Reinforcing fibers have been widely used to improve physical and mechanical properties of cement-based materials. Most fiber reinforced composites (FRC) involve the use of a single type of fiber to improve cement properties, such as strength or ductility. To additionally improve other parameters, hybridization is required. Another key challenge, in the construction industry, is the implementation of green and sustainable strategies based on reducing raw materials consumption, designing novel structures with enhanced properties and low weight, and developing low environmental impact processes. Different recycled fibers have been used as raw materials to promote circular economy processes and new business opportunities in the cement-based sector. The valuable use of recycled fibers in hybrid FRC has already been proven and they improve both product quality and sustainability, but the generated knowledge is fragmented. This is the first review analyzing the use of recycled fibers in hybrid FRC and the hybridization effect on mechanical properties and workability of FRC. The paper compiles the best results and the optimal combinations of recycled fibers for hybrid FRC to identify key insights and gaps that may define future research to open new application fields for recycled hybrid FRC. Cement-based materials have been used in structural applications for many decades even though they have low tensile strength, ductility and crack resistance. The incorporation of steel bars or the addition of dispersed fibers are the most popular reinforcing strategies to overcome the brittleness of concrete. Steel, glass, synthetic polymeric fibers and natural-based fibers are the main reinforcing fibers used in cement-based materials to increase ductility, flexural and tensile strength and to avoid crack propagation ,2.Many researchers have studied the effects of different types of fibers and their combination (hybrid composites) on workability, mechanical properties and shrinkage of cement-based materials ,6,7,8,9.On the other hand, recycling, waste valorization and circular economy concepts have been widely developed in this period, through strong research efforts aimed to improve the sustainability of FRC production, use and management (at the end of its life) ,17. ThesMany studies have focused on using recycled reinforcing fibers from recycled plastics, end-of-life-tires and construction waste. Recycling the waste to produce new materials, like concrete or mortar, has been raised as one of the best solutions, due to economic and ecological advantages as well as energy saving in their disposal ,35. TherIn 2016, the amount of generated construction and demolition waste in Europe was around 374 million tons . The EurMore than 120 works were reviewed and classified into three categories depending on the nature of used fibers. This review analyzes the properties of recycled fibers of different natures and their effect on mechanical properties of hybrid FRC and neatly summarizes the best results obtained on each reviewed work and assesses the optimal combinations of fibers for hybrid FRC containing recycled fibers.The information used in this paper has been collected from SciFinder Scholar, Web of Science and Google Scholar databases and from the previous experience of the authors in this field. These are three databases with wider data coverage, and they complement each other. The largest free database is Google Scholar. It contains nearly 400 million documents comprising articles, patents and citations . HoweverA wide range of recycled fibers have been studied for R-FRC formulation, as shown in The use of steel fibers is common in hybrid formulations. Waste tires is the most used source to produce recycled-tire steel fibers (RTSF), but other sources such as waste metal lathes, have also been studied with promising results . RTSF arThe use of RGF in R-FRC as a reinforcing fiber is less common than steel. In this case, it is mainly used as glass powder as a pozzolanic aid to replace part of the cement powder . RGF is RPF are recovered from many different sources with municipal waste the most common, especially from high density polyethylene (HDPE) and polyethylene terephthalate (PET). Many studies have demonstrated the possibility of using different types of RPF in R-FRC production, such as PET ,62,63,64The dimensions and properties of the recycled fibers mainly depend on the original source and the recycling process. For example, mechanical recycling of tires, shredding, cutting the fibers and producing short thin fibers, while pyrolysis of tires keeps the original steel fiber dimension . Table 1The RTSF size distribution is broad and they are partially deformed, which increases mechanical agglomeration. Most of the researchers that use RTSF in hybrid R-FRC, do it for structural application. Steel is one of the most promised recycled fibers because of its high strength and ductility, especially in RSF from tires. In this case, the flexural and tensile strengths are higher than many of the industrial steel fibers, because of their different composition . Steel hAlthough there are several works on the use of virgin glass fibers in hybrid FRC, especially combined with synthetic polymeric fibers, for example PP, there are not many researchers that have used RGF in hybrid R-FRC formulations. RGF are mainly designed to be thermal and electrical insulators and to be highly compatible with polymeric matrixes. They have the drawback of their poor ductility, which can be compensated by a combination with polymeric fibers. Alkali resistant glass fibers have the advantage of their high chemical strength and their high compatibility with the cement matrix, but the composition of RGF is different from the alkali resistant glass fibers, which affects the R-FRC durability. RGF are mainly recovered from building waste, for example insulator composites and automotive wastes. Furthermore, while the morphology of virgin fibers is homogeneous and they are well dispersed, RGF are heterogeneous, form bundles and they can contain part of the polymer matrix. These facts affect their reinforcing ability ,57,82.As it is well known, the morphology and properties of polymeric fibers vary notably with the nature and source of the fibers ,83. The The effect of recycled fibers on FRC properties depends on their morphology, chemical composition and mechanical properties, which are determined by the waste source and the recycling process. Apart from their mechanical properties, the reinforcing efficiency of fibers is determined by their homogeneous dispersion and the bonding ability with the matrix. Therefore, the selection and properties of waste fibers is key to assure an optimal FRC reinforcement performance and therefore to reach the same performance of the standard industrial fibers reinforced composite .The kind, origin and dose of fibers affects the stress–strain characteristics. The reinforcing effect of RPF is often lower than that for RSF from tires, but they are also able to increase load capacity and residual strength, although a minimum dose could be required to observe those effects. For example, PET fibers only increase load capacity, toughness and energy absorption of plain concrete at doses of 0.18% and higher . SimilarIn the case of steel fibers, there are controversial results when comparing published works. Recycling affects their morphology, but it does not necessarily cause a detrimental effect on the mechanical properties of the fibers ,105. ForWhen glass fibers are used as reinforcement in FRC, chemical composition is a key issue. Glass fibers in cement matrix can produce an expansive gel due to the highly alkali environment, in long-term affecting the durability of concrete. Due to this, especially alkali resistant glass fibers are preferred as reinforcement in FRC. However, RGF are recovered from composites with other kinds of matrix, for example thermal insulators, reinforced polymers, electrical insulators composites, among others; they do not have such a high durability on matrix cement. However, RGF recovered from woven fiber sheets have been used by Mastali et al. (2016)  with higIn general terms, the presence of recycled plastic waste (fibers or aggregates) produces a reduction of density (5–25%) of concrete or mortar ,60,62. TThe use of PET fibers decreases notably workability of concrete independently of their geometry and dimension ,115,116.However, the incorporation of recycled PET has not a clear effect on compressive strength. Guendouz et al. (2016)  found thFadhil and Yaseen (2015)  found thGuendouz et al. (2016)  studied The most common effect of using fibers is the reduction of workability of fresh concrete regardless the nature of the fibers ,123,124.Furthermore, many of the recycled fibers tend to mechanically knit during mixing in fresh concrete, which hinders their dispersion in the matrix and reduces workability. This phenomenon is called “balling” and it is favored by broad size distributions and a variety of shapes ,95. To aTo solve the workability limitations and the fiber balling, while keeping a high compressive strength, Chu et al. (2021)  proposedGuendouz et al. (2016)  and de OTherefore, it is clear that the concrete composition must be optimized considering the recycled fibers characteristics to achieve the required workability and a good fiber dispersion . To imprAir content can increase with fibers addition too, especially if the specific surface is high and the fiber is grouped in bundles with aspