Cardiovascular pathologies maintain the leading position in mortality worldwide. Atherosclerosis is a chronic disease that can result in a variety of serious complications, such as myocardial infarction, stroke, and cardiovascular disease. Inflammation and lipid metabolism alterations play a crucial role in atherogenesis, but the details of relationships and causality of these fundamental processes remain not clear. The oxidation of LDL was considered the main atherogenic modification of LDL within the vascular wall for decades. However, recent investigations provided a growing body of evidence in support of the multiple LDL modification theory. It suggests that LDL particles undergo numerous modifications that change their size, density, and chemical properties within the blood flow and vascular wall. Oxidation is the last stage in this cascade resulting in the atherogenic properties. Moreover, recent investigations have discovered that oxLDL may have both anti-inflammatory and pro-inflammatory properties. Oxidized LDL can trigger inflammation through the activation of macrophages and other cells. After all, oxidized LDL is still a promising object for further investigations that have the potential to clarify the unknown parts of the atherogenic process. In this review, we discuss the role of oxLDL in atherosclerosis development on different levels. Cardiovascular disease (CVD) is one of the leading causes of premature death and disability in Europe. According to the World Health Organization (WHO), about 75% of all deaths from CVD can be prevented by following a healthy lifestyle. A healthy lifestyle includes smoking cessation, a healthy diet, and sufficient physical activity .Brown and Goldstein were the first to postulate that LDL has to undergo some structural changes to achieve atherogenic properties . They alOxidative stress manifests itself in excessive ROS generation and oxidation of LDL particles. The emergence of oxLDL is crucial for the progression of CVD linked to atherosclerosis. The main factor underlying oxidative stress is a disbalance between radical production (reactive oxygen and/or nitrogen species formation) and radical scavenging systems (the antioxidant defense system) . Also, hOxLDL can trigger the expression of adhesion molecules on the cell surface and thus stimulate the activation of endothelial cells . These aApart from the scavenger receptors, as SR-A, SR-BI, and CD36, oxLDL also binds to lectin-like oxidized low-density lipoprotein receptor-1 . LOX-1 cUnder normal conditions, LOX-1 expression is very low, but it can be enhanced in response to proatherogenic or proinflammatory triggers. The LOX-1 level is upregulated in endothelial cells at the early stages of atherogenesis and in advanced plaques. Also, intimal SMCs and macrophages exhibit enhanced expression of LOX-1 in human carotid atherosclerotic plaques . This isOverproduction of oxLDL triggers the LOX-1 expression in VSMCs and also triggers apoptosis . Expressvia CD36, which results in the intracellular nucleation of cholesterol crystals in lysosomes. This process activates inflammasome with the same result as when the cholesterol crystals are phagocytosed (Lysophosphatidylcholine (LPC) treatment can also increase LOX-1 expression in SMCs. This, subsequently, leads to an increase in oxLDL uptake. Anti-LOX-1 antibodies were shown to inhibit the uptake of oxLDL after the LPC stimulation . OxLDL aocytosed .Oxidative modification has been attracting the attention of researchers for the last two decades. Therefore, it is the most well-investigated LDL modification for now. What is more, antioxidant compounds, including probucol, probucol analogs, vitamin E, coenzyme Q, diphenylphenylenediamine, and butylated hydroxytoluene were investigated in the scope of atherosclerosis and oxLDL in various animal models. Mostly, the results of these investigations were successful . The oxiOxidative stress is considered an important risk factor for the pathogenesis of various diseases, such as cancer, age-associated disorders, neurodegenerative diseases, autoimmune disorders, and CVD. There is more than one way through which oxidative stress influences the development of CVD. Regarding atherosclerosis, oxidation of LDL particles in the vascular endothelium was reported to be an initial event in the atherosclerotic plaque formation. Thus, phenotypical changes in endothelial cell surfaces are triggered by the production of intracellular ROS. Moreover, superoxide generates cytotoxic peroxynitrite and lowers the activity of nitric oxide. The platelet aggregation is enhanced, and vascular function is modulated by superoxide through vasoconstriction .Oxidative stress can be a part of cancer development and the aging process. When the organism ages, the activity of the endogenous defense system lowers, and the ROS generation enhances, leading to the continuous damage of cellular structures. For example, inhibition of paraoxanase activity by high serum levels of anti-beta-2-glycoprotein I (b2GPI) antibodies leads to the enhancement of oxidative stress levels. Paraoxanase has antioxidant features and protects LDL from oxidative injury . EndotheROS formation involves several enzymes and enzymatic systems, such as NADPH oxidase (NOX), uncoupled endothelial nitric oxide synthase (eNOS), lipoxygenases (LOX), and others .NADPH oxidases are a group of enzyme complexes that consist of several subunits and generate superoxide from molecular oxygen with the NADPH as the electron donor. P22phox and a Nox homologue, two membranes bound subunits, and also few cytosolic regulatory subunits form an NADPH oxidase complex . This st−/− mice with genetic deletion of Nox1. Nox2 deficiency alleviated atherosclerosis in the descending aorta of model animals. However, this effect was not observed in the aortic sinus  with the use of molecular oxygen as an electron acceptor. Xanthine oxidases can be found in blood plasma and within the population of endothelial cells. Also, elevated levels of XO were observed in atherosclerotic plaques . Xanthin oxidase .Notably, uric acid is another product of xanthine oxidases, which in high blood concentration may result in clinical manifestation of gout, which, in turn, is associated with the enhanced burden of atherosclerosis-related events. The activity of xanthine oxidases triggers the expression of scavenger receptor CD-36 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in macrophages and vascular smooth muscle cells, which contributes to the binding of oxLDL particles. Thus, the over-production of uric acid is associated with foam cell formation .ENOS produces nitric oxide playing a crucial vasoprotective role for the endothelium, but in pathologies associated with oxidative stress, the functioning of eNOS can be altered . OxidatiOxidized LDL is derived from different sources, including metal ions, reactive oxygen species (ROS), lipoxygenase, and myeloperoxidase, and can contain various parts. So, we can propose the following general definition: oxLDL is a particle obtained from circulating LDL that may have peroxides or their degradation products generated within the LDL molecule or elsewhere in the body associated with the particle. At the same time, an exact mechanism of LDL oxidation is still unclear .Among types of oxidative modification of LDL particles, there are non-enzyme-mediated modifications, including interaction with proteoglycan, free radical, glycosylation, and modifications mediated by enzymes . Also, depending on the LDL component that underwent oxidation, modifications are divided into lipid component modification and protein component modification . In bothLDL is a complex particle with variative oxidation sensitivity. Oxidation of LDL is a gradual process, during which oxidation is occurring continuously, from mild to extensive, containing different ratios of various potentially toxic components of oxidized proteins and oxidized lipids. It explains the heterogeneity of the composition, metabolism, and biological characteristics of oxidized LDL particles. Lipid aldehyde and sterol and lipid peroxide are oxidized and exist in different proportions. All types of bioactive lipids of oxidized LDL communicate with molecular targets of the cell through various mechanisms and play physiological or pathological roles, mechanisms of which are still not clearly understood .The history of modified LDL investigations began in 1981 when Henriksen et al. found out that overnight incubation of cultured endothelial cells with native LDL results in the transformation of the latter . LDL obtThe first promising success of the antioxidants uses for atherosclerosis treatment in various animal models resulted in clinical trials that were aimed to prove the oxidative theory at last . NaturalOxidative stress is an important trigger of lipid oxidation . OxidatiAtherosclerosis was believed to develop similarly in humans and model animals, which, at least in part, confused the results of clinical trials. So, antioxidant therapy was shown to be efficient in animals, but not in humans. Despite the disappointing outcome of these trials, several investigators continued to discuss the potential of the oxidative modification hypothesis.There are several potential reasons for the fail of antioxidant therapy in humans. For example, vitamin