\r\n\tEqually important are the consequences deriving from the extraordinary nature of the present times. The COVID-19 pandemic and the restrictive measures to contain the infection (lockdown and "physical distancing" in primis) have revolutionized the lives, and a distortion/modification of habits, rhythms, arrangements will continue to be necessary. \r\n\tGovernments have implemented a series of actions to mitigate the spread of infections and alleviate the consequent pressure on the hospital system. On the other hand, the Covid-19 pandemic has caused a series of other cascading effects that will probably be much more difficult to mitigate and which expose to complex consequences. The past two years have brought many challenges, particularly for healthcare professionals, students, family members of COVID-19 patients, people with mental disorders, the frail, the elderly, and more generally those in disadvantaged socio-economic conditions, and workers whose livelihoods have been threatened. Indeed, the substantial economic impact of the pandemic may hinder progress towards economic growth as well as progress towards social inclusion and mental well-being.
\r\n
\r\n\t \r\n\tAlthough in all countries the knowledge on the impact of the pandemic on mental health is still limited and mostly derived from experiences only partially comparable to the current epidemic, such as those referring to the SARS or Ebola epidemics, it is likely that the demand for intervention it will increase significantly in the coming months and years. The extraordinary growth of scientific research in the field of neuroscience now offers the possibility of a new perspective on the relationship between mind and brain and generates new scenarios in understanding the long wave of the pandemic and in the prospects for treatment. Moreover, the pandemic also has led to opportunities to implement remote monitoring and management interventions.
\r\n
\r\n\t \r\n\tOverall this volume will address the complex relationship existing between COVID-19, mental health, acquired knowledge, and possible interventions taking a highly multidisciplinary approach; from physiological and psychobiological mechanisms, and neuromodulation through medical treatment, psychosocial interventions, and self-management.
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Devoted researcher of the European Innovation Partnership on Active and Healthy Aging, appointed Assistant Specialty Chief Editor of Frontiers in Psychology -Neuropsychology and Scientific Director of the Italian National Institute of Philanthropy.",coeditorOneBiosketch:"An academic and industrial investigator involved in basal research, drug discovery, and development of potential psychiatric drugs, covering depression, anxiety, OCD, schizophrenia, and sexual dysfunctions.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo",profilePictureURL:"https://mts.intechopen.com/storage/users/233998/images/system/233998.png",biography:"Sara Palermo has an MSc in clinical psychology and a PhD in experimental neuroscience. 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\n
1. Introduction
\n
Alzheimer’s disease is a progressive neurodegenerative disease that clinically presents as a gradual onset of dementia, beginning with mild cognitive and functional deficits, leading eventually to an inability to carry out everyday tasks. Alzheimer’s disease and other dementias have a reported worldwide prevalence of approximately 42 million people, with an age-standardized rate of 761 per 100,000 [1]. Current therapeutics are limited to symptomatic approaches, such as acetylcholinesterase inhibitors and NMDA receptor (NMDAR) antagonists, which aim to enhance the function of unaffected neurocircuitry but do not target the underlying cause of the disease, thus there is a desperate need for approved disease modifying therapies.
\n
Alzheimer’s disease is characterized by the dual pathological hallmarks of extracellular senile plaques and neurofibrillary tangles, composed of the amyloid-β (Aβ) peptide and tau protein, respectively. In addition, the primary familial forms of the disease are caused by mutations that directly affect Aβ homeostasis [2]. Due to both the pathological and genetic link to disease initiation, Aβ has been a prominent target for the development of disease-modifying therapeutics.
\n
One such therapeutic approach is anti-Aβ immunotherapy. Active immunotherapy approaches utilize either the ability of the immune system to raise polyclonal antibodies against a therapeutic composed of an Aβ sequence-derived antigen and adjuvant, while passive immunotherapy approaches treat a patient with monoclonal antibodies with known antigen binding capabilities. While a large amount of research and development has been carried out regarding active immunotherapy towards AD targets [3], this chapter will focus on passive immunotherapy in AD, with the goal of describing what has been learned from past clinical studies, and what lessons may be applied to future efforts.
\n
\n
\n
2. Aβ
\n
\n
2.1. Mechanisms of Aβ pathophysiology
\n
The primary component of senile plaques is Aβ, a small peptide derived from the amyloid precursor protein (APP). In AD, Aβ is formed via sequential cleavage of APP by β-secretase [4] and the presenilin-1 (PS1) subunit of γ-secretase [5], respectively. This results in peptides of varying length, ranging from 38 to 43 amino acids [6], of which Aβ1–42 is the most amyloidogenic [7]. A central tenet in the understanding of causative factors of AD is the amyloid cascade hypothesis [8], which holds that the pathological increase of amyloidogenic Aβ in AD is a central initiating event in disease, that precedes and initiates a cascade of events that lead to other pathologies such as the formation of neurofibrillary tangles, inflammation, oxidative stress, neuronal dysfunction, and cell death [9]. While the amyloid cascade hypothesis has been challenged since first proposed [10, 11], there is abundant evidence from in vitro and in vivo studies confirming the significant role Aβ plays in inducing neurotoxicity, synaptic dysregulation, and pathology.
\n
Degeneration of cultured neurons by treatment with aggregated forms of Aβ has been observed in multiple laboratories, and appears to correlate with extent of aggregation [7, 12]. Strong evidence indicates that soluble aggregated forms of Aβ might exert direct toxicity to neurons [13, 14, 15] through a variety of mechanisms, including (but not limited to) disruption of plasma membranes [16], dysregulation of mitochondrial function and dynamics via direct interaction [17], and excitotoxicity [18]. Confirming the centrality of Aβ’s role in neurotoxicity, myriad transgenic mouse models expressing mutant APP or APP/PS1 recapitulate many AD phenotypes, including plaque pathology, synaptic dysfunction, decreased cognition, neuroinflammation, and neuronal loss (reviewed in [19]).
\n
One of the earliest mouse models of Aβ plaque deposition was the PDAPP mouse (Line109). These transgenic mice exhibit high human APP expression (>10-fold higher than endogenous levels), which is accompanied by extracellular Aβ plaque deposition, development of neuritic dystrophy, gliosis, and loss of synaptic and dendritic structures in the hippocampus [20]. The PDAPP mouse model was instrumental to demonstrate that therapies developed to clear Aβ deposits could potentially ameliorate functional deficits. Schenk and colleagues were the first to develop an active immunization approach using aggregated Aβ1–42 [21], which resulted in prevention of plaque formation in mice immunized before the development of pathology, and more importantly demonstrated that the induced polyclonal response can promote plaque clearance in aged PDAPP mice via phagocytosis by resident microglia. This breakthrough was later extended by administering the anti-N-terminal Aβ monoclonal antibody (mAb) 3D6 directly to PDAPP mice (passive immunotherapy); antibodies crossed the blood-brain barrier (BBB), localized to pathological features, and induced the opsonization and clearance of senile plaques in a microglia-dependent manner [22]. These preclinical findings validated Aβ-directed passive immunotherapy as a potential therapeutic strategy for AD.
\n
\n
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2.2. Aβ passive immunotherapy in the clinic
\n
The first Aβ immunotherapy clinical trial utilized active vaccination with Aβ1–42 (AN1792) and was halted during Phase IIa due to the appearance of meningoencephalitis, likely due to the infiltration of T-cells in the brain as a result of the presence of T-cell epitope(s) in the antigen, which contained the full-length Aβ1–42 peptide [23]. However, long-term follow-up indicated that patients that developed an immune response displayed modest but significant sparing of function, as assessed by the Disability Assessment for Dementia (DAD) and the Dependence scale [24]; in addition, autopsy of a patient immunized with AN1792 without meningoencephalitis displayed an absence of plaque pathology at autopsy and the presence of Aβ-reactive microglia, indicating that AN1792 was successful at engaging phagocytes to remove plaques [25].
\n
Concerns for safety in active Aβ vaccination trials shifted most development efforts to passive immunotherapy, which carries less risk of an inflammatory response to drug. An overview of clinical Aβ antibody efforts described in the following text is listed in Table 1.
