways or protein interaction networks up and/or downstream of the GWAS identified genes, other, previously elusive, proteins can be identified that could play a role in disease progression. This can either yield new drug targets or repurposing opportunities of drugs that already inhibit the elucidated target. For example, pathway analysis was performed on data sets containing gene expression data from human hosts infected with many different respiratory viruses. This identified 67 conserved biological pathways that could play an important role in respiratory viral infections. Comparing these pathways to a drug-target database resulted in drugs like pranlukast and amrinone, drugs with a different indication, that could potential be used in treating viral infections [53].
Empirical evidence is still highest order of evidence and remains the golden standard for drug screening, including drug repurposing. Since experimental assays provide the most immediate evidence of drug activity [51] they are not only used to discover potential repurposing candidates from libraries but they are also essential in validating hits from computational approaches.
Inhibition assays can serve to identify target-specific drug efficacy, including inhibition constants. Binding assays are very powerful as they can also provide binding constant information [54]. Immediate use can be made of the identified binding drug that might not be highly specific or effective but it could serve as a temporary stop gap in emergency situations (like pandemics). Whilst the repurposed drug is being used as a sort of band aid, drug development can be undertaken in parallel, using the drug as the starting point. Rapid SAR approaches can then be utilized to improve the drug binding and efficacy [55]. The fact that the resulting drug would ideally be quite similar to the approved drug could lead to accelerated approval processes.
Binding assays aim to detect the interaction(s) between two (bio)molecules, such as protein-protein, peptide-protein, nucleic acid-protein, small molecule-protein, or small molecule-nucleic acid and ideally also evaluate the degree of the interaction [56]. These assays can be used in two ways, in screening approaches to qualitatively identify hits that interact with the target and in a quantitative way to characterize the binding affinity.
There are many examples of different types of qualitative assays that have been used in drug repurposing approaches. Among the most common are immobilization or affinity chromatography, where either the target or the drug are immobilized on a matrix or column followed by exposure to a drug library or potential binding targets [57]. The complexes that have formed can then be eluted and identified using analytic methods. DNA-encoded libraries encompassing wide chemical space have been used in such approaches. After eluting complexes binding compounds are identified by sequencing the DNA-barcode attached to the binding compound. This technique can also be applied to approved drug libraries [58].
The aforementioned assays are aimed at screening large libraries for hits. However, obtaining detailed binding information such as dissociation constants (KD), is crucial in the identification and development of potent drugs. Several biophysical techniques are available to quantify these interactions. Microscale Thermophoresis (MST) can be used to measure binding affinity by detecting changes in molecular motion in a temperature gradient in the presence and absence of different compound concentrations [59]. Differential scanning fluorimetry (DSF) can be used to measure protein unfolding temperature by monitoring in fluorescence of a probe that binds to hydrophobic moieties in a denaturing temperature gradient. Upon binding of drugs to the protein it can stabilize the complex, leading to a shift in unfolding temperature. By using a range of drug concentrations and measuring the effect on the thermal shift the KD can be calculated [60]. Surface plasmon resonance (SPR) is a technique in which the target or drug of interest is immobilized on a thin metal film. A light source is aimed at the other side of the film and the surface Plasmon resonance angle is detected. When a drug or target binds to the immobilized partner the local mass at the sensor surface changes, causing a shift in the angle of reflection proportional to the mass. By measuring these changes in the presence and absence of drug or target, association and dissociation constants can be determined [61]. Isothermal titration calorimetry (ITC), one of the golden standards in KD determination, can directly measure all binding parameters by measuring heat transfer. When binding of drug to target occurs, enthalpy changes (heat absorbed or released) of the system can be measured by a highly sensitive calorimeter. By titrating ligand against the target of interest the Kd, stoichiometry, enthalpy and entropy can be directly measured in the native states of the binding partners since no modifications are required [62].