E and other used antioxidants can be oxidized within the organism and thus acquire toxic properties instead of beneficial effects, and the properties of their constituents, such as β-, δ-, and γ-tocopherols and tocotrienols for the vitamin E, should be taken into account. Also, the period of the antioxidant use can be too short for the beneficial effect to be observed. Another possible reason is the insufficiency of only one used antioxidant, or, in contrast, an additional antioxidant effect can be unnoticeable on the background of the use of statins, aspirin, and other cardioprotective drugs, which exhibit an antioxidant effect on their own. In all investigations, antioxidants were used only after the disease has manifested itself, while the efficacy of pre-treatment was not assessed. The choice of a suitable antioxidant compound is a big challenge. Thus, the antioxidants that affect mitochondrial oxidation by crossing the membrane of mitochondria may be a better choice than the traditional antioxidants. And, of course, the theory of oxidant origin of atherosclerosis is imperfect and does not consider other mechanisms and pathways involved in atherogenesis.via binding to the CD36 receptor. Another example of anti-inflammatory consequences of oxLDL action is the interaction of oxLDL with B cells via binding to the CD36 receptor. This leads to anti-oxLDL production, which has anti-inflammatory activity  and TNF receptor-associated factor 6 (TRAF6) . IRAK1 aNumerous proatherogenic features exhibited by oxLDL are potentially caused by oxidized phospholipids comprising oxLDL structure. Oxidized phospholipid products can be recognized by autoantibodies as the principal epitopes . An ideaInterestingly, anti-pneumococci antibodies exhibited reactivity with pneumococci as well as with minimally oxidatively modified LDL . MoreoveThere are no available data on particular side effects that can accompany the result of immunization against atherosclerosis every time. The most alarming is the uncontrolled immune reactions and alterations of the normal lipid metabolism. It is beyond doubt that the possibility of such side effects should be considered in clinical trials.Oxidative stress is an important part of atherosclerosis pathogenesis. It involves the improper balance between ROS production and the activity of antioxidant systems. Thus, numerous enzymatic systems participate in oxidative stress development and resolution. Oxidizing of LDL particles is one of the consequences of alterations in the functioning of both prooxidant and antioxidant systems. Moreover, oxidation of LDL particles in the vascular endothelium was reported to be an initial event in the atherosclerotic plaque formation.LDL oxidation is undoubtedly an important atherogenic modification of native LDL, that takes place mostly in the vascular wall. Oxidation has been believed to be the only modification, i.e., responsible for the atherogenic properties of LDL particles for decades. However, modern findings provide a growing body of evidence suggesting the existence and importance of numerous LDL modifications that affect both the physical and chemical properties of particles. All these modifications form a cascade, all steps of which contribute to atherosclerosis development.Even though oxidation is not the only atherogenic modification of LDL, it still has numerous different functions in the development of atherosclerosis. What is more, it has recently been shown that oxLDL may exhibit both anti-inflammatory and pro-inflammatory properties according to the stage of oxLDL exposure and the degree of oxidation.OxLDL was demonstrated to be involved in the foam cell formation and stimulation of the immune response. OxLDL acts through various mechanisms, among which are interaction with scavenger receptors, modulating inflammation-related molecular pathways, including miRNA regulation and NLRP3 inflammasome activation.Despite the significant role of oxidized LDL in atherogenesis, the understanding of the disease initiation and development progresses, and a new theory was formulated. It was shown that there are multiple modifications of LDL that allow particles to get the atherogenic properties, and the conception of multiple modifications was suggested. Moreover, traditional attitudes have been changed completely due to the recent findings concerning the event sequence in the atherosclerosis initiation.Taken together, all available data on oxidized LDL indicates the importance of oxLDL as a therapeutic target. The most promising is the use of anti-oxLDL antibodies by different strategies, including active immunization with oxidized or native LDL or derivatives and passive administration of anti-oxLDL antibodies.Writing—original draft preparation, AP; writing—review and editing, AM, DK, VM, EG, NN, AO.This research was funded by the Russian Science Foundation, grant number 20-15-00337.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the lack of an effective vaccine and antiviral treatment, convalescent plasma (CP) has been a promising therapeutic approach in past pandemics. Accumulating evidence in the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic corroborates the safety of CP therapy and preliminary data underline the potential efficacy. Recently, the Food and Drug Administration (FDA) permitted CP therapy for coronavirus disease 2019 (COVID-19) patients under the emergency use authorization, albeit additional clinical studies are still needed. The imminent threat of a second or even multiple waves of COVID-19 has compelled health authorities to delineate and calibrate a feasible preparedness algorithm for deploying CP as an immediate therapeutic intervention. The success of preparedness programs depends on the interdisciplinary actions of multiple actors in politics, science, and healthcare. In this review, we evaluate the current status of CP therapy for COVID-19 patients and address the challenges that confront the implementation of CP. Finally, we propose a pandemic preparedness framework for future waves of the COVID-19 pandemic and unknown pathogen outbreaks. The world is currently confronted with an unprecedented threat of a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . In latePassive immunity is a relatively old approach that dates back to 1890, decades before the development of antimicrobial therapies ,11,12. ECP could be considered an effective therapy in emergency situations where specific treatments are still lacking. CP was used in recent disease outbreaks and pandemics. For instance, during the outbreak of SARS in 2003 , the infCP therapy could potentially control and divert the epidemic trend and save human lives. This treatment can be adopted in emergency situations to prevent the excessive flux of cases from overcrowded hospitals to intensive care units (ICUs). Besides CP, the pharmaceutical industry has expressed its interest in passive immunity by embarking on the search for effective monoclonal antibodies (mAbs). However, in contrast to mAbs, CP therapy requires fewer resources and can be quickly implemented in an efficient and safe manner. Therefore, this strategy could be added to a pandemic preparedness roadmap, in which the involved organizations in CP clinical trials are rapidly informed and organized once emerging infectious diseases appear.With a daily increase in the number of new SARS-CoV-2-infected cases and existing concerns for multiple waves of the pandemic in the coming seasons, it is currently the right time to outline the challenges that confront the implementation of CP in clinical practice. On 23 August 2020, the FDA issued a EUA for convalescent plasma in COVID-19 patients. Importantly, this authorization should not replace clinical trials since critical data concerning safety and efficacy are still needed ,29,30,31After identifying the novel coronavirus as the etiology of COVID-19 in China, countries started to look for antiviral therapies and the development of potential vaccines. Simultaneously, experts expected to obtain early FDA approval to launch clinical trials to evaluate the safety and efficacy of CP therapy. However, the initial strategy presented by the WHO primarily focused on preventing the spread of the virus . In contNext to the FDA guidelines, the European Medicines Agency (EMA) also implemented a protocol for starting clinical trials to evaluate CP therapy in Europe . The AmeConcerted efforts primarily aim to ramp up the collection and transfusion of CP to treat COVID-19 patients and curb the pandemic trend. In hindsight, health experts witnessed a substantial delay in the announcement of CP clinical trials by health authorities at an international level, while swift decision-making is essential for the wide implementation of CP therapy under emergency conditions . IdeallyUnlike chemically based medicine, CP is a biological therapy that relies on the availability of patients that recovered from the infection. Eligible patients for plasma donation should have raised substantial titers of neutralizing antibodies, which is pivotal for the success of this treatment. The recruitment of plasma donors starts with calling the recovered patients by hospitals, family doctors or the public announcement of blood transfusion organizations like the Red Cross. Furthermore, healthcare