Bapineuzumab, directed at the N-terminus of Aβ, was the first monoclonal antibody therapy developed to target Aβ in AD. It was first tested in a phase I study in AD patients with single ascending doses ranging from 0.5 to 5 mg/kg administered every 13 weeks to evaluate safety, tolerability, and pharmacokinetics (PK) [26]. A significant safety finding of this study was the presence of vasogenic edema (VE) in the highest-dose cohort: 3/10 patients displayed these abnormalities, two of whom were asymptomatic. Due to the observation of VE at 5 mg/kg a dose regimen ranging from 0.15 to 2 mg/kg, administered every 13 weeks for 18 months was selected for the multiple ascending dose phase II trial [27]. In the phase II trial, study completers that received all 6 planned infusions displayed significant improvements in DAD score and the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog), though this effect was not observed in the intent-to-treat population. VE was observed in ~10% of bapineuzumab treated patients (half of whom were asymptomatic), in comparison to 0% of the placebo group; the appearance of VE was dose-dependent and appeared early during the course of treatment. Interestingly, the majority (10/12) of VE cases occurred in carriers of the APOε4 allele, a risk factor for aggressive AD [28].
\n
Two phase III trials for bapineuzumab were completed to evaluate efficacy in patients with mild to moderate AD who were either APOε4 carriers or non-carriers in separate trials, with a lower dose regimen in the carrier trial [29]. These trials did not meet the co-primary cognitive and functional endpoints, though CSF phospho-tau, a proposed biomarker of neurodegeneration in AD, did decrease in both studies and positron emission tomography-Pittsburgh B (PET-PIB) imaging revealed less amyloid pathology in the APOε4 carrier group treated with bapineuzumab compared to placebo. One important finding is that of the subgroup that underwent PET-PIB imaging, 6.5% of APOε4 carriers and 36.1% of non-carriers did not have detectable PET-PIB signal at trial entry, raising concerns about misdiagnosis and improper subject selection in the trials. While these studies did not succeed in meeting primary endpoints, they did provide information to guide future trials, particularly in understanding MRI abnormalities, such as VE and microhemorrhages.
\n
During the course of the phase III trials, the observation that VE and microhemorrhages correlated with anti-amyloid dose levels was more pronounced in APOε4 carriers, and were normally transient and asymptomatic [30] led to the formation of an Alzheimer’s Association-led workgroup composed of industry and academic experts to advise the FDA on potential routes to monitor VE and microhemorrhages. The term amyloid-related imaging abnormalities (ARIA) was adopted to address the spectrum of MR imaging abnormalities observed with anti-amyloid therapies, spanning from sulcal effusion and vasogenic edema seen on FLAIR MRIs to hypointensities (hemosiderin deposits) on T2* MRI. The ARIA terminology was further subdivided to ARIA-E (sulcal effusion and edema) and ARIA-H (hemosiderin deposits) [31]. Recommendations from the workgroup included (a) standardization of technical and monitoring practices for MRI, (b) exclusion from trials of patients with preexisting ARIA-H, and (c) monitoring of symptoms potentially associated with ARIA. The adoption of these standards, and the understanding that ARIA is largely a short-lived treatment related effect inherent to many anti-amyloid therapies, opened the possibility of testing higher and more frequent drug administration regimens with appropriate patient safety monitoring.
\n
In parallel with bapineuzumab, two additional anti-Aβ passive immunotherapies underwent contemporaneous clinical trials: Ponezumab, directed at the C-terminus of Aβ, underwent Phase I and IIa trials, but was discontinued after Phase IIa [32]. Solanezumab, directed at an internal epitope of Aβ and hypothesized to function by binding soluble species in the CNS and periphery, failed a phase III trial in mild AD patients [33], and a trial conducted in prodromal patients was discontinued. However, it is currently being tested in genetically-defined Alzheimer’s disease populations, with results expected in 2021 (clinicaltrials.gov; Identifier: NCT02008357).
Whereas the first generation of Aβ therapeutic mAbs differed in binding to distinct antibody domains (N-, mid-, and C-terminus), the second generation are intended to primarily bind specific conformations and aggregation states. Gantenerumab, currently in two phase III trials for mild and prodromal AD, binds a discontinuous epitope consisting of the N-terminus and an internal epitope, implying a unique conformational binding specificity (clinicaltrials.gov; Identifiers: NCT01224106, NCT02051608) [34]. Crenezumab, currently in phase II and phase III trials for autosomal dominant AD and prodromal-to-mild AD, respectively, is reported to selectively bind soluble and insoluble aggregates, but not monomers (clinicaltrials.gov; Identifiers: NCT01998841, NCT03114657) [35]. In contrast to other therapeutic mAbs, crenezumab is engineered on an IgG4 backbone to reduce effector function, and microglial-mediated phagocytosis of Aβ deposits is not anticipated. BAN-2401, is in clinical development in a large phase II study in early AD patients; is proposed to selectively bind Aβ protofibrils (clinicaltrials.gov; Identifier: NCT01767311) [36].
\n
A promising antibody candidate from this group that is currently in the clinic is aducanumab. Aducanumab is a human mAb that selectively targets soluble aggregates and fibrils, and binds the N-terminus of Aβ. Preclinical studies demonstrate that the chimeric form of aducanumab peripherally administered to an APP transgenic mouse (a) crosses the BBB and binds to plaques (b) reduces calcium overload in neurons [37], and (c) reduces plaque burden in a dose-dependent manner [38]. An interim report from a double-blind, placebo controlled phase Ib study revealed a dose-dependent decrease of amyloid PET signal that corresponded with significant slowing of cognitive decline at 52 weeks at the highest dose level, 10 mg/kg [38]. While ARIA was reported at a similar frequency compared with previous trials, adherence to guidelines formalized by the Alzheimer’s Association ARIA working group [31] allowed for higher and more frequent dosing, potentially contributing to the positive results seen in these early studies. Aducanumab is currently in phase III trials in prodromal early AD patients, with endpoints and patient populations informed by the successful phase Ib study [39]. Interestingly, enrollment for these phase III clinical trials was recently increased by approximately 15% due to patient variability in the primary functional endpoint [40].
\n
\n
\n
\n
\n
3. Tau
\n
While most passive immunotherapy clinical trials in AD have been directed at Aβ, key discoveries regarding tau function and contribution to disease mechanisms have prompted significant efforts directed towards tau. Hyperphosphorylated and aggregated tau protein are the main component of neurofibrillary tangles (NFTs), which, together with Abeta plaques, are considered a primary hallmark in Alzheimer’s disease. Because of its intracellular localization, tau deposits have historically been thought to be unavailable to immunotherapeutic treatments. However, results outlined in this section indicate the potential for targeting tau through a passive immunotherapeutic approach.
\n
\n
3.1. Tau biology and pathophysiology
\n
Since the discovery that NFTs are composed of the microtubule-associated protein tau [43, 44, 45], many efforts have been devoted to elucidating molecular mechanisms of tau pathophysiology. Tau is an intracellular microtubule binding protein, which is involved in the regulation of microtubule stability and dynamics. In the brain, tau exists principally as six different isoforms, which vary in the absence or presence of N-terminal acidic repeats and a microtubule repeat; these differences are due to the splicing in or out of exons 2, 3, and 10 [46]. In normal physiological situations, the specific ratio of tau isoforms is developmentally regulated, likely due to the changing needs of microtubule fluidity versus stability throughout development and maturity [47].
\n
Tau is an intrinsically disordered, natively-unfolded protein [48] whose physiological function is tightly regulated by post-translational modifications—principally via phosphorylation, which regulates microtubule binding affinity [49, 50]. In the AD brain, tau aggregates to form hyperphosphorylated NFTs and inclusions, composed of paired-helical and straight filaments [51]. In contrast to the intrinsically disordered nature of monomeric tau in solution, these structures adopt an ordered structure composed of a β-sheet core comprised of central residues, surrounded by a disordered coat comprised of the C- and N-termini of the molecule [52]. In AD, the appearance of tau pathological features positively correlates with dementia and disease progression [53, 54], leading to the hypothesis that the formation of tau pathology is a primary causative agent in the development of AD.