Where binding assays are typically focused on identifying target-drug interactions, phenotypic screening takes a more disease-centric approach. Phenotypic assays aim to identify compounds that show effects on disease-relevant outcomes [63]. These are usually performed on cell lines or organelles engineered to function as disease models. Since the assay is target agnostic less, or no, information about specific targets is obtained. However, the fact that it is agnostic also means that there are more potential targets available within this complex environment, which could lead to the discovery of new targets that would otherwise be left unexplored [63]. There are also additional benefits to this approach in the context of drug repurposing. Since the assays are disease based and compounds are approved drugs or clinical candidates it means that if positive outcomes are obtained the drug already has positive properties and shown efficacy in more complex systems, which is beneficial to real world applications [64].
One of the most frequent reasons for drugs failing in (pre)clinical trials is the determination of a side effect that cannot be ignored. Most commonly this is determined to be a dangerous side effect that argues against further clinical investigation of the compound. However, one man’s meat is another man’s poison. These drugs with unwanted side effects can be given new indications through a drug repurposing strategy. Side effects-based drug repurposing links indications with clinical effect and is one of the common strategies employed for drug repurposing [65, 66]. A key example in this area is Sildenafil, which was originally entered into clinical trials as a drug to treat hypertension and angina [65, 67, 68, 69, 70]. Unfortunately, Phase I clinical trials suggested that it had little effect on angina. However, use of Sildenafil causes a significant side effect: marked penile erections. This lead to the discovery that Sildenafil could be used as a treatment for erectile dysfunction (ED) [71]. In 1988, Sildenafil was approved by the FDA for the treatment of ED. Such repurposing approaches could be termed serendipitous repurposing, as the new indication area is revealed during clinical trials. As a result, such repurposing is relatively rare.
Over the last decades the world has seen multiple severe viral outbreaks resulting in millions of deaths. Among the deadliest were the Influenza pandemics such as H1N1 (1918), H2N2 (1957), H3N2 (1968) and H1N1 (2009). The HIV/AIDS epidemic that was first recognized in the 1980s and went global has also caused up to an estimated amount of 36 million deaths and is still ongoing. Besides the large, deadly pandemics there have been smaller but very impactful localized epidemics such as Dengue virus (DENV), Zika virus (ZIKV), Ebola virus (EBOV) and Middle East respiratory-syndrome corona virus (MERS-CoV) which pose serious challenges to public health. Most recently in 2019 there was an outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which caused the COVID-19 pandemic, affecting nearly every country in the world with over 226 million reported cases to date [72]. Despite the advances in controlling viral pathogens that come with the widespread mass vaccination, there are no approved specific (effective) therapies for the treatment of most viral infections.
By exploring new targets and mechanisms, drug repurposing provides new indications for old drugs. The major time advantage of repurposing is that this approach allows repurposed drugs to quickly enter clinical trials, which is of significant importance in reacting to disease outbreaks, especially in the case of worldwide pandemics.
The outbreak of COVID-19, caused by SARS-CoV-2, has spread across the world. There is, as yet, no specific treatment for COVID-19 approved. Drug repurposing provides a fast and economical option for the identification of medications targeting SARS-CoV-2.
SARS-CoV-2 is a member of of the betacoronaviruses family. It is a single-stranded RNA virus, characterized by large crown-like spikes protruding on the viral surface and an unusually large RNA genome which encodes four main structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) [62, 73, 74]. Like other coronaviruses, SARS-CoV-2 cell entry is mediated by the spike glycoprotein. The spike glycoprotein is composed of two subunits, S1 and S2, which mediate viral-host attachment and viral-host membrane fusion cascade, respectively [75]. SARS-CoV-2 spike recognizes and binds to the human ACE2 (hACE2) receptor through its receptor-binding domain (RBD) and is primed and activated by proteolytic cleavage by enzymes such as Furin and transmembrane serine protease 2 (TMPRSS2) [76, 77]. Spike, ACE2, Furin and TMPRSS2 have been shown to play a key role in mediating viral-host fusion attachment and fusion, and the Furin cleavage site on the Spike protein has been indicated as one of major reasons SARS-CoV-2 is so infectious [78, 79]. This makes these potentially promising drug targets for COVID-19 treatment [80, 81].
Inhibition of the Spike-Ace2 interaction is a primary target for drug repurposing as it is crucial to viral entry.
Another promising target is TMPRSS2, a serine protease. TMPRSS2 is associated to the host endothelial cell surface and cleaves the viral spike glycoprotein after binding to ACE2, activating it. The activation of spike protein then facilitates viral entry [84]. Camostat mesilate (a serine protease inhibitor) has been approved for the treatment of chronic pancreatitis, postoperative reflux esophagitis and kidney or liver disease fibrosis [81, 84, 85]. Since it is an established serine protease inhibitor it is a prime candidate to inhibit the TMPRSS2. An
Besides direct membrane fusion, SARS-CoV-2 can also invade cells via endocytosis [88, 89]. This route involves several proteins that play an important role in endosome formation, such as two-pore channel 2 (TPC2), Cathepsin L (CTSL) and Vacuolar-type ATPase (V-ATPase) [90]. These proteins are indicated to be potentially interesting therapeutic targets for COVID-19 treatment.
Tetrandrine is a bisbenzylisoquinoline and calcium channel blocker, known for its anti-inflammatory, immunosuppressive, oncological, and cardiovascular bioactivity [48, 49]. The compound has been shown to be effective in the treatment of silicosis [90, 91, 92]. According to an
The now infamous anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) were also posited to inhibit endocytosis of SARS-CoV-2 [93, 94]. CQ and HCQ are potentially involved in blocking cleavage of spike by raising the pH of the endosomes, preventing cathepsin L-mediated proteolysis, which is a key element in membrane fusion after binding ACE2. Whilst many potential mechanisms of action have been suggested, none have been rigorously demonstrated. In addition, a recent large meta-data analysis has shown that there is no evidence that treatment with CQ or HCQ reduces COVID-19 mortality in patients [95]. To the contrary, evidence is available that shows HCQ is responsible for a small increase in mortality outcomes. These compounds garnered lots of attention when the presidents of prominent countries started promoting CQ and HCQ as wonder drugs that could combat COVID-19 [96]. However, as mentioned before most evidence points towards the contrary and the WHO recommends against the treatment with these drugs [97]. These cases have shown an important risk in the use of drug repurposing: in the age of hyper connectivity and social media echo chambers dangerous, unfounded ideas can avoid scrutiny and rigorous investigation, leading to large groups of people self-medicating with alternative treatments that have no scientific basis. This poses a problem in general drug development but even more so in drug repurposing cases where these compounds tend to be far more easily obtainable by the general public as they are approved and often available for purchase in pharmacies.