personnel can inform the recovered patients before discharge to encourage them to donate plasma. Throughout the recruitment process, the privacy and confidentiality of the donor should be guaranteed and comply with ethical regulations . Donated plasma should be collected through voluntary and nonremunerated transfusions. Directed donations are not recommended and plasma units should be sent anonymously to the hospitals . CurrentTo construct a timeline for CP collection, it is highly important to understand the neutralizing antibodies’ kinetics postinfection and recovery. For instance, knowing when the antibodies reach the maximum concentration after infection and for how long it persists in the blood is pivotal information. Results showed that in SARS-CoV-infected cases in 2003, the neutralizing antibody concentration reached the highest level within four months after the onset of disease and remained positive up to 24 months postinfection ,46. In cIt has been reported that some recovered patients do not develop a detectable titer of neutralizing antibodies . SimilarThe success of collecting convalescent plasma depends on the willingness and eligibility of the recovered individual to donate plasma. According to previous experiences, some recovered patients avoid participating in the collection of CP. Furthermore, the donor eligibility to donate plasma is based on health records, blood screening, hematocrit level and platelet count according to the BRN standards of the WHO ,56,57. APrecautionary strategies should be implemented for the safe administration of CP therapy to mitigate the risk of transmitting SARS-CoV-2. Regarding the reports of SARS-CoV-2-positive blood samples, implementing RT-PCR screening tests for the donor and convalescent plasma before transfusion is highly recommended. This test could be listed in the standardized blood screening panel that is used to determine donor eligibility for blood donation. Without the approval of the blood screening department, collected CP should be kept in quarantine (within 24 h after collection) and can only be released for transfusion after receiving clearance.The implementation of pathogen-reduction techniques provides an extra safety step in preventing the transmission of SARS-CoV-2 through blood transfusion. However, these techniques are not available in all countries. Therefore, SARS-CoV-2 molecular screening of the donated blood is recommended to guarantee the safety of the plasma. Besides molecular techniques, antibody testing has been proposed to confirm viral clearance in the donor. This approach can be faster and less laborious, albeit antibodies are not good indicators of viral clearance . For insSome reports have demonstrated detectable levels of SARS-CoV-2 RNA in patients discharged from hospitals ,65. In tConflicting results are concerns in routine screening and could have a far-reaching impact on CP collection. The clinical relevance of finding positive stool samples combined with negative oral swabs should be further investigated. Although the symptoms could be resolved, the patients could still carry the virus while visiting the plasma donation center ,35. ReceThe collection of plasma should comply with the highest quality standards to guarantee the safety of both the donor and recipient. Preferably, plasma should be collected through a routine apheresis method. This method is an automated and closed system that separates 400–800 milliliters of plasma from whole blood and returns the remaining cells and other blood components to the donor . The totIn addition to a high-quality plasma collection infrastructure, the viral neutralizing capacity of CP should be determined postdonation. The titer of neutralizing antibodies can be highly different between individuals and might not reach sufficient thresholds ,70. The Currently, some diagnostic and quantification methods, e.g., ELISA, are making progress to replace PRNT ,58,70,73A standardized level of neutralizing antibodies is still lacking. Early clinical case series with a limited number of patients used various neutralizing antibody concentrations. In China, an initial study started with a neutralizing antibody titer of >1:40, while another trial observed an improved efficacy of CP therapy with more than 1:640 ,34 Tabl. In the In addition to neutralizing antibody titers, a growing body of evidence implies that the timing of CP therapy is an important indicator of therapy success. Previous reports on CP therapy revealed that a delayed administration could be one of the main causes of therapy failure . Until nThe most optimal timing for CP therapy is expected to be within three to five days after the onset of disease symptoms. Within this timeframe, the antiviral activity of CP can prevent the development of tissue damage ,89. The 2 saturation level, could indicate if the transfusion of more units is needed [The dosage of CP can be highly variable and depends on clinical indications, either preventive or curative. The required dosage or volume of CP is primarily determined by the neutralizing antibodies’ titer, estimated half-life of the antibodies and body weight of the recipient . The vols needed .The process of CP transfusion should be closely monitored. Generally, the transfusion of a single dose takes approximately 30 min to 1 h . Some prAccording to recent clinical trials, the impact of CP therapy on clinical parameters should appear during the first week after transfusion ,34,70. MTo evaluate the efficacy of CP, it is important to measure the level of neutralizing antibodies before and after CP therapy by longitudinal sample collection. In two recent studies performed in China, a significant increase in neutralizing antibodies of more than 1:640  and >1:4Current data indicate that the occurrence of serious adverse events (SAEs) after CP therapy is very low and mostly absent ,30,31. HTransfusion of blood products carries a risk of transmitting bloodborne pathogens. Several strategies have been implemented to minimize this risk, including the screening of donated blood and a medical background assessment of the donor. Besides screening, blood products can be actively treated with pathogen-reduction techniques . HoweverOther risks might emerge from transfusion-related reactions, including transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO). These two SAEs can lead to pulmonary edema and are potentially lethal . The chaAnother risk factor of CP is related to the presence of non-neutralizing or suboptimal antibodies. Docking of these antibodies on the surface of the virus could potentiate the cellular uptake of the virus in a mechanism called antibody-dependent enhancement (ADE) . InsteadTo implement an efficient and safe infrastructure for CP therapy during a pandemic, the recruitment of donors and mass collection of plasma are necessary within a short timeframe. This requires access to specific technologies for blood transfusion and blood fractioning. Recent improvements in plasma apheresis techniques  shortened the time and improved the efficiency of plasma. Depending on the available facilities and the phase of the pandemic, collected plasma could be fractionated to acquire hyperimmunoglobulin (HIG) formulas . The benAnother prophylactic or treatment option includes the use of mAbs derived from B lymphocytes. Like antibodies, these cells can be isolated from individuals that survived viral infection. This approach has demonstrated promising effects in animals infected with SARS-CoV-1, in vitro models of MERS-CoV and patients infected with the Ebola virus ,117,118.Convalescent plasma therapy is an old therapeutic tool that, after the introduction of antibiotics, was pushed to the side-line. However, the threat of emerging pathogens in past decades revived the use of CP therapy while immediate vaccines and therapeutic medicines were still lacking. Today, the world is confronted with a devastating pandemic. Now more than ever, CP therapy is in the spotlight again. CP therapy has demonstrated high potential as a possible curative intervention and could curb infectious pandemics. The characteristics of this treatment make it an appropriate and prompt therapeutic strategy that can be implemented in pandemic preparedness. Therefore, clinical studies have been launched in all continents, with the majority of trials registered in the Americas and Europe A. AlthouWe have witnessed a delay in the deployment of CP therapy as a potential treatment option for COVID-19 patients. Mounting evidence derived from recent clinical trials underlines the safety and potential efficacy of this approach. The imminent threat of a second or even multiple waves of COVID-19 compels health authorities to delineate and calibrate a feasible preparedness algorithm for deploying CP as an immediate therapeutic intervention. However, the success of preparedness programs depends on the interdisciplinary actions of the scientific community, politicians, and blood transfusion authorities. Here, we will outline important aspects that should be regarded for the implementation of CP therapy in preparedness guidelines .In an emerging pandemic, large-scale multicenter clinical trials are needed to evaluate the available treatment options. Valuable time was lost during the initial days of the pandemic and we must take lessons from these experiences for future emergencies. For instance, ambiguous messages concerning the COVID-19 pandemic hampered the implementation of clinical trials and patient recruitment in the US . To act Besides the clinical and scientific field, support from governmental institutes in both financial and legislative matters is imperative during the initial phases of the pandemic. From a financial perspective, governments should support the initial steps of plasma collection and laboratory testing and stimulate clinical research in the safety and efficacy of CP treatment. These efforts provide the tools for defining the dynamics of infection, clinical course of the disease and potential plasma donors. At the same time, effective steps should be taken to find the optimal titer of neutralizing antibodies. The optimal timing of CP administration and the possibility of plasma fractionations should be investigated.Successful implementation of CP therapy heavily depends on the availability of plasma. Blood banks should aim for the acquisition of sufficient stock during the heights of the pandemic. In contrast chemically based antiviral therapies, CP is derived from human resources, which requires individuals that survived infection and acquired an adequate titer of neutralizing antibody. Therefore, the number of potential donors that mounted a robust immune response can become limited if the peak of the epidemic drops . FurtherBesides regulatory aspects, the evolution of the virus should be tracked meticulously. For instance, the accumulation of viral mutations could negatively affect the efficacy of CP treatment . TherefoThe success of CP therapy fully depends on voluntary nonremunerated plasma donations of recovered patients. To inform the target population, national campaigns can be launched to increase awareness of the availability of this treatment. Different information channels, including social media, can be used to inspire grassroots engagement and participation in the donation process . The motIn the upcoming months, without the availability of vaccines and curative treatments, the demand for CP and other available medicines will keep increasing. Needless to say, mass screening of (a)symptomatic individuals can guide authorities in programming their preparedness actions. Equitable access to facilities for deploying CP therapy in all countries is an imperative element for the preparedness roadmap. Critical concerns over limited resources in low- and middle-income countries should be addressed by actions of solidarity. For instance, political–economic sanctions, economic restrictions and logistic limitations should be lifted in time to make CP therapy widely available ,130,131.The use of CP therapy has proven to be an effective strategy in previous epidemics. CP therapy is not only a promising approach for the transition time to develop an efficient and safe vaccine but also for the prophylactic potential after the pandemic. Importantly, it can help the healthcare workers that are exposed to infected individuals on the frontlines . It is sIn conclusion, the implementation of CP therapy in response to an emerging pandemic requires a global effort between multiple actors from various disciplines. By learning and synchronizing our efforts in the ongoing pandemic, we can certainly turn a tragic pandemic into a beacon for the next phases of current and future pandemics.


Preterm birth, defined as delivery at less than 37 weeks’ gestation, is one of the most pressing clinical problems in obstetrics worldwide . DespitePreterm birth is not only the major contributor to neonatal morbidity and mortality globally, it also accounts for the increasing numbers of intergenerational non-communicable diseases. It is estimated that 106 million disability-adjusted life years are lost annually to preterm birth. Thus, preterm birth is a high priority public health problem and it is essential to reduce the rate of preterm birth in order to achieve the health-related Millennium Developmental goals set forth by the WHO in 2000 .These goals can only be achieved if understanding of the pathogenesis of the multifactorial nature of preterm birth improves. Hence, a significant number of research endeavors aim to unearth markers and mediators accounting for the onset of preterm birth. In this special issue, we have compiled a comprehensive update on clinical, socioeconomic, and pathophysiological aspects currently known to be involved in preterm birth. Deindl and Diemert highlight features of the heterogeneity of the syndrome and focus on its connection with health care structures. The authors further summarize the structural modalities required for the prevention of preterm birth by discussing various care levels of hospitals .To date, the accurate prediction and subsequently prevention of preterm birth is not yet within reach. Clearly, such prediction-based prevention of preterm birth is a highly desired goal and, thus, pursued by a number of researcher and clinicians. Pizzella et al. put forward evolving techniques to predict preterm birth, focusing on cervical imaging technologies. Currently used and emerging imaging techniques such as brightness-mode ultrasound, Raman spectroscopy, and photoacoustic endoscopy are discussed in the light of their advantages and disadvantages in assessing cervical remodeling. The authors propose that a combination of several imaging approaches, combined with clinical epidemiologic characteristics, holds the potential to accurately predict preterm birth . Along tSince dysfunctions of maternal immune adaptations have been linked to the onset of preterm birth, Green and Arck examine the current knowledge of the bidirectional communication between fetal and maternal systems and its role in the immunopathogenesis of preterm birth . Much reMenon et al. also acknowledge the importance of fetal-maternal immune tolerance and focus in their review article on inflammation of fetal membranes associated with preterm birth and preterm pre-labor rupture of the membranes. Both arise from distinct pathophysiologic pathways but share inflammation as a common underlying mechanism. Their review summarizes the mechanisms of fetal membrane cellular senescence, transitions, and the generation of inflammation that contributes to term and preterm parturitions .Humberg and colleagues follow-up on these aspects and discuss sustained inflammation in the context of preterm birth and resulting consequences for the neonate. Here, the onset of chorioamnionitis is suggested to act as a first inflammatory hit. Postnatal confrontation of the prematurely born neonate with a drastically altered antigen exposure, such as hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia can then create a second inflammatory hit .Blois and colleagues introduce galectins, an evolutionary conserved family of glycan-binding proteins, a pivotal mediator controlling fetal-maternal immune tolerance. In their review, the functional role of galectins in shaping cellular circuits that characterize a healthy pregnancy is comprehensively discussed. Moreover, the current understanding of galectins in term and preterm labor and the contribution of galectin-glycan circuits as key immunological pathways sustaining maternal tolerance and preventing microbial infections is proposed. This deeper understanding of the glycoimmune pathways regulating early events in preterm birth could provide a broad translational potential for the treatment of preterm birth .Bayar et al. follow-up on microbial challenges, but also microbiome-mediated health advantages during pregnancy. In their review article, the complex interplay between the vaginal microbiome in pregnancy and its association with preterm birth is discussed in depth. Advances resulting from an improved understanding of the human microbiome are proposed, such as an improved awareness of the functional role of vaginal microbiota in both health and in disease .Fetal medicine opens a new territory by treating the fetus as a patient. Hence, fetal therapy can improve perinatal survival or prevent severe long-term handicap. In utero fetal interventions can be divided into ultrasound-guided minimally invasive procedures, fetoscopic procedures, and open hysterotomy procedures, which carry an inherent risk of ruptured membranes and preterm birth. Therefore, Valenzuela et al. comprehensively discuss fetal therapies and their influence on preterm birth. They summarize the conditions that may benefit from fetal therapy and review the current therapies on offer in the light of their risk of ruptured membrane and preterm birth .In summary, preterm birth has dire consequences for mother, child, and society in general. Babies who survive preterm birth often face disabilities, such as cerebral palsy, lung disease, blindness, and deafness. Continuous research endeavors addressing these not only persistent but also growing inequalities are urgently needed. With the present special issue addressing key features of the pathogenesis as well as clinical consequences of preterm birth, we sought to provide an updated platform summarizing current insights and future directions. This shall aid researcher and clinicians alike to continue striving for a deeper knowledge of preterm birth in order to lowering its rate globally.