\n
While the stereotypic appearance and progression of tau pathology down the perforant pathway—the neurocircuit from the entorhinal cortex to the hippocampus—has been described [55, 56], the molecular mechanisms underpinning this observation had remained elusive. Neurons in the performant path have long been known to be selectively vulnerable to insult such as hyperactivity [57] and expression of AD-related presenilin mutations [58], but the discovery that, when injected into the brain parenchyma, tau from a mutant mouse could simulate the formation of tau aggregates in a previously healthy animal [59] allowed the possibility that this progression may be mediated by aggregated and misfolded forms of the protein. This was strikingly confirmed in mice with tau expression restricted to the entorhinal cortex: in these mice, tau pathology propagated from the region of expression to distant efferent neurons [60, 61], demonstrating that direct cell-cell contact was not required for propagation, and that the pathological signal could be spread trans-synaptically. The demonstration that tau itself was present in interstitial fluid [62], could be secreted from neurons [63], and passed between cells [64] and neurons [65] provided evidence that tau species themselves could be directly transmitted between neurons in vivo, providing a potential mechanistic basis for the propagation of tau pathology. Although tau and Aβ are likely associated with different pathophysiological processes in Alzheimer’s disease, the presence of pathogenic extracellular tau species could theoretically also be targeted by immunotherapeutic approaches, in this case by a different mechanism of action: interception/sequestration and prevention of cell-to-cell transmission.
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\n
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3.2. Tau passive immunotherapy
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An overview of preclinical and clinical tau antibody efforts described in the following text is listed in Table 2.
Tau clinical and preclinical antibodies discussed in this chapter.
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Pioneering tau immunotherapy studies demonstrated that immunization with phospho-tau peptides (phosphorylated at Ser396/404) in two different tau transgenic lines raised anti-tau antibodies, which immunohistochemically stained the brains of P301L-tau transgenic mice. In addition, active immunization resulted in reductions in tau pathology. The mice also displayed improved performance in motor tasks [66, 67]. Purified anti-tau antibodies from immunized mice were peripherally injected into naïve transgenic mice and localized to neurons in the brain displaying tau pathology, demonstrating their ability to cross the blood-brain barrier (BBB) and localize to their target. In a separate study performed by the same lab, passive administration of the mAb PHF1, directed at the Ser396/404 phosphoepitope, also resulted in reductions in tau pathology in mice compared to isotype control [68]. The findings from this series of studies were proposed to be due to two potential mechanisms: (a) antibody-mediated clearance of extracellular tau deposits and (b) intracellular uptake of tau antibodies. The efficacy of passive immunotherapy using PHF1, as well as the conformational antibody MC1, were also confirmed in independent labs [69, 70], bolstering early evidence of this novel promising therapeutic avenue.
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An antibody targeting a different phosphoepitope, pSer409, also shows promise in preclinical models; however, conclusions regarding the mechanism of antibody function were considerably different than those proposed in the initial active and passive studies described in the prior paragraph. In this study, a highly selective mAb was able to bind tau phosphorylated at Ser409 and specifically bind AD brain tissue. The mAb was shown to neutralize oligomer-induced neurotoxicity; however, the neutralization activity of the antibody was reduced in mixed neuron-microglial cultures. Antibody engineered with reduced effector function (REF) maintained neutralization activity in mixed neuron-microglial cultures, while the wild-type anti-pSer409 antibody did not prevent neurotoxicity and in fact promoted the release of pro-inflammatory cytokines from microglia [71]. Both wild-type and REF variants of the antibody prevented the progression of tau pathology in the tau P301L mouse, leading the authors to conclude that phagocytic clearance of tau structures was not a contributing mechanism of action to efficacy in the transgenic mouse model. In addition, the lack of FcR message found in isolated neurons prompted the conclusion that receptor-mediated uptake did not occur. The antibody examined in this report has been developed into a therapeutic candidate, which is currently in clinical development (clinicaltrials.gov; Identifier: NCT03289143).
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Additional studies have been conducted to identify and target post-translationally modified forms of tau to explore effects of antibody treatment. One compelling approach targets a unique structural isoform of tau induced by phosphorylation of tau at T231. Phosphorylation of tau at T231 occurs during disease progression; the prolyl isomerase Pin1 normally binds and converts the pT231/Proline motif from a toxic cis form to a soluble nontoxic trans form [72]. A mAb targeting cis but not trans pT231-tau detects pathology during mild cognitive impairment (MCI) [73]. In addition to AD, this post-translational signature (as well as others) appears in the brains of traumatic brain injury (TBI) patients. When administered peripherally in a murine TBI model carried out in tau transgenic mice, the cis-pT231 tau antibody prevented the spread of tauopathy and cortical LTP deficits, and improved performance in the elevated plus maze, which was correlated to TBI-induced disinhibition behavior in patients [74]. Another effort targeting disease-specific forms of tau is centered around developing antibodies that bind soluble oligomeric tau—hypothesized to be the most toxic form of the molecule [75]—and have minimal binding to monomeric or mature NFTs [76]. Tau oligomer-specific monoclonal antibodies (TOMAs) were dosed via intracerebroventricular (i.c.v.) infusion to tau P301L mice. Strikingly, a single i.c.v. injection reduced tau oligomers and histopathology, and rescued deficits in rotarod and spontaneous alternation tests. Examination of serum revealed oligomeric tau and antibody/antigen complexes, suggesting peripheral clearance as a mechanism of action [77].
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Informed by studies indicating the potential for the propagation of tau pathology across cell membranes [64], as well as the demonstration of trans-synaptic transmission in vivo [60, 78], an independent effort to discover tau antibodies that interrupted cell-to-cell transmission yielded phosphorylation-independent antibodies that blocked uptake of tau aggregates to cultured cells [79, 80]. When administered to tau transgenic mice centrally via an Alzet minipump, these antibodies slowed the advance of tau pathology, as measured by immunohistochemical and biochemical means [79]. One of the efficacious antibodies used in this report, HJ8.5, was used in a peripheral administration model to further explore its potential as a therapeutic agent [81]. HJ8.5 is a high affinity anti-N terminal mAb that recognizes residues 25–30, which are present on all splice isoforms of tau. In this study, P301S tau transgenic mice were dosed intraperitoneally over a 3-month period with 10 or 50 mg/kg of HJ8.5. The high dose cohort displayed decreases of insoluble tau, AT8 staining, and thioflavin S staining. In addition, this cohort exhibited improvements in sensorimotor function compared to isotype control and low-dose cohorts. The preclinical efficacy profile, as well as the concordance of in vivo data with mechanistic in vitro studies, propelled the humanized analogue of this antibody into the clinic (clinicaltrials.gov; Identifier: NCT03391765) [82]. Interestingly, a separate effort focused on discovering antibodies and epitopes important for uptake and transmission determined that while N-terminal antibodies could indeed block uptake of recombinant and AD patient-derived tau, there were other epitopes with potentially more potent function, notably antibodies binding C-terminal to the acidic inserts [83].
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A key component of the amyloid cascade hypothesis is that Aβ aggregation induces, either indirectly or directly, fibrillization of tau as well as other disease processes (reviewed in [84]). The finding that extracellular secreted and truncated forms of tau (termed eTau) could regulate Aβ levels demonstrated a potential upstream role of tau in relation to Aβ, complementary to the amyloid cascade hypothesis. In this study, secreted eTau was isolated from iPSC neurons derived from patients with AD; treatment of neurons with eTau displayed increases in secreted Aβ, and these increases could be prevented via application of eTau-binding antibodies such as MC1 and IPN002, which recognizes residues 17–28. Aβ levels were not affected by PHF1 antibody, as the PHF1 epitope is not present in eTau. This finding was recapitulated in transgenic P301L-tau mice; peripheral treatment with IPN002 resulted in reductions in Aβ in the interstitial fluid and cortical tissue [85]. These findings were recently confirmed by a different group using mAbs that target very similar N-terminal tau epitopes; in these studies, behavioral improvements as well as decreases in Aβ were noted in mice transgenic for mutant forms of presenilin, APP, and tau [86, 87]. IPN002 has been developed into a clinical therapeutic and is undergoing clinical trials as BIIB-092/BMS986168 (clinicaltrials.gov; Identifier: NCT03068468) [88].
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Though the success of preclinical studies with tau antibodies has provided sufficient rationale to begin exploration in the clinic, a greater understanding of the full range of factors involved in tau toxicity and the mechanisms of action of tau passive immunotherapy are needed. These mechanisms may be different than those proposed for Aβ immunotherapy. There remain conflicting details from the studies presented here, such as the relative contribution of microglial-mediated phagocytosis, the relative importance of eTau-mediated Aβ production, the extent of trans-synaptic transmission in transgenic mice with widespread expression in the brain, and the optimal epitope to target. Gaining a clearer understanding of these factors continues are a current research focus.