After invading host cells, the coronavirus comes into the next stage of its life cycle: translation, replication, transcription and Assembly. This process mainly involves five different proteins: Mpro, RdRp, nsp14, MTHFD1 and Plpro, which have different functions [74, 98]. Mpro is also known as 3C-likeprotease (3CLpro) and proteolytically processes the majority of the polyprotein into functional polypeptides [99]. Similar to 3CLpro, Plpro is a viral protease that is responsible for cleaving polyproteins to generate a function replicase complex [100]. RNA synthesis, critical for viral replication, is performed by RdRP and its cofactors nsp7 and nsp8. Nsp14 has an exonuclease activity that supports RNA synthesis with an unusual RNA proofreading function. A study performed by Tinghua University showed that knockdown of MTHFD1, a key enzyme in cellular production of purine, dTMP and methyl groups, significantly inhibits viral replication [101]. As a result of their key functions in the viral life cycle these proteins are promising potential targets for antiviral drugs development. Clofazimine is an anti multi-bacillary leprosy drug which was approved for medical use in 1986. A recent study performed by The University of Hong Kong showed that clofazimine inhibits both viral spike glycoprotein mediated cell fusion and replication of SARS-CoV-2
Genome analysis has demonstrated that SARS-CoV-2 and SARS-CoV genes globally share >80% nucleotide identity and >89% similarity [73, 103, 104]. As a result, the key steps in the CoV family viral life cycle within the host cell are likely to be highly conserved. A key feature of this process is the expression of non-structural proteins (nsps). Subsequent to cell entry, two extended polypeptides (pp1a and pp1ab) from the CoV viral genome are generated by the host cell translation machinery [105, 106]. These two polypeptides then self-cleave into 37 distinct non-structural (nsp) proteins [107] and anaylsis has demonstrated that the CoV family possesses several proteases involved in this essential self-cleavage process: the papain-like protease (PLpro), and the 3C-like proteinases (3CLpro or Mpro) [108]. CoV generally encode two PLpros within nsp3, with the exception of gamma-CoV, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 [100]. Thus, 3d unlike structural/accessory protein-encoding genes, which can show significant sequence variation in order to select between different potential host cell receptors, CLpro plays a central and critical role in CoV replication in host cells and the similarity in essential function leads to a high sequence similarity between the proteases of the CoV family, in particular beta-CoV [105, 106]. This increased similarity in the structure of the 3CLpro has the consequence of high structural between 3CLpro of different CoV family members—and the concomitant increased likelihood of cross-species function of CoV 3CLpro inhibitors and the potential to repurpose these inhibitors. The high sequence homology within Cov 3CLpros also provided high quality model templates—subsequently supported by the availability of high-resolution diffracting crystals—to perform both computational docking experiments, as well as molecular validation by X-ray crystallography [109]. There also exists the potential for the discovery and the development of a pan-anti-CoV inhibitor [110, 111].
This potential has been partially realized in not only the discovery of entirely novel SARS-CoV2 3CLpro inhibitors [99, 112, 113] (refs), but also in a number of reports describing successful identification of potential repurposing candidates [109].
For example, we and others have previously reported the results of a molecular docking experiment that indicated a class of well tolerated compounds (gliptins) as potential SARS-CoV2 inhibitors. For example, Anagliptin, a DPP4 inhibitor, is a well-established treatment for diabetes that is used by millions of patients. It has an excellent safety profile [114]. Computational docking demonstrated an efficient binding, with predicted H-bonds made to the backbone atoms of Gly163, Gly271, and Tyr268 and the side chain of Tyr273. Docking experiments also proposed that α-ketoamide inhibitors of hepatitis C virus (HCV) protease would be potential inhibitors of SARS-CoV-2 3CLpro. Efforts were concentrated on broceprevir and telaprevir as the docking poses were supported by experimental structure analyses (Figure 1). Subsequent biochemical assays demonstrated that broceprivir indeed displays strong binding to isolated 3CLpro of SARS-CoV2 and inhibits viral replication in cellular assays.
Boceprevir (green), a HCV NS3/4A protease inhibitor, bound to SARS-CoV-2 3C-like protease (gray surface representation) with several key drug-protein interactions shown. Hydrogen bonds are shown as yellow dotted lines. PDB accession code: 6zru.
Similarly to CQ and HCQ, ivermectin, originally an anthelmintic, also gained widespread attention as a potential treatment for COVID-19 and some
Clinical symptoms resulting from SARS-CoV-2 infection are heterogeneous. Recent reports have shown that the cytokine storm effect may play a significant role in disease progression, potentially leading to multiple organ failure and death [119]. Immune response-related proteins have been proposed as potential targets for treatment options [120, 121]. Even though effectively suppressing cytokine storm does not directly combat the viral infection itself, it can be a crucial treatment option against COVID-19. It has previously been demonstrated that melatonin has beneficial effects on infection induced models of respiratory disease and associated complications [122]. Recently evidence also surfaced that it can inhibit COVID-19 induced cytokine storm [123]. Tocilizumab, an interleukin antagonist used for rheumatoid arthritis, is an immunosuppressor and was thus posited to be effective at reducing inflammation caused by SARS-CoV-2 [124]. It has recently become one of the first drugs to be recommended by the WHO as an effective treatment against COVID-19 [125]. Even though this is very promising there is an issue with the availability and affordability of this drug [126].