Influenza virus infection is a major health care concern associated with significant morbidity and mortality worldwide, and cause annual seasonal epidemics and pandemics at irregular intervals. Recent research has highlighted that viral components can be found on the extracellular vesicles (EVs) released from infected cells, implying a functional relevance of EVs with influenza virus dissemination. Therefore, exploring the role of EVs in influenza virus infection has been attracting significant attention. In this review, we will briefly introduce the biogenesis of EVs, and focus on the role of EVs in influenza virus infection, and then discuss the EVs-based influenza vaccines and the limitations of EVs studies, to further enrich and boost the development of preventative and therapeutic strategies to combat influenza virus. Orthomyxoviridae family, and can infect the nasal and tracheal airways, and then spread throughout the upper and lower respiratory tract  and matrix protein (M), influenza viruses are usually classified into three different serotypes: influenza A virus (IAV), influenza B virus (IBV), and influenza C virus (ICV)  were found on the EVs released from infected cells, demonstrating a functional relevance of these vesicles with virus dissemination in the body during an infection   to DCs and MΦ, and then the viral RNAs are internalized and recognized by PRRs to produce a large quantity of type I interferon and pro-inflammatory cytokines. For example, IAV-RNA can be recognized by TLR7 in plasmacytoid DCs (pDCs), triggering the signal to induce antiviral innate immune responses  in this subject, and the murine muscle cell-derived exosomes were purified and injected in mice can lead to a well detectable antigen-specific CD8+ T cell response associating with a cytotoxic activity potent enough to kill peptide-loaded and/ or antigen-expressing syngeneic cells, suggesting that this kind of vaccine platform was applicable for further pre-clinical and clinical investigations or applications. Schorey et al. have enumerated the potential advantages to using exosomes as vaccines in their review  could inhibit the HA activity of influenza viruses and suppress the replication of influenza viruses (Khatri et al., So far, however, some limitation would still affect the EVs studies. For example, nomenclature of EVs have been originated in many literature in accordance with their size, origin and functions, such as microvesicles, microparticles, exosomes, ectosomes, oncosomes, and so on (Colombo et al., More importantly, some questions such as double-sided actions of EVs in influenza virus infection, and their role in cytokine storm frequently accompanied by ARDS, and even the stability and safety of exosome-based vaccines with foreign antigens on the recipient remain clarified. Therefore, further studies are still needed to investigate EVs composition and function during the pathogenesis process of influenza virus infection.YJ, CX, and WL contributed to the conception and design of the study. YJ wrote the first draft of the manuscript. LY, HG, and JY wrote sections of the manuscript. CX proofread the manuscript. All authors contributed to manuscript revision and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lightweight aggregate concrete manufactured by solid waste or recycled by-products is a burgeoning topic in construction and building materials. It has significant merits in mitigating the negative impact on the environment during the manufacturing of Portland cement and reduces the consumption of natural resources. In this review article, the agricultural and industrial wastes and by-products, which were used as cementitious materials and artificial lightweight aggregate concrete, are summarized. Besides, the mechanical properties, durability, and a few advanced microstructure characterization methods were reviewed as well. This review also provides a look to the future research trends that may help address the challenges or further enhance the environmental benefits of lightweight aggregate concrete manufactured with solid waste and recycled by-products. The low density LWAC can be used as non-structural applications, while the high density LWAC can be used as structural applications. The mediate density LWAC can be used in both structural and non-structural applications depending on the field requirements [Light weight aggregate concrete (LWAC) has been widely applied in constructions with the merits of lightweight, heat preservation, fire resistance, low shrinkage, and creep resistance under normal conditions . The mosIt was reported that  the LWACThe United States is one of the earliest countries that applied the LWAC. Since 1913, the shale concrete has been successfully prepared and implemented in building bridges (Lightweight-Aggregate-History). In Asia, Japan began to produce and use LWAC in 1955 and then it has been widely used for building urban roads, bridges, railways, and marine constructions . China bIt is no doubt that the production of high-strength LWAC has significant benefits in modern constructions. However, for the production of high-strength LWAC, the high-quality Portland cement, and artificial lightweight aggregates are the key factors that govern the final properties of LWAC. As well-known, the production of high-quality Portland cement is an energy-intensive process, and the manufacture of LWA also requires a large amount of energy consumption , which pThe primary purpose of developing green high-performance light-weight aggregate concrete is to reduce the carbon footprint. It was reported that the LWAC can be prepared by using recycled materials as aggregate  and ceme2 emissions [Portland cement, which provides good mechanical properties, high economic value, and excellent durability, has been widely used as the cementitious binder in modern constructions . Howevermissions . Accordimissions  and othemissions  are the In order to reduce the energy consumption and improve the properties, special type cement can be used to partially or entirely replace Portland cement in light-weight aggregate concrete, especially for the aggressive environment, such as marine area, and sulfate or chloride attack. With exposure to these environments, calcium aluminate (CA) cement, calcium sulfoaluminate (CSA) cement, and supersulfate (SS) cement have been applied to manufacture durable LWAC with exposure to aggressive environment.2 with forms of tricalcium silicate (C3S) and dicalcium silicate (C2S), the main oxides of CAC are CaO and Al2O3 in the form of monocalciumaluminate (CA) instead of C2S and C3S. Although the CA cement has an outstanding performance, the high price (four to five times higher than the Portland cement) has significantly confined its wide applications, except some extreme cases, such as high temperature or acid attacking. It was claimed that the high-temperature resistance of CA cement lightweight aggregate concrete is better than the normal Portland concrete. This study compares the high-temperature resistance of CA/expanded clay aggregate LWAC and OPC/natural aggregate concrete. The results showed that after exposure to 1000 °C, the residual mechanical properties of the CA/expanded clay aggregate LWAC is better than the OPC/natural aggregate concrete [CA has significant merits compared to Portland cement, including the rapid hardening, high temperature and temperature change resistance, chemical attack resistance, biogenic corrosion resistance, impact resistance, and abrasion resistance. Unlike the Portland cement, in which the main oxides are CaO and SiOconcrete .Apart from CA cement, calcium sulfoaluminate (CSA) cement generally has a higher strength in the early and late stages compared to OPC ,18. CSA-e (C4AF) . The ye’quations , which cquations ,22,23,24The excellent corrosion resistance of CSA results from the formation of a dense pore structure according to these reactions. A previous study has evaluated the interactions between the OPC, CSA in LWAC . In thisBecause of the low heat of hydration and the excellent corrosion resistance with exposure to aggressive environments, supersulfate cement intrigues broad interests in recent years. Mixed with blast furnace slag, calcium sulfate, and alkaline activators, supersulfate cement showed its great potential as a promising binder to prepare durable concrete with exposure to the aggressive environment . The effOne of the most impressive merits of the supersulfate cement LWAC is its environmental resistance with exposure to chloride or sulfate attacking. Grounds investigated the resistance of decomposed ettringite to sulfate solutions when supersulfate cement samples are exposed to sulfate . The preAlthough the CA, CSA, and SS cement are considered to have application prospects because