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Clinical trials with Aβ immunotherapies have demonstrated the importance of proper clinical diagnosis, patient selection, sensitive cognition tests, and effective biomarkers to monitor efficacy and disease progression. Though some general commonalities may exist in the clinical design of Aβ and tau passive immunotherapy trials, there are substantial differences in the targets and any potential clinical development approaches. In contrast to Aβ, there are a number of non-AD tauopathies such as progressive supranuclear palsy (PSP) [89] and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [90] that may provide alternative clinical development pathways to test novel tau-directed therapeutic approaches. In contrast to AD, these diseases present pathological signatures composed almost uniformly of tau and neurofibrillary tangles; in addition, FTDP-17 is an autosomal dominant disorder, genetically validating the causative role of tau. Diagnosis of these and other tauopathies have historically been made solely based on clinicopathology; due to the difficulty of diagnosis from to the overlap of symptomologies with other neurodegenerative disorders, as well as the lack of clear biomarkers, diagnosis is only confirmed at autopsy [91]. Modern tau PET imaging agents are currently under clinical investigation [92]; while early generations of tau PET tracers displayed nonspecificity and suboptimal binding and PK characteristics, the newest class of tracers display improved specificity, PK properties, and may allow for improved diagnosis in tauopathies as well as an ability to monitor tau pathology in AD clinical trials [93].
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4. New targets and technologies
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4.1. Targeting the immune system in AD
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The vast majority of passive immunotherapeutic approaches in AD have targeted Aβ and tau; this is a natural outcome of the primacy of these proteins as the principal pathological hallmarks of the disease. The association of mutations of APP (and proteins that modulate its generation, such as presenilin-1) to familial AD, and the high degree of correlation between tau pathological development and cognition, strengthen the validity of these two proteins as important causative disease agents. However, new approaches, primarily targeting immunomodulatory proteins, are also currently under development.
\n
The presence of neuroinflammatory processes and signatures in AD has been well established, but the exact role they play in disease etiology, or whether neuroinflammation has a primarily protective or harmful role, has not been clear (reviewed in [94]). Studies examining the complement cascade have helped to understand this duality. The synaptic pruning activity carried out by microglia is regulated by complement [95]. The initiating protein of the classical complement cascade, C1q, is enriched in the developing mouse CNS and localizes to synapses; genetic ablation of this protein results in misregulated innervation due to increased presence of synapses [96]. While C1q is normally downregulated after development, it is elevated in normal aging [97] and disease, including AD [98]. In a transgenic APP mouse, C1q localizes to synapses, and is required for pathological synapse loss. Treatment of C1q knockout mice with oligomeric Aβ displayed no synaptic loss, indicating that C1q is a required mediator of Aβ-induced toxicity. Interestingly, an anti-C1q antibody rescued Aβ-induced synaptotoxicity in vivo, and LTP impairment in situ, when compared to isotype control [99]. These data hinted at the promise of C1q immunotherapy to provide protective benefits by neutralizing a key mediator of Aβ-induced microglial overactivation, which results in synaptic loss. The anti-C1q antibody used in this study has been developed into a human therapeutic, and is beginning clinical trials (clinicaltrials.gov; Identifier: NCT03010046) [100].
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The mounting evidence of involvement of the adaptive immune system in restraining the advance of AD pathology has opened the possibility of directing passive immunotherapies to the periphery, which considerably eases the challenge of achieving sufficient drug exposure in the CNS to affect pathology. Microglia resident in the brain are known to be recruited to sites of injury such as senile plaques, but the finding that peripherally-derived bone marrow stem cells are able to enter the CNS, and differentiate into microglia [101, 102], was the first direct evidence that repopulation and recruitment of microglia from the periphery was an active process. This finding was extended to AD mouse models with the finding that peripherally-recruited microglia are mobilized by Aβ, recruited to the site of senile plaques, and are able to clear plaques via phagocytosis [103]. The protective role of these immune cells in the presence of AD-like pathology was confirmed with the observation that (a) knocking out the chemokine receptor CCR2 in an APP-transgenic mouse resulted in decreased recruitment of monocytes to Aβ plaques [104], and (b) the specific ablation of bone-marrow derived cells via diphtheria-toxin receptor expression resulted in increased Aβ plaques [105]. Furthermore, increasing trafficking of macrophages by inhibiting the normally immunosuppressive regulatory T-cells through pharmacologic or genetic methods results in reduced Aβ pathology [106].
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Elucidation of the biology of inhibitory signaling pathways and proteins such as Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), known as immune checkpoints, led to the development of antibody therapeutics for use in cancer (reviewed in [107]). These therapies function by neutralizing immune checkpoints and activating T-cells, which prompts antitumor activity. The characterization of checkpoint signaling pathways, along with the findings that peripheral immune cells modulate AD-like pathology in a regulatory T-cell (Treg)-dependent manner, has prompted examination of the PD1/PD-L1 axis in AD. In a recent study, AD transgenic mice were treated with an anti-PD1 antibody to blockade the PD1/PD-L1 axis. Remarkably, checkpoint blockade in this model resulted in substantial rescue of performance in a behavioral assay of memory and cognition after a single dose, and mice exhibited decreases in Aβ pathology with only two dose administrations [108]. The effect on pathology was observed even in mice with profound amyloid burden. While the findings of a profound effect on functional measures after such a short dose regimen are very exciting, they should be taken with a note of caution. A follow-up study, carried out by three pharmaceutical companies using three transgenic models and numerous PD-L1 antibodies was attempted to recapitulate these results. Despite peripheral immune activation, in all instances neither reductions in Aβ pathology nor infiltration of peripheral monocytes were detected [109]. Further studies are needed to elucidate the potential of checkpoint modulation.
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4.2. Increasing blood-brain barrier (BBB) penetrance for passive immunotherapeutics
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A significant barrier in the development of passive immunotherapeutics for AD is the low percentage of circulating antibody that crosses the BBB. Animal studies have indicated that ~0.1–0.5% of IgG enters the CSF from the periphery [110, 111], which is borne out by preclinical [112] and clinical [113, 114] data obtained with antibodies tested for use in AD. This has led to trials with increasing amounts of antibody administered to patients ([82]; clinicaltrials.gov, Identifier NCT03318523) with the hope of delivering sufficient amounts of antibody to the CNS to achieve a clinical effect. There are, however, indications that concentrations of antibodies are higher in brain parenchyma than what is present in CSF. The chimeric form of aducanumab reported brain:plasma AUC ratios when tested in a transgenic APP model of 1.3% [38]. This is in agreement with the finding that the concentration of protein analyte present in the interstitial fluid is approximately 10-fold higher than in the ISF [62, 115]. This could be due to the rapid turnover of CSF volume [116] compared to ISF, longer elimination times of antibodies in brain parenchyma compared with CSF, or increased residence time due to target-mediated binding. Nevertheless, methods and technologies to increase BBB penetrance of biomolecules urgently need to be applied to antibodies and other proteins.
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One of the more promising approaches to increase penetrance of protein therapeutics into the brain utilize endogenous receptors that transcytose between the brain and periphery, such as transferrin receptor (TfR) [117], insulin receptor [118], and LDL receptor-related protein 1 (LRP1) [119]. Protein engineering approaches feature fusion of the therapeutic molecule to proteins, ligands, or peptides that bind these receptors and facilitate transcytosis across the BBB (reviewed in [120]). One of the best understood receptor-mediated delivery systems is the use of TfR, though a similar path has been taken in the development of technologies that utilize insulin receptor. Increased brain uptake of transferrin/antibody fusion proteins were detected in rats [121], though the relatively large size (~80 kDa) of full-length transferrin make this impractical for biotherapeutic use. The detection of increased transcytosis of anti-TfR antibodies and antibody fragments [122, 123], and later advances in antibody generation technologies, enabled bispecific antibodies that bind TfR as well as target [124]. As understanding of the transcytotic properties of TfR binding moieties have increased, so has the understanding of how best to incorporate properties to ensure delivery to the brain. For example, reducing TfR affinity improves delivery, as a low affinity anti-TfR moiety will release from the receptor faster than a high affinity moiety [124]. As receptor-binding fusions enter the clinic, further questions regarding safety and distribution changes brought about by higher CNS concentrations will need to be continually addressed [125, 126]. Work continues to identify receptors that may be useful for increasing BBB concentrations of antibodies to allow engagement with wider range of drug targets [127, 128].