Researchers at Johns Hopkins found that the drug prazosin, an alpha-1 blocker used to treat high blood pressure, can prevent cytokine storms and that it significantly strengthened survival following inflammatory stimuli in preclinical models. This study is now in clinical trials [127].
Sepsis is a systemic inflammatory response syndrome reulsting from dysregulation of host immunity. It is one of the deadliest clinical symptoms of severe SARS-CoV-2-infected patients [128]. Sepsis treatment normally mainly relies on the administration of intravenous antibiotics. However, since SARS-CoV-2 viral sepsis is not bacterial in nature the efficacy is low. Treatment is difficult, typically consisting of supplying oxygen and assisted breathing using a ventilator. Cocktails of antivirals and immune suppressors are also given but usually only have limited effect [129]. Approximately one-third of the discharged patients will die and one-sixth will suffer severe persistent impairments in the following year [130]. These facts taken together demonstrate the urgency and significance to find new treatments.
Sepsis is associated with pyroptosis (inflammatory programmed cell death) that is triggered by proinflammatory signals [131]. When viruses invade the host cell, inflammasomes are activated which in turn triggers an inflammatory response [132]. Pore-forming protein gasdermin D (GSDMD) is cleaved by activated Caspase-1, releasing its N-terminal domain [133]. The GSDMD N-terminal domain induces the formation of a large plasma membrane pore, resulting in pyroptosis [134]. Under normal circumstances pyropthosis can be good response, being able to trigger cell death of infected cells, releasing the pathogens and stimulating subsequent phagocytosis, protecting against infections [135]. However, excessive activation of pyroptosis will exacerbate sepsis or excessive cell death, causing immunity dysregulation [136, 137].
Disulfiram is approved for the treatment of chronic alcoholism. In a study conducted by Boston Children’s Hospital, researchers found that disulfiram posesses inhibiting potential towards GSDMD both in
Not only large global pandemic diseases are worth investigating for drug repurposing opportunities. Smaller, localized viral epidemics still plague many countries to this date. These diseases tend to fly under the radar since they typically occur in poorer regions of the world, meaning less research money is being spent on novel drug development. Drug repurposing could be the solution for these diseases due to the far faster and cheaper development pipeline.
Dengue virus (DENV) is a single-stranded RNA virus, enveloped by a bilayer lipid membrane. The premembrane (prM) protein and envelope glycoprotein adhere to the membrane. Dengue virus can infect humans through mosquito bites. Symptoms, that include high fever, severe headache, muscle and joint pain, nausea, vomiting, swollen lymph nodes and rash, usually appear 3–14 days post-infection [139]. Most patients will recover in 2–7 days, while a small number of patients’ conditions may worsen accompanied by bleeding, thrombocytopenia and plasma protein effusion. Up to 22,000 people die from Dengue annually and currently there are no therapies to treat this infection [140].
Ulipristal, a FDA approved small molecule, is an elective progesterone receptor modulator (SPRM), that has been demonstrated to be a potent inhibitor of DENV, most likely by blocking viral entry [141]. The antiviral activity was evaluated by
Zika virus (ZIKV) is another virus that is propagated by mosquitoes and belongs to the genus of flaviviruses. ZIKV infection generally causes only mild symptoms, including fever, rash, conjunctivitis, muscle and joint pain, and headache. However, it has shown severe tetatogenic impacts, being able to cause a range of neurological complications, such as Guillain-Barre syndrome and microcephaly, in the fetuses of infected pregnant women [142].