of its low carbon dioxide emissions and low energy requirements, it is worth noting that the challenges from academic and practical perspectives are mainly the high manufacturing cost and the lack of understanding the phase formation and hydration process of the mineral contents, and the unpredictable long-term durability.It has been widely recognized that Portland cement production not only consumes tremendous energy but also contributes to significant greenhouse gas emissions. As a result, the search for sustainable and low-carbon cementitious materials to replace Portland cement is burgeoning in recent years. The use of supplementary cementitious materials (SCMs) in normal concrete constructions has been investigated for several decades and showed a few promising benefits to enhance the mechanical properties and durability of concrete materials. However, the effects of the SCMs on the properties and durability of LWAC have yet been systematically investigated, especially by using the solid recycling wastes as SCMs or low-carbon cementitious materials.In order to study the effect of different SCMs on the carbonization resistance of LWAC, Bogas  selected2 emissions can also be significantly reduced by this substitution. It is worth mentioning that the slag had no obvious effect on the bond strength of concrete of the LWAC [Ground granulated blast slag (GGBS) as SCMs can partially replace cement, which can improve the workability of concrete by 30% compared with OPC concrete . It is mthe LWAC .In addition to these conventional SCMs, a few other cementitious materials use for LWAC comes into our views. Lynn  was concBui et al.  studied The application of SCMs to ordinary concrete has obtained relatively good application rules and application values. However, the use of these reused SCMs for lightweight aggregate concrete and special concrete under extreme environments is still in the experimental stage. The practical ways and effects need long exploration, especially insufficient research on its durability. An extensive systematic analysis on SSA in concrete and concrete-related products showed that this material had the potential for some different forms, such as lightweight aggregate production and fine aggregate ,39,40,41Reusing waste materials from agricultural and industrial wastes to prepare light-weight aggregates is an effective way to maximize the use of natural resources and reduce energy consumption . In geneAgricultural residues are extensively discarded or landfilled as solid wastes. Their utilization efficiency is quite low so that this waste accounts for a severe environmental problem. Recycling utilization of these wastes, such as oil palm shells, coconut shells, and corn cob, as lightweight aggregates to manufacture LWAC has brought broad interest in recent years.Oil palm shell (OPS), as a kind of by-product of oil palm-based agriculture, has the potential to serve as the lightweight aggregate of concrete. The amount of waste OPS is huge, and the most majority of OPS is from many Asian countries such as Malaysia, Indonesia, and Thailand, as shown in Shafigh  used theIf the dry density was considered, the control OPS concrete was about 20.8% lighter than the normal-weight concrete. Using OPBC sand instead of ordinary sand will further reduce the density of the concrete samples. When the proportion of the OPBC sand were 12.5%, 25%, 37.5%, and 50%, the densities were 21.7%, 22.2%, 26.2%, and 27.4% lighter than ordinary concrete, respectively, shown in In addition to OPS, coconut shell (CS) is also a large amount of agricultural waste in the coconut industry. It can be used as coarse aggregates or as a potential building material in the construction industry, which is helpful to solve the environmental problem of using recycling solid waste . It was 2 with the combination of Al2O3. This means that the corn cob ash can be used as a cementitious material. Corn cob as a lightweight aggregate for producing lightweight concrete in the non-structural applications was first researched by Pinto, and they measured the density, compressive strength, and thermal insulation properties of the corn cob LWAC. The results were compared with a non-structural lightweight concrete made with a lightweight artificial aggregate, namely, the expanded clay. The results pointed out that, although the compressive strength of the corn cob lightweight concrete is lower than the expanded clay lightweight concrete, the thermal conduction coefficient showed its advantages as non-structural applications [Apart from OPS, corn cob, an agricultural solid waste from maize and corn was also widely incorporated with cementitious powder to prepare lightweight concrete. Previous studies ,55 have ications .The cork industry generates large quantities of waste, which has been studied for the application in the construction industry. In terms of grain density, the density and absorption of the loose body are comparable to that of expanded perlite, vermiculite, and other artificial light aggregates. Compared with expanded perlite or vermiculite, the use of cork particles as lightweight aggregate can reduce energy consumption, consume renewable resources, and be more cost-effective. Besides, cork has a high absorption value and can be used as a lightweight aggregate for internal curing of concrete. As for other physical properties, the advantages of cork as a lightweight aggregate are verified .Besides these materials, Ozturk et al.  revealedAlthough the reuse of agricultural waste as an aggregate of lightweight concrete can achieve the acceptable performance of LWAC, its property still has room for improvement. Many industrial wastes include drill cutting, and steel cutting has been widely applied as aggregates.Drill cuttings consist of a fine mix of rock particles produced by drilling for oil and gas during either exploration or production, and they will be contaminated with drilling fluids and contain high concentrations of chloride salts . This liIn addition to drilling cuttings, waste plastic is another recycled material as aggregates. Colangelo proposed polyolefin waste aggregate (PWA) refined from recycled plastic materials as LWA instead of natural aggregate in the manufacture of LWAC . It can Steel cutting is another under-utilized resource. El-Sayed  did reseIt was claimed that if the raw materials were appropriately selected, the LWAC would show its distinctive advantage compared to the NWC . HoweverTo improve the mechanical properties of LWAC, reducing the water-binder ratio is a widely used method. However, when the coarse aggregate is replaced by the lightweight aggregate, the volume of the aggregates will be significantly increased, and the water-binder ratio will be considerably reduced. This brings a negative impact on the workability of the LWAC. Pierce et al.  used cruAlthough many industrial and agricultural wastes have been recycled and reused for manufacturing lightweight aggregates, or as supplementary cementitious materials to replace Portland cement, their utilization efficiency is still quite low. As a result, how to high-effectively reuse these wastes remains a significant challenge. Furthermore, in the actual production process, using industrial waste to manufacture aggregate often needs additional processing, which inevitably consumes energy and causes secondary pollution. Exploring environmentally friendly and cost-effective approaches are imperative to develop green LWAC.Concrete composite can be considered as a two-phase material, i.e., the aggregates embedded in the cementitious binder phase. According to the properties of aggregate and mortar, concrete can be divided into two categories. In the first type of concrete, including NWAC and some LWAC, the relatively strong aggregates are embedded in the relatively weak cementitious binder matrix. The short-term strength mainly depends on the water-cement ratio and the cementitious binder. In the second type of concrete, the relatively weak aggregates are embedded in the relatively strong cementitious binder matrix; hence, the influence of the aggregate on the strength of the concrete must be considered. By comparing the relationship between the mortar strength and the concrete strength, the influence of the aggregate on the overall compressive strength of concrete can be evaluated, as shown in Yap  aimed toThe mechanical properties of the LWAC made of oil palm shell (OPS) as the lightweight aggregates had been tested by Teo . The resAfter the investigation of the OPS, another study claimed that using palm oil clinker (POC) to replace the OPS as coarse aggregates has a positive impact on the mechanical properties of the LWAC . In thisThe application of granulated cork with bark (GCB) as lightweight aggregate to prepare concrete