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5. Conclusions and future perspectives
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AD provides a monumentally challenging drug development landscape. The uncertainty about disease etiology, variability in patient genetics and disease progression, and difficulties in early diagnosis are all but a noncomprehensive list of hurdles to developing effective drugs. Though development of therapeutics to slow or halt AD disease progression, including passive immunotherapeutics, have not yet yielded clinical benefit, the prospect of applying lessons learned in the clinic towards validated targets such as Aβ and tau provides optimism for future success. In addition, our understanding of the mechanisms of other principal contributing factors to disease progression will provide a variety of new targets to explore. Combined with advances in drug technology to increase the availability of biomolecules in the CNS, these clinical and biological advances offer great promise around future success in treating AD.
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Acknowledgments
\n
There is a wealth of excellent studies in the areas of study covered by this chapter—unfortunately, we were unable to list them all. We thank the many researchers not recognized here who have contributed greatly to the field. We would also like to thank the thoughtful review and comments provided by Enchi Liu and Ellen Rose.
\n
Conflict of interest
PJD and WZ are employees of Prothena Biosciences.
\n',keywords:"amyloid-β, tau, passive, immunotherapy, Alzheimer’s disease",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60332.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60332.xml",downloadPdfUrl:"/chapter/pdf-download/60332",previewPdfUrl:"/chapter/pdf-preview/60332",totalDownloads:1103,totalViews:240,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:50,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"November 6th 2017",dateReviewed:"March 7th 2018",datePrePublished:null,datePublished:"July 18th 2018",dateFinished:"March 29th 2018",readingETA:"0",abstract:"The development of therapeutics for the treatment of Alzheimer’s disease (AD) has been challenged with a myriad of obstacles: an evolving and incomplete understanding of disease etiology and progression, challenges with early diagnosis, multifactorial genetic and environmental factors that contribute to patient variability, and the cost of conducting lengthy clinical trials. One approach that has garnered a significant amount of attention and resources for its potential as a disease modifying approach is passive immunotherapy directed at clearing amyloid-β (Aβ) species, a pathological hallmark of Alzheimer’s disease. While passive immunotherapeutic trials directed at Aβ have not yet demonstrated clinical benefit, they have prompted important advances in the application and understanding of biomarkers, patient selection, novel functional readouts, and safety monitoring. Application of these lessons has enabled more recent clinical trials to incorporate better trial designs and refine inclusion criteria to optimize patient population enrollment. In addition, new passive immunotherapy targets emerging in the clinic have emerged, as well as novel technologies to enhance future antibody therapeutics. Taken together, the advances in research and clinical science have prepared the passive immunotherapy field to advance emerging promising disease modifying treatments in AD.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60332",risUrl:"/chapter/ris/60332",book:{id:"6614",slug:"alzheimer-s-disease-the-21st-century-challenge"},signatures:"Philip J. Dolan and Wagner Zago",authors:[{id:"232660",title:"Ph.D.",name:"Philip",middleName:null,surname:"Dolan",fullName:"Philip Dolan",slug:"philip-dolan",email:"pdolan@prothena.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"232661",title:"Dr.",name:"Wagner",middleName:null,surname:"Zago",fullName:"Wagner Zago",slug:"wagner-zago",email:"wzago@prothena.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Aβ",level:"1"},{id:"sec_2_2",title:"2.1. Mechanisms of Aβ pathophysiology",level:"2"},{id:"sec_3_2",title:"2.2. Aβ passive immunotherapy in the clinic",level:"2"},{id:"sec_3_3",title:"2.2.1. First-generation Aβ passive immunotherapies",level:"3"},{id:"sec_4_3",title:"2.2.2. Second-generation Aβ passive immunotherapies",level:"3"},{id:"sec_7",title:"3. Tau",level:"1"},{id:"sec_7_2",title:"3.1. Tau biology and pathophysiology",level:"2"},{id:"sec_8_2",title:"3.2. Tau passive immunotherapy",level:"2"},{id:"sec_10",title:"4. New targets and technologies",level:"1"},{id:"sec_10_2",title:"4.1. Targeting the immune system in AD",level:"2"},{id:"sec_11_2",title:"4.2. Increasing blood-brain barrier (BBB) penetrance for passive immunotherapeutics",level:"2"},{id:"sec_13",title:"5. Conclusions and future perspectives",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"},{id:"sec_17",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Group GBDNDC. 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Prothena Biosciences, South San Francisco, CA, USA
Prothena Biosciences, South San Francisco, CA, USA
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1. Introduction
A pandemic presents a special kind of health crisis that requires “collective responsibility” together with changes in communication techniques ([1], p. 515). Previous research has confirmed that communication during a health crisis is crucial [2] in order to create awareness for the existence of a health threat [3, 4]. Hence, health risk messages disseminated during the crisis should be both instructing and adjusting, informing the public of which precautionary measures to take to reduce physical harm and the virus from spreading, while also providing individuals with guidance as to how to deal with the psychological threats of the crisis [5].
In the event of a pandemic, the government becomes a key actor in managing the (health) crisis [6, 7]. Conditioned by high degrees of trust, messages distributed on part of the government can drive the general population to comply with its recommended actions [8, 9, 10, 11]. This is the case, since health messages for which the government is the identified source are perceived as both credible and relevant [7, 12], for individuals are convinced that the government can control the crisis [13]. This is in line with previous research, which suggests that controllability and responsibility for the health threat influence the public’s risk perceptions and, consequently, responses to these risks [14].
The primary aim of this chapter is to present some guidelines for effective health risk message design, drawing input from established crisis communication literature in general and some recent studies on COVID-19 risk communication in particular. To this end, recommendations regarding message presentation and design will be presented, before limitations and directions for future research are addressed.
2. Communicating during a health crises
Pandemics qualify as a form of health crisis [1]. As crises present situations for which individuals are neither prepared nor possess knowledge of how to deal with the uncertain circumstances [15], they actively seek support and guidance [16, 17]. In order to mobilize the affected public as a partner [18, 19], individuals’ need for information must be satisfied. Useful information is usually based on scientific facts. Following the Office and Science and Technology [20], science communication comprises all communication activities between different stakeholder groups, and, as in the case of a health crisis, takes place between “the government and the public”. In line with Burns et al. [21], one of the many objectives of science communication is to raise awareness for and create familiarity with new aspects of science. Consisting of three separate processes – i.e. communication, consultation and participation [22] – science communication needs to be designed strategically to fill existing (knowledge) gaps and present information in an appealing manner [23]. Only this way, the public’s understanding of science can be assured [21]1.
Media messages afford individuals with instruction and, thus, present respondents’ primary sources of information in crises [26, 27, 28]. Message credibility and trust is elevated, if the government is the identified source [12, 29], highlighting its central role in the crisis management process [6, 7]. On the one hand, it can help sensitize people for the risks associated with the crisis and, on the other hand, encourage them to adopt preventive measures [30]. For this reason, governmental officials are advised to invest in “well-coordinated health communications” to assist individuals in managing their daily lives in times of upheaval [31]. Previous studies have investigated how the public responds to a government’s overall health risk communication, for instance during the avian influenza [12], SARS [32], or Ebola [33]. Findings confirm that the government is perceived to be in the position to mitigate potential health risks [13].
In the event of a crisis, governments are advised to engage in intensified communication [9, 10]. In order to build community trust and engagement, communication must be open and transparent, as well as scientifically based in order to facilitate the public’s preparedness to deal with the health threat [9, 16, 34]. This call seems to be expressive of recent social developments towards a knowledge or information society [35]. Thereby, knowledge (re)production centers on documented scientific knowledge (e.g., scientific findings), which no longer solely has its origin in natural sciences but is also based on social sciences [29]. Moreover, this kind of knowledge is increasingly discussed in the media. While science communication is concerned with raising awareness for and creating familiarity with new aspects of science (as part of a “Public Understanding of Science” and “Public Awareness of Science”, [24, 25]), messages disseminated during any (health) crisis need to be designed strategically to present information in an appealing manner in order to draw respondents to (scientific) message content [21].