There are no currently approved specific therapies for ZIKV infection [143]. However, a screening study utilizing 774 approved drugs has shown promising results. In vitro studies showed that ivermectin (anthelmintic), mycophenolic acid (an immunosuppressant), and daptomycin (a lipopeptide antibiotic) can inhibit ZIKV, resulting in reduced infection rates [144].
Ebola virus is one of numerous hemorrhagic fever viruses, which was first discovered in 1976. It can cause severe viral haemorrhagic fever with case fatality rates vary from 25 to 90% [145]. It is characterized as a non-specific febrile illness (symptoms may include anorexia, arthralgia, headache, malaise, myalgia and rash) in the early infection and progresses to severe gastrointestinal symptoms (nausea, vomiting and high-volume diarrhea) in the first week [146]. To date, a monoclonal antibody (mAb114) and a cocktail of three antibodies (REGN-EB3) have been approved for the treatment of Ebola [147, 148]. Besides these biologics there has also been attempts at drug repurposing for this disease. Several drugs such as Amiodarone (anti-arrhythmia), bepridil (anti-angina pectoris), teicoplanin (antibiotic), amiodarone (ventricular fibrillation/tachycardia) and favipiravir (RNA polymerase inhibitor) have shown therapeutic potential for Ebola, but their efficacy requires further confirmation [149, 150, 151].
A warning of the potential for a coronavirus pandemic was provided by the Middle East respiratory syndrome coronavirus (MERS-CoV). While the impact of this outbreak was significantly less than that of the current SARS-CoV2 outbreak the urgent need for MERS-CoV treatments was recognized, also including a focus on repurposing approaches and a call for the development of pan-corona virus inhibitors [152]. Suggested repurposing agents included GS-5734, which has previously demonstrated antiviral against multiple viral families, including
Similarly, lopinavir-ritonavir (a molecule designed as an inhibitor of the HIV-1 protease inhibitor) was proposed as a repurposing target of the 3CLpro of both SARS-CoV and MERS-CoV during their respective outbreaks [155, 156]. Combination therapy approaches in both cases resulted in improved patient outcomes, thereby offsetting the lacking of designed affinity that is a hallmark of repurposed compounds. In the example of SARS-CoV, a study on a combined therapy with ribarivin (a guanosine analog with activity against multiple viral families that inhibits viral RNA synthesis by RdRp) demonstrated both reduced viral load and improved clinical outcomes [157]. Whereas, a clinical trial of lopinavir-rotonavir in combination with IFN-β1b targeted therapies was proposed for MERS-CoV patients in Saudi Arabia [158]. Ribarivin itself was also a focus for repurposing during the SARS-CoV and MERS-CoV outbreaks. However, while efficacy of ribarivin alone could be demonstrated
Screening of an FDA-approved compound subset against viral replication in culture identified lopinavir and an additional 3 compounds with IC50 values in the low micromolar range (chloroquine, chlorpromazine, and loperamide) [156]. This again demonstrates not only the potential for experimentally based repurposing screens to identify potential agents, but also suggests that the relatively limited potency of the agents identified may require the assessment of combination therapies to provoke a clinical response. This additional limitation of identifying appropriate combination therapies may well represent a common theme as a complicating factor in repurposing strategies.
In summary, the relatively conserved elements of the viral life cycle offer many opportunities to reexamine compounds developed to address previous outbreaks for efficacy against novel outbreaks. Clear examples are shown in the results against non-structural proteins above, which often maintain significantly higher sequence homology across species due to a conserved mechanism than structural proteins. However, while this sequence conservation indeed leads to a degree of “cross-talk” between nsp inhibitors, the required exquisite and intricate nature of the interaction between a successful drug and its target will almost inevitably reduce the efficacy of a monotherapy. As a result, it is likely that while repurposing can identify promising candidates, care must be taken not to hope for a single effective solution in existing drugs (e.g. Ivermectin, hydroxychloroquinine, etc.). Rather, functional (clinical) solutions are much more likely be found in careful clinical trials of combination therapies of drugs identified through repurposing screens.