has been investigated most recently . In this3, as aggregates. The mechanical testing results demonstrated that, with using the recycled concrete as lightweight aggregates, the compressive, splitting tensile strength, and the modulus of elasticity have increased 14%, 32%, and 22%, respectively. It was claimed that the recycled aggregates obtained from the non-structural lightweight concrete can satisfy the requirements and be used in structural LWAC.Apart from the agricultural wastes, many types of industrial wastes, including recycled concrete, recycled clay bricks, fly ash, and various types of sludge, were also used as lightweight aggregates to prepare LWAC. Bogas  investigThe demolished waste clay bricks were used as lightweight aggregates to prepare LWAC . The dem2, Al2O3, Fe2O3, CaO, MgO, K2O, and Na2O are about 46%, 18%, 9%, 5%, 1%, 2%, and 2%, respectively. The 28 days compressive strength and splitting tensile strength can reach 56 MPa and 3.0 MPa, respectively, and the measured modulus of elasticity is about 19 MPa. An interesting phenomenon being observed in this study was the 7 d compressive strength had reached 91% of the 28 d compressive strength. This was the reason that the loading transfer mechanism between the hydrated cement paste and the lightweight aggregates. The microstructure analysis of the ITZ revealed that the cement paste had penetrated into the lightweight aggregates, which reinforced the interfaces between the aggregates and the cement paste.Except using the recycled construction materials as lightweight aggregates, using industrial wastes to prepare lightweight aggregates is another important branch of the LWAC manufacturing method. Lo  prepared2 (55%), Fe2O3 (14.3%), Al2O3 (20.6%), K2O (2.7%), CaO (2.7%), MgO (1.4%), and balance (3.5%). This study investigated the synergistic impact of the aggregates and cememtitious binder. The sludge ceramsite was 100% used as the coarse aggregates and the cement was partially replaced by GGBS. It was found that, although using the SC along with RA and GGBS had significantly reduced the compressive strength, if solely using SC as coarse aggregate, the compressive strength of the LWAC can reach about 13.9 MPa. The elastic modulus results of all samples were in the range of 6.5–9.5 MPa. Unlike the statement from Zhao’s study [Sludge ceramsite (SC), recycled aggregates (RA), and ground granulated blast-furnace slag (GGBS) were used as coarse aggregates, fine aggregates, and supplementary cememtitious materials to prepare the LWAC . The mai’s study , the micFrom compression and crack development perspectives, microcracks often occurred at the interface between the binder and the aggregate. As the stress increases, the cracks in the vicinity of aggregates gradually expanded, and the cracks in the mortar interlocked each other until the failure occurred, as demonstrated in It is not surprising that the mechanical properties of the LWAC is relatively lower than NWC, and the strengths of the LWAC decrease with increasing content of LWA ,79,80,81Shrinkage is one of the primary reasons that account for the cracks. The early age cracks of cement-based materials will lead to premature degradation of concrete structure, so as to shorten its service life. To reduce shrinkage and improve resistance to shrinkage cracking performance of cement-based materials, a variety of methods were adopted, including (1) expansive-based cement/admixture which compensate the shrinkage through the expansion-induced stress ,87; (2) Internal curing, also known as self-maintenance curing, refers to a curing method that relies on pre-absorbent materials to release water to maintain sufficient moisture inside the concrete under adiabatic conditions, it was developed to eliminate self-desiccation and reduce autogenous shrinkage . In receThe self-shrinkage reduction mechanism of the lightweight aggregates is primarily from the gradually releasing of the internal water. During the hydration process, a humidity gradient is formed between the internal curing agent and the cementitious material, and the capillary pressure difference will be generated so that the moisture in the LWA will be released to compensate for the loss of humidity .The effects of LWA performance and mixing parameters on the auto-shrinkage performance have been studied previously. Harmful effects of internal curing on the early strength had been reported in most cases . HoweverEarly age crack that emerged on cementitious materials caused by the autogenous shrinkage plays a significant role in determining the strength of concrete materials, especially for LWAC. Therefore, one of the best ways to reduce early age cracks in the cement matrix is the incorporation of SCMs. Meddah investigated the effect of SF on autogenous shrinkage of LWAC. The results showed that the greater the autogenous shrinkage, the greater the induced internal tensile stress, and the appropriate SCMs can increase the volume stability . Bentz  establisThe shrinkage reducing agent is composed of polyether or polyalcohol organic matter or their derivatives . The mecShrinkage reducing admixture (SRA) is a water-soluble organic chemical with low viscosity, whose main function is to reduce the surface tension of the solvent . At the As for the research of lightweight aggregate concrete, most of them were focused on the aggregate types , mechaniThe carbonation of concrete is a diffusion process of carbon dioxide through the porous microstructure of concrete. The ingressed carbon dioxide reacts with the calcium hydroxide and forms calcium carbonate, which reduces the pH value of the pore solution as low as 11, and thus results in the corrosion of the steel reinforcement in concrete . As wellAlthough LWAC exhibits excellent performance, its carbonization mechanism is still lacking to the best of our knowledge. Newman  pointed RS) to the total aggregate is another factor that determined the carbonation resistance. It was claimed that the increase of the VRS can slightly escalate the carbonation of the LWAC. The main contribution of this study is that the potential mechanisms of the impacts were pointed out. It was believed that the high w/b ratio will lead to the high porosity, which increase the potential carbonation degree of the LWAC, and the increase of VRS will result in a high specific surface area of the waste clay brick, which enhance the pozzolanic reaction between the Ca(OH)2 and the clay bricks. This will dwindle the amount of the Ca(OH)2 in cementitious binder and thus mitigate the carbonation problem of the LWAC. This mechanism is worthy of further systematically investigation.Zhao recycled the waste clay bricks as lightweight aggregates for the LWAC preparation . The wasApart from the w/b ratio, the mineral admixture is another important factor that determines the carbonation resistance of the LWAC. Gao  investigIn the physical and chemical deterioration mechanism of concrete, chloride ion and/or other corrosive ions diffusion in concrete is the most noteworthy phenomenon. The microstructure of concrete is the main factor controlling this process, which is related to water transport and ion diffusion in concrete . The porGüneyisi et al.  used silThe water saturation condition of the LWA is the main factor affecting the freeze resistance of LWAC. Zhu  carried In Tang’s study , lightwem is the magnitude as defined in seismology; m is equivalent to the log scale of the amplitude “a” of the AE signal. N is the number of signals with a magnitude greater than m, and the coefficient b is the negative slope of the logN–m plot.Acoustic emission (AE) is a relatively new method that can be used to explore the mechanism of explosive spalling of LWAC at high temperature ,120. Theb  varies with the type of damage. At the initial stage, a large number of low-amplitude acoustic emission signals were generated. Later, fewer signals were produced, while the amplitude was high. This means that the value of b decreases gradually as the sample approaches the impending failure. This is at the heart of the so-called b-value analysis used to assess damage [Specifically, the coefficient index s damage . By moniMeans of neutron radiography (MNR) can be used for the visualization and quantification of liquid water transport . The higNon-destructive techniques (NDTs) play an essential role in the quality control of new buildings and the evaluation of the service condition of existing concrete structures ,128. TheThe research work in recent years provides a framework for further research on the improvement of the mechanical properties of LWAC produced by waste and recycled by-products. The physical properties of LWAC, mixing ratio design method, freshness, and hardening properties of LWAC were discussed.It was found that many