3. Health campaigns in crisis situations
Effective risk communication is a requirement in case of health emergencies and crises [2] and can assist the public in managing the crisis [36]. Health crises, including epidemics and pandemics, do not present an exception to this trend. For this reason, governments throughout the world heavily depend on health campaigns, described as “a systematic effort to change health behaviors (or attitudes and beliefs about health and/or social and environmental conditions that mediate health behaviors) within a target population of people who are at risk for a health problem or problems” [37]. Health messages by the government are also known as Public Service Announcements (PSAs, [38]). Contrary to traditional advertising messages, these materials set out to change individual behaviors. For this reason, they have been commonly used in health crises [39].
With PSAs appealing to individuals to change their behaviors and instructing them on how to achieve these proposed behavioral changes, they are in line with health campaigns’ three communicative objectives: awareness, instruction or persuasion [37, 40]. In case of a health crisis, health campaigns primarily intend to raise awareness for the severity of the threat amongst the affected population and offer instruction to individuals on how to utilize self-protective measures [41, 42]. As such, PSAs appeal to individuals’ self-efficacy [16, 43, 44]. For instance, health messages spread during the H1N1 influenza emphasized the need to take up hygiene measures, such as “hand washing, sanitizer use, covering of coughs and sneezes, and staying at home” ([16]: p. 5). Similar message content was also employed as part of national COVID-19 health campaigns.
Albeit different campaign themes exist, amongst them community building [16], messages typically center on risk reduction strategies [5, 30]. Particularly during health emergencies, information on which preventive measures should be taken is valuable [45]. These measures, for instance, could be nonpharmaceutical interventions (NPIs), which are nation-wide actions proposed by the government to resolve the health crisis [31]. NPIs are useful in controlling the pandemic and are, thus, often labeled “community mitigation strategies”. With measures often concerning “disruptive actions” ([44], p. S2), individuals are forced to reconfigure their daily lives and routines [46]. For this reason, health risk messages must be carefully designed to prevent controversial arguments and negative emotions from surfacing [19, 47, 48].
Campaigns advocating NPIs rely on media messages to reach diverse publics in crisis situations [49]. While an increasing amount of research is available on how health messages are used to create awareness amongst the population during risk situations [33, 50, 51, 52, 53]. In this chapter we review articles pertaining to health risk message design and focus on the special case of pandemics and emerging infectious diseases [8].
4. Method
The purpose of this paper is to present the cumulated results of an excessive literature review, looking at propositions for and examples of health risk messages disseminated during previous epidemics and pandemics, as well as during COVID-19. Hence, this review will only include articles from the field of risk communication and health communication which were released between 2000 and 2020, even though parallels to messages addressing ongoing pandemics, such as HIV/AIDS and Cholera, can be found.
We used keywords such as risk, health risk, risk communication, health communication, epidemic, pandemic and a combination thereof to compose our sample. With this scope in mind, we conducted a search using national library databases. We covered the major journals in strategic communication, risk communication, and health communication, such as The Journal of Risk Research, Environmental Research, The Journal of Business Research, The Journal of Public Relations Research, Public Relations Review, The European Journal of Communication, Public Health, Health Communication, The Journal of Health Communication, Health Education and Behavior, The Journal of Allergy and Clinical Immunology, The Journal of Communication in Healthcare, The Journal of Health Management, The American Journal of Public Health, The Journal of Urban Health and Public Understanding of Science. From these sources, we limited our selection to articles dealing with any type of health crisis, including Zika, Ebola, H1N1, the avian influenza and COVID-19. We screened them to a list of 115 pertinent references on health risk communication and message design, which constituted our sample.
With the above considerations we have now summed up some recommendations for designing health risk messages. For government officials, it is now of great interest to learn more about how health risk messages can be designed to benefit not only their own agenda, but also whole populations affected by crisis situations. After reviewing relevant (and recent) literature, it becomes obvious that scholars have devoted their research to studying communication during crisis situations in detail. In the following, several recommendations for designing and drafting health risk messages will be presented.
5. Recommendations for designing health risk messages
5.1 Be open and transparent
The availability of timely and transparent information allows the public to derive at a realistic assessment of the health threat [3, 4, 54]. Building on previous research, messages disseminated in times of disruption should “[e]mphasize the rationale and importance of adherence to public health measures that some people may consider intrusive (e.g., quarantine)” (US Department of Health and Human Services 2008). Providing a solid reasoning is seen as paramount, given that in recent years, individuals trust in the validity of scientific findings has decreased considerably [55]. Hence, PSAs must address the necessity for specific crisis mitigation strategies and actions.
5.2 Focus on relevant message content
Experts have determined that ensuring public access to information – and thus engaging in a process of constant communication – is seen as essential in crisis situations [56]. Thereby, different forms of information need to be distinguished: instructing information, preventive information, and reactive information [57]. Instructing information covers three areas: information on the pandemic, the public’s primary needs, and precautionary measures [57]. Through preventive information, public opinion regarding the crisis is sensitized, whilst through reactive information, the affected population is informed about the crisis progression, and a potential panic and the spread of rumors can be prevented [1]. For instance, public health campaigns in Austria, Australia and the U.S. (New York) highlighted the necessity to either stay at home, socially distance or wear masks. For instance, the example inFigure 1emphasizes the necessity to cut back on visits from grandparents or social distancing.
Figure 1.
Austrian PSAs advising grandparents to refrain from visiting their grandchildren (left) and social distancing (right). (Source: https://www.bmkoes.gv.at/).
5.3 Present information consistently and “straight to the point”
In the process of encouraging individuals to follow the proposed preventive actions [58, 59, 60], information should be presented in a straight-forward manner [16] and in “one voice”. Moreover, messages should use simple language [61], and be consistent in terms of message content, as inconsistency can lead to confusion and undesired health outcomes: “A well-crafted national message [has] the potential to build unity around the goal of defeating the virus through behavior change, preferably with clear, unambiguous recommendations of what actions to take” ([61], 1736). For example, when the crisis first surfaced, the Austrian government stressed the importance of staying home; after the first lockdown, when social distancing was in order, the campaign commonly referenced the baby elephant as a metaphor to remind individuals to keep their distance (of 1.5 m; seeFigure 2).
Figure 2.
Austrian PSAs featuring the baby elephant. (Source: https://www.bmkoes.gv.at/).
5.4 Appeal to individuals’ self-efficacy
According to Fishbein and Ajzen [62], effective communication should stress which behaviors have to be changed, further providing the public with clear instruction as to how this change can be obtained [3]. Therefore, message should appeal to individuals’ self-efficacy [63, 64]. Self-efficacy is activated if identification with message content is high [43, 44]. Clear communication can boost individual self-efficacy and help mitigate the risks associated with the health threat [61]. If individuals feel empowered, this can then improve the relationship between the public and the government lastingly [10]. Governments throughout the world familiarized individuals with how they could contribute to preventing the virus from spreading, e.g. through personal hygiene, reducing their social contacts, or self-isolating. Examples of Australian campaign resources are presented inFigure 3.
Figure 3.
Australian PSAs presenting risk mitigation strategies. (Source: https://www.health.gov.au/resources/).
5.5 Align message content with social norms
As individual behavior is influenced by social norms, i.e. how people in one’s immediate environment react [65], health communication messages should promote these norms [29, 39], which can induce behavioral change. Besides the relevance of collective norms2 [67], norms that require personal investment (e.g., social distancing, personal hygiene) are presumed to predict behavioral intentions even more strongly [68]. Apart from stressing individual benefits, governments also highlighted how individual actions would contribute to the overall social good (e.g., “Let’s be COVIDSAFE together” in Australia or “Because your mask doesn’t protect you. It protects me” as part of the Mask Up America Campaign; seeFigure 4).
Figure 4.
Prosocial Appeal as part of #MaskUpAmerica. (Source: https://www.idsociety.org/public-health/covid-19/)
5.6 Use prosocial appeals
The risks associated with any crisis have been renowned to elicit negative emotions in individuals [69], further influencing their risk perceptions [70, 71, 72]. Therefore, the negative emotions associated with the pandemic should be counterbalanced with positive emotional appeals [29, 73]. This, for instance, can be achieved through “prosocial motivation” or a collective orientation, in the course of which the positive impact of a certain behavior on the community elicits hope in recipients [74, 75]. Likewise, higher intentions to comply with proposed behaviors can be achieved if prosocial appeals are used [76]. In addition to the examples mentioned above, also the Austrian and German government emphasized the need for collective action (e.g. Austria’s Schau auf Dich, Schauf auf Mich campaign and Germany’s #besonderehelden video campaign; seeFigure 5).
Figure 5.