The current combination of virtual,
Response speed is a key factor facing outbreaks. Drug repurposing is a practical solution that provides multiple benefits beyond classical drug discovery. Perhaps the greatest advancement in this area has been the improvements in computational techniques, that has developed in parallel with advances in structural biology—both of which continue to improve. These structural views of the proteins driving disease expand the number of experiments that can be performed
The authors would like to acknowledge the support of their friends and family over the recent pandemic.
The authors declare no conflicts of interest in the contents of this manuscript.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
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\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
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\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
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\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
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\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
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\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
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\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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Studies on the photocatalytic degradation of emerging organic compounds like cyanotoxins, VOCs, phenols, pharmaceuticals, etc., by employing variety of modified semiconductors, are summarized, and a mechanistic aspects of the photocatalysis has been discussed.",book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Fatima Imtiaz, Jamshaid Rashid and Ming Xu",authors:[{id:"292882",title:"Dr.",name:"Jamshaid",middleName:null,surname:"Rashid",slug:"jamshaid-rashid",fullName:"Jamshaid Rashid"},{id:"302498",title:"Ms.",name:"Fatima",middleName:null,surname:"Imtiaz",slug:"fatima-imtiaz",fullName:"Fatima Imtiaz"},{id:"308434",title:"Prof.",name:"Ming",middleName:null,surname:"Xu",slug:"ming-xu",fullName:"Ming Xu"}]},{id:"69599",title:"Introductory Chapter: Fundamentals of Semiconductor Photocatalysis",slug:"introductory-chapter-fundamentals-of-semiconductor-photocatalysis",totalDownloads:881,totalCrossrefCites:1,totalDimensionsCites:1,abstract:null,book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Mohammed Muzibur Rahman",authors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}]},{id:"67490",title:"Rare-Earth-Based Materials for Heterogeneous Photocatalysis",slug:"rare-earth-based-materials-for-heterogeneous-photocatalysis",totalDownloads:826,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Recently, the synthesis of rare-earth-based nanostructures as a significant class of materials with photocatalysis activity has attracted the attention of researchers. Many studies have shown their applications in various fields, specifically in photocatalysis. There are different methods to synthesis of rare-earth nanostructures. In this study, we discuss about modification of rare-earth-based materials. Also production methods and their advantages and disadvantages have been presented, briefly. Finally, photocatalytic applications of rare-earth nanostructures are highlighted.",book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Sahar Zinatloo-Ajabshir and Zahra Sayyar",authors:[{id:"292583",title:"Dr.",name:"Sahar",middleName:null,surname:"Zinatloo_Ajabshir",slug:"sahar-zinatloo_ajabshir",fullName:"Sahar Zinatloo_Ajabshir"},{id:"296400",title:"Dr.",name:"Zahra",middleName:null,surname:"Sayyar",slug:"zahra-sayyar",fullName:"Zahra Sayyar"}]},{id:"67697",title:"TiO2 Nanoparticles Supported on Hierarchical Meso/Macroporous SiO2 Spheres for Photocatalytic Applications",slug:"tio-sub-2-sub-nanoparticles-supported-on-hierarchical-meso-macroporous-sio-sub-2-sub-spheres-for-pho",totalDownloads:925,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Supporting a photocatalyst, such as titania nanoparticles (TiO2 NPs), is a good strategy to improve its performance since it can facilitate the photocatalyst recovery from the aqueous media and provides a high surface area for pollutant adsorption. Among the several advanced functional materials used as TiO2 NP support, the hierarchical meso/macroporous SiO2 spheres not only show the advantages associated to its chemical nature but also the dendritic