solid waste materials, from both industrial and agricultural by-products, can be used as supplementary cementitious materials and lightweight aggregate materials to prepare green lightweight aggregate concrete. Several main industrial by-products, including silica fume, fly ash, lime powder, ground granulated blast slag, and various sludge, have been investigated as replacement of Portland cement. The results indicated that, provided with proper design and manufacturing process, these industrial by-products can be used as cementitious materials to prepare green lightweight aggregate concrete.Apart from the supplementary cementitious materials, it was found that, many types of agricultural by-products, including oil palm shell, oil palm-boiler clinker, coconut shell, corn cob, cork, and tobacco wastes, and several industrial wastes, including drill cuttings, waste plastic, recycled clay bricks, various sludge, and steel cutting can be used as lightweight aggregates for manufacturing green lightweight concrete. The mechanical properties testing results shows that the lightweight aggregate concrete manufactured from the above mentioned agricultural and industrial by-products can meet the field application requirements. Although the durability testing of the lightweight aggregate concrete is quite limited, several studies have shown that the durability of the lightweight aggregate concrete is strictly correlated to the porosity and the saturation degree of the lightweight aggregates.(1)The chemical reaction mechanisms between the recycled aggregates and cementitious binders should be investigated systematically. So far, the chemical bonding between the aggregates and the cementitious binders remains unclear. Further studies should focus on the chemical analysis of the aggregates, cementitious binder, and the interfacial area to elucidate and characterize the chemical reactions of the various recycled lightweight aggregates and the cementitious binders.(2)For the lightweight aggregate concrete in the construction, prewetting of the lightweight aggregate is an appropriate way to reduce water absorption and improve the workability. The interface wettability between the lightweight aggregate and the cementitious pastes needs to be investigated. The impact of the saturation degree of various recycled aggregates on the workability, mechanical properties, and even durability should be further investigated.(3)The porosity of the aggregates is another critical factor that determines the final properties of lightweight aggregate concrete. So far, the relationship between the porosity of the recycled lightweight aggregates and the final properties of the lightweight aggregate concrete is still lacking, especially when the chemical compositions of the lightweight aggregates were different.(4)At present, researches on lightweight aggregate concrete mainly focus on high strength, which is an inevitable trend of future development. However, the durability challenge and the segregation resistance in engineering applications are worthy of this concern.Although previous studies have demonstrated that the green lightweight aggregate concrete made of solid waste materials have a great potential to be widely used in practical applications, they are still facing several critical challenges need to be further investigated:


The roles of the hypothalamus and particularly the lateral hypothalamus (LH) in the regulation of inflammation and pain have been widely studied. The LH consists of a parasympathetic area that has connections with all the major parts of the brain. It controls the autonomic nervous system (ANS), regulates feeding behavior and wakeful cycles, and is a part of the reward system. In addition, it contains different types of neurons, most importantly the orexin neurons. These neurons, though few in number, perform critical functions such as inhibiting pain transmission and interfering with the reward system, feeding behavior and the hypothalamic pituitary axis (HPA). Recent evidence has identified a new role for orexin neurons in the modulation of pain transmission associated with several inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. Here, we review recent findings on the various physiological functions of the LH with special emphasis on the orexin/receptor system and its role in mediating inflammatory pain. The functions of the lateral hypothalamus (LH) in the regulation of vital body functions have become a popular research topic. Important among these functions is that of the regulation of inflammatory pain. The LH is also a site for integration of autonomic and endocrine responses, and a crucial regulator of pituitary function and homeostatic balance . It is dThe LH plays a key role in regulating autonomic functions and relays information to all major parts of the brain including the major hypothalamic nuclei . ConvergThe LH is involved in numerous functions, including sleep, arousal, and the regulation of the autonomic nervous system (ANS) . More im1)-adrenoceptors of the LH has been linked to behavioral activation and exploration, despite the insignificant number of these receptors in the LH  . StudiesGlutamate neurons of the LH mediate important physiological processes in the CNS. Studies have shown that LH glutamate neurons produce behavioral functions opposite to those of LH GABA neurons. In mice, optogenetic activation of putative glutamate neurons of the LH suppressed feeding and produced aversion-related phenotypes , while tNeurons expressing melanin-concentrating hormone (MCH) are also widely present in the LH. Functional and anatomical studies showed that MCH neurons co-express the vesicular glutamate transporter 2 (VGLUT2), indicating a glutamatergic identity , and proAnother type of neuron found in the LH is the galanin-containing neuron . These nAnother neuronal population of the LH involved in the regulation of feeding behaviors is the leptin-receptor (LepRb) expressing neuron. LepRb-expressing neurons are widely expressed in the brain, but are particular enriched within the hypothalamus and the brainstem . In miceSubstance P and neurotensin-releasing neurons are also found in the LH . SubstanOn the other hand, neurotensin neurons of the LH are involved in the regulation of the sleep/wake cycle  and are By being an extensively researched population of cells in the past recent years, orexinergic neurons, and especially those of the LH, have been shown to have different roles in inflammatory pain and in the balance of psychological functions . OrexineOther neuronal populations in the LH not mentioned above include neurons that express cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, encephalin, urocortin-3 and corticotropin-releasing hormone  and orexin B . These neuropeptides originate from the same precursor known as prepro-orexin . Orexin-in situ hybridization and immunohistochemical techniques indicate that orexin neurons in the LH mostly express the vesicular glutamate transporters, VGLUT1 and VGLUT2, suggesting that they are glutamatergic , a peptide that plays a role in the regulation of feeding behavior, metabolism and energy balance . This neignaling .in situ hybridization, immunohistochemistry and quantitative reverse transcription–polymerase chain reaction in rodents found that these receptors are widely distributed throughout the brain and spinal cord , Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). In particular, findings indicate that patients with MS have significantly lower serum  and cereThe neuronal network of the LH has been implicated in many vital physiological functions in the body such as feeding behavior, reward systems, sleep/wakefulness cycle, stress regulation and inhibition of inflammatory pain. Integrated in this network are orexin neurons; though few in numbers, they play a big part in controlling several aspects of bodily functions because of their extensive projections in the CNS and the abundance of orexin receptors in peripheral organs. The role of these neurons in mediating inflammatory processes and regulating pain perception has been highlighted in several studies, however, more experiments are needed to better understand the signaling mechanisms underlying their anti-inflammatory and anti-nociceptive effects. Future work should also focus on better understanding the role of the orexin system in inflammatory disorders. The multifunctional role of orexin receptors makes them a credible therapeutic target for disorders characterized by inflammatory pain and could ultimately be used in clinical practice to help patients cope with their symptoms.MF and IS contributed to the initial design of the review and wrote the first draft of the manuscript. WN and GM wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.