Austrian PSAs emphasizing prosocial and collective action, such as staying at home if feeling unwell (left) and shopping for at risk groups (right). (Source: https://www.bmkoes.gv.at/).
5.7 Emphasize the necessity of proposed measures
Besides stressing the necessity for engaging in selected NPIs, messages also must point out why it is essential to do so [3, 77]. This builds upon previous research, which has demonstrated that increased efficacy levels are reliable in predicting individual behavior [78]. One potential way, for instance, could be to increase the perceived relevance of message content or the similarity to the source, which have proven successful in mitigating negative message consequences [79, 80, 81], e.g., the spread of the virus.
5.8 Evoke positive emotions
Individuals’ risk perceptions usually incorporate emotional aspects [53] that have been found to drive individuals to take up protective behaviors in crisis situations [82, 83, 84]. Hence, the use of (positive) emotion has been found to be conducive to behavioral change [85], also in times of crisis, where emotions have been found to drive (health) risk message reception, e.g., by impacting individuals’ willingness and motivation to take up precautionary measures (e.g., [86, 87, 88, 89]). Positive emotions can be evoked, for instance, by presenting individuals as heroes, as it is the case in both the German public health campaign and the New York #maskupamerica campaign (seeFigure 6).
While some audiences seek out facts and scientific information, others are more drawn to emotional and personalized message content [37]. Thereby, message appeals describe promotional cues that are used to drive both recipients’ interest and attention [90]. While informative appeals utilize rational arguments in a matter-of-fact presentation [91], emotional appeals, on the other hand, are based on images or videos to facilitate comprehension amongst message recipients [92]. Emotional appeals allow organizations to gain support from the affected public in times of crisis [93, 94, 95], and researchers have identified a number of advantages associated with the use of an emotional message presentation, such as an increased “attention to messages, recall, positive attitudes, and compliance to recommended behaviors” ([37]: p. 249). In this context, stories or personal recounts are recommended, and have been employed in numerous countries, such as Austria, the U.S. and Germany.
5.10 Employ strong visuals
Health risk communication’s reliance on an emotional (visual) presentation might stem from the fact that visuals drive risk perceptions more than factual information [96, 97]. In case of strong emotional reactions, individuals’ likelihood to ignore factual information is increased [98, 99]. Therefore, the use of pictures is recommended and can increase the likelihood of a message receiving fixation [100]. For example, the Austrian government decided to feature individuals in their domestic environments when encouraging them to stay at home (seeFigure 7).
Figure 7.
Austrian PSAs featuring individuals in their domestic settings. (Source: https://www.governor.ny.gov/).
5.11 Create Identification
As pandemics evoke negative emotional responses – first and foremost, fear [29] - that affect whole populations, crisis communication itself should not only center on people [101] but also familiarize them with proper behavior, e.g., by featuring role models [102, 103]. If identification is high, people are driven into compliance, which can positively effect crisis management [104, 105]. Governments have featured a number of role models in their campaigns, including health-care workers (U.S.), or celebrities (as narrators in the U.S.).
5.12 Feature community members
Besides medical experts or celebrities [39], a number of studies has highlighted the importance of featuring nonpolitical sources, whose statements are perceived as credible and trustworthy [77, 106, 107]. For instance, people have been found to easily relate to individuals who are similar to them (i.e. “community ambassadors”; [16]). Previous research has been able to demonstrate that similarity with the testimonial featured in a promotional or risk message can be a useful tool to increase message effectiveness [108, 109], as well as message credibility and acceptance [110]. As community members resemble real people, individuals are also more likely to follow their lead and take up proposed behaviors [111]. This strategy has been employed in several countries, including the U.S., Germany, and Austria (for examples, seeFigure 7above).
5.13 Take individual health literacy levels into account
Messages also must be reflective of individuals’ respective health literacy levels3 [48, 72, 114]. Numerous studies determined individual’s health literacy is rather low [48, 114, 115, 116]. “Barriers that keep the people we want to become more scientifically literate from understanding what we do [is that] they do not know the terminology”. For this reason, messages must ensure that people do not feel overwhelmed with the information they are presented with. Governments seem to have taken this advice to heart by predominantly broadcasting simple messages, such as it was the case in Austria, Germany, and Australia.
5.14 Reduce message complexity
While low health literacy levels can result in unintended health outcomes [51], messages low in complexity can enhance both individuals’ message processing and willingness to act on the recommendations presented therein [51]. More complex messages, however challenge individuals as they require more elaborate health literacy skills for individuals to not only understand the message, but also align message content with existing knowledge [117]. Examples for reduced and simplified messages can be found for Germany, Austria, as well as for UNICEF and FIAF, who heavily relied on visual (instructive) information. For examples from Austria, seeFigure 8.
Figure 8.
Austrian PSAs with strong visuals but low in complexity. (Source: https://www.governor.ny.gov/).
5.15 Present information in dual mode
Health campaigns have been found to increasingly rely on videos [118], which present information in dual form, meaning in both textual and visual form. In the first instance, facts can be both presented in written and auditory form (voiceover or narration) and might be supported by illustrations and pictograms (e.g., [51]). Narration particularly caters to individuals with low health literacy levels, who can process spoken information more readily than written information [119]. Personal stories that are directly linked to the health-cause and narrated by testimonials, can increase identification and message impact [108, 110]. Videos’ dual-mode presentation information processing and message recall [120, 121]. For example, campaign videos in Germany and Austria were dubbed, while textual information was complemented with pictograms in Austria and Australia (seeFigure 9).
Figure 9.
Austrian PSAs utilizing information and pictograms. (Source: https://www.governor.ny.gov/).
5.16 Tailor information to individual needs
If individuals act upon the proposed actions by the government depends on the impact – both in economic and social terms – associated with the health risk [18, 44], as well as their ability to make sense of the information they are presented with [122]. Governments are, therefore, advised to tailor their communications to individual information needs [123, 124, 125]. In Austria, for example, campaign messages differed, depending on the message’s designated target group (e.g., elderly at-risk people, general population, etc.).
5.17 Utilize switch buttons
According to previous research, individual message preferences vary, and different message formats are preferred [16, 54]. For this reason, messages must be provided where individuals are likely to encounter them [126, 127], taking generational differences and media preferences into consideration. For instance, campaign messages in Austria and Germany concluded with links to the Government’s website, where additional information could be retrieved.
6. Conclusion
If crisis strikes, government officials are called upon to act quickly and engage in increased communication [6, 7]. The present study reviewed some existing literature and combined it with insights from health communication, in an attempt to provide some recommendations for effective COVID-19 health risk message design. This is crucial, for individuals’ risk perceptions have been found to predict their likelihood of engaging in preventive behaviors, also in the case of pandemics [82] and in the case of emerging infectious diseases (EID) [8].
At any time during the crisis, message complexity should be reduced [122, 128], requiring lesser cognitive capacities on behalf of individuals to process message [51]. This is specifically important, if scientific evidence is presented. Only if message match the audience’s cognitive capacities, individuals can play an active role in managing health risks. Moreover, visual (affective) stimuli can elicit emotions in individuals, and enhance message acceptance and learning, specifically if new information is presented [121].
Communication strategies are further recommended to take audiences’ attitudes and inherent needs for comprehensive and instructional information – which appeals to their self-efficacy [43] – into account [129]. Hence, government officials are advised to optimize message presentation, especially when the problem or risk addressed in this message affects whole populations. As such, it is important to increase both the identification with and the relevance of message content, evoking individuals into compliance. In order to increase identification and create familiarity with proper crisis behavior, communication should center on the affected population [18, 80, 104] and feature community members [43]. In order to increase message comprehensibility, information needs to be presented in simple language and in a straight-forward-manner, while also reducing message complexity [100, 120], e.g., through the inclusion of visuals. If message content is too complex, effectiveness can be enhanced by presenting information in dual form, i.e. by combining visual/auditory and textual elements [51]. For instance, narration can increase a message’s persuasive impact [130], while also aiding respondents’ identification with the message [131]. A dual-more presentation can thus help overcome respondents’ potential resistance to message content [132], while also favoring those with low health literacy rates – a problem, that still challenges health communication in the age of COVID-19 [48, 114].