fibrous structure provides a porous network that offers many benefits to be exploited in optical and catalytic devices. In this chapter, different synthetic approaches to design hierarchical meso/macroporous silica and the strategies to support TiO2 NPs regarding the photocatalytic performance of these materials are shown.",book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Keyla M. Fuentes, Margarita Sánchez-Dominguez and Sara A. Bilmes",authors:[{id:"93593",title:"Dr.",name:"Margarita",middleName:null,surname:"Sanchez-Dominguez",slug:"margarita-sanchez-dominguez",fullName:"Margarita Sanchez-Dominguez"},{id:"290978",title:"Ph.D.",name:"Keyla M.",middleName:null,surname:"Fuentes",slug:"keyla-m.-fuentes",fullName:"Keyla M. Fuentes"},{id:"300173",title:"Prof.",name:"Sara",middleName:null,surname:"Aldabe Bilmes",slug:"sara-aldabe-bilmes",fullName:"Sara Aldabe Bilmes"}]},{id:"64785",title:"Effect of Annealing on Metal-Oxide Nanocluster",slug:"effect-of-annealing-on-metal-oxide-nanocluster",totalDownloads:793,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Recently, the development of optoelectronic devices based on metal-oxide nanocluster has attracted intensive research interest. Nanoclusters are suitable for these because of their large surface-to-volume ratio and the presence of abundant oxygen vacancies or trap states. Metal–oxides such as ZnO, In2O3, and TiO2 synthesized using different technique produces high surface area films consisting of clusters and provides complete control over the film morphology. In this chapter, some of the metal oxides nanocluster film has investigated, and the effect of annealing on the structural, optical and electrical properties of the grown films when subjected to different annealing temperatures will be studied. Theoretically, these properties are presumed to improve after the heat treatment as the crystallinity, and the grain size of the film has increased due to the diminishing of oxygen vacancies. Thus, the greater surface-to-volume ratio, the better stoichiometry and higher level of crystallinity compared to bulk materials make nanocluster-based devices very promising for the mentioned application.",book:{id:"7671",slug:"concepts-of-semiconductor-photocatalysis",title:"Concepts of Semiconductor Photocatalysis",fullTitle:"Concepts of Semiconductor Photocatalysis"},signatures:"Naorem Khelchand Singh and Rajshree Rajkumari",authors:[{id:"263847",title:"Dr.",name:"Naorem Khelchand",middleName:null,surname:"Singh",slug:"naorem-khelchand-singh",fullName:"Naorem Khelchand Singh"},{id:"276260",title:"Ms.",name:"Rajshree",middleName:null,surname:"Rajkumari",slug:"rajshree-rajkumari",fullName:"Rajshree Rajkumari"}]}],onlineFirstChaptersFilter:{topicId:"958",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:16,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:4,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"June 25th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:54,paginationItems:[{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:22,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"80963",title:"Pain Perception in Patients Treated with Ligating/Self-Ligating Brackets versus Patients Treated with Aligners",doi:"10.5772/intechopen.102796",signatures:"Farid Bourzgui, Rania Fastani, Salwa Khairat, Samir Diouny, Mohamed El Had, Zineb Serhier and Mohamed Bennani Othmani",slug:"pain-perception-in-patients-treated-with-ligating-self-ligating-brackets-versus-patients-treated-wit",totalDownloads:21,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Trends in Orthodontics",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"80964",title:"Upper Airway Expansion in Disabled Children",doi:"10.5772/intechopen.102830",signatures:"David Andrade, Joana Andrade, Maria-João Palha, Cristina Areias, Paula Macedo, Ana Norton, Miguel Palha, Lurdes Morais, Dóris Rocha Ruiz and Sônia Groisman",slug:"upper-airway-expansion-in-disabled-children",totalDownloads:35,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"80839",title:"Herbs and Oral Health",doi:"10.5772/intechopen.103715",signatures:"Zuhair S. Natto",slug:"herbs-and-oral-health",totalDownloads:55,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg",subseries:{id:"1",title:"Oral Health"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. 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His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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