There are several limitations to the list of recommendations presented herein. Even though the study is based on a comprehensive literature review, it only focused on research articles from the field of strategic communication and health communication. Moreover, the national campaign examples only offer insights into the communication strategies utilized by the German, Austrian, U.S. American (New York) and Australian government. PSAs might be conceptualized differently in other parts of the world. Future research should also emphasize how campaign messages have changed as the COVID-19 pandemic progressed.
Acknowledgments
The author acknowledges the financial support by the University of Klagenfurt.
\n',keywords:"health risk communication, COVID-19, health campaigns, health message design, literature review",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75456.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75456.xml",downloadPdfUrl:"/chapter/pdf-download/75456",previewPdfUrl:"/chapter/pdf-preview/75456",totalDownloads:427,totalViews:0,totalCrossrefCites:2,dateSubmitted:"December 21st 2020",dateReviewed:"February 3rd 2021",datePrePublished:"March 2nd 2021",datePublished:"December 22nd 2021",dateFinished:"February 27th 2021",readingETA:"0",abstract:"Literature describes a pandemic as a unique form of health crisis, which requires intensive communicative efforts. The government is a key actor in such situations for it is not only particularly trusted to manage a crisis, but also can obtain compliance on part of the affected population. Scholars agree that health messages are important tools to create awareness for the (health) threat. Particularly during health emergencies, information on which preventive measures should be taken is most valuable. With measures often concerning “disruptive actions”, messages must be carefully crafted to counteract negative emotions and controversial arguments. The present chapter presents a checklist for successful campaign design in health risk situations by paying specific attention to COVID-19. To this end, we conduct an extensive literature review and highlight how scientific information should be presented, as well as which message appeals and design features should be utilized to provide the population with targeted and timely information. This is essential against decreasing health literacy rates, which have to be considered in the message design process. To illustrate our case, we will refer to selected national health campaigns which were successfully utilized to manage the risk associated with the COVID-19 pandemic. The chapter will conclude with some limitations and directions for future research.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75456",risUrl:"/chapter/ris/75456",signatures:"Isabell Koinig",book:{id:"10226",type:"book",title:"Risk Management",subtitle:null,fullTitle:"Risk Management",slug:"risk-management",publishedDate:"December 22nd 2021",bookSignature:"Muddassar Sarfraz and Larisa Ivascu",coverURL:"https://cdn.intechopen.com/books/images_new/10226.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-906-2",printIsbn:"978-1-83968-905-5",pdfIsbn:"978-1-83968-907-9",isAvailableForWebshopOrdering:!0,editors:[{id:"260655",title:"Dr.",name:"Muddassar",middleName:null,surname:"Sarfraz",slug:"muddassar-sarfraz",fullName:"Muddassar Sarfraz"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"333702",title:"Dr.",name:"Isabell",middleName:null,surname:"Koinig",fullName:"Isabell Koinig",slug:"isabell-koinig",email:"isabelle.koinig@aau.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Communicating during a health crises",level:"1"},{id:"sec_3",title:"3. Health campaigns in crisis situations",level:"1"},{id:"sec_4",title:"4. Method",level:"1"},{id:"sec_5",title:"5. Recommendations for designing health risk messages",level:"1"},{id:"sec_5_2",title:"5.1 Be open and transparent",level:"2"},{id:"sec_6_2",title:"5.2 Focus on relevant message content",level:"2"},{id:"sec_7_2",title:"5.3 Present information consistently and “straight to the point”",level:"2"},{id:"sec_8_2",title:"5.4 Appeal to individuals’ self-efficacy",level:"2"},{id:"sec_9_2",title:"5.5 Align message content with social norms",level:"2"},{id:"sec_10_2",title:"5.6 Use prosocial appeals",level:"2"},{id:"sec_11_2",title:"5.7 Emphasize the necessity of proposed measures",level:"2"},{id:"sec_12_2",title:"5.8 Evoke positive emotions",level:"2"},{id:"sec_13_2",title:"5.9 Emotionalize message content",level:"2"},{id:"sec_14_2",title:"5.10 Employ strong visuals",level:"2"},{id:"sec_15_2",title:"5.11 Create Identification",level:"2"},{id:"sec_16_2",title:"5.12 Feature community members",level:"2"},{id:"sec_17_2",title:"5.13 Take individual health literacy levels into account",level:"2"},{id:"sec_18_2",title:"5.14 Reduce message complexity",level:"2"},{id:"sec_19_2",title:"5.15 Present information in dual mode",level:"2"},{id:"sec_20_2",title:"5.16 Tailor information to individual needs",level:"2"},{id:"sec_21_2",title:"5.17 Utilize switch buttons",level:"2"},{id:"sec_23",title:"6. 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Learning and Instruction 17(6), 722-738'},{id:"B120",body:'Lang, A. (2000). The limited capacity model of mediated message processing. Journal of Communication 50, 46-70'},{id:"B121",body:'Mayer, R.E. & Moreno, R. (2002). Animation as an aid to multimedia learning. Educational Psychology Review 14(1), 87-99'},{id:"B122",body:'Sorensen, K., Van den Broucke, S., Fullam, J., Doyle, G., Pelikan, J., Sonska, Z. et al. (2012). Health literacy and public health: A systematic review and integration of definitions and models. BMC Public Health 12, 80. https://doi.org/10.1186/1471-2458-12-80'},{id:"B123",body:'Lwin, M.O., Vijaykumar, S., Fernando, O.N.N., Cheong, S.A., Rahnayake, V.S., Lim, G., Theng, Y.-L., Chaudhuri, S. & Foo, S. (2014). A 21st century approach to taking dengue: Crowdsourced surveillance, predictive mapping and tailored communication. Acta Tropica 130(Feb), 100-107'},{id:"B124",body:'Rousseau, C., Moreau, N., Dumas, M.-P., Bost, I., Lefebvre, S., and Atlani-Duault, L. (2015). Public media communications about H1N1, risk perceptions and immunization behaviors: A Quebec-France comparison. Public Understanding of Science 24(2), 225-240'},{id:"B125",body:'Stolow, J.A., Moses, L.M., Lederer, A.M. & Carter, R. (2020). How Fear Appeal Approaches in COVID-19 Health Communication may be harming the Global Community. Health Education & Behaviour 47(45), 531-535'},{id:"B126",body:'Kim, K.S., Sin, S.C.J. & Tsai, T.I. (2014). Individual differences in social media use for information seeking. The Journal of Academic Librarianship 40(2), 171-178'},{id:"B127",body:'Young, D. & Bleakley, Y. (2020). Ideological health spirals: An integrated political and health communication approach to COVID-19 interventions. International Journal of Communication 14, 3508-3524'},{id:"B128",body:'Mazor, K.M., Calvi, J., Cowan, R., Costanza, M.E., Han, P.K., Greene, S.M. et al. (2010). Media messages about cancer: What do people understand? Journal of Health Communication 15(S2), 126-145'},{id:"B129",body:'George, A. & Selzer, J. (2007). Kenneth Burke in the 1930s. Columbia; SC: University of South Carolina Press'},{id:"B130",body:'Escalas, J.E. (2004). Narrative processing: Building consumer connections to brands. Journal of Consumer Psychology 14, 168-180'},{id:"B131",body:'Green, M.C. & Brock, T.C: (2000). The role of transportation in the persuasiveness of public narratives. Journal of Personality and Social Psychology 79, 701-721'},{id:"B132",body:'Dillard, J.P. & Shen, L. (2005). On the nature of reactance and its role in persuasive health communication. Communication Monographs 72, 144-168'}],footnotes:[{id:"fn1",explanation:'The arguments presented in this chapter build on a "Public Understanding of Science" and "Public Awareness of Science", both of which attest to the general public’s attitudes, behaviors, or opinions towards science and scientific knowledge [24, 25].'},{id:"fn2",explanation:'Collective norms describe "prevailing codes of conduct that either prescribe or proscribe behaviors that members of a group can enact" ([66], p. 29).'},{id:"fn3",explanation:"In general, health literacy is defined as an individual’s ability to process and comprehend health information [112]. A more broadly speaking, health literacy encompasses individuals’ reading and writing skills, their ability to distinguish relevant from irrelevant information as well to critically analyze and reflect upon the information retrieved [113]."}],contributors:[{corresp:"yes",contributorFullName:"Isabell Koinig",address:"isabelle.koinig@aau.at",affiliation:'
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AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
Substantially contribute to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
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CHANGES IN AUTHORSHIP
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AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{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",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"26",type:"subseries",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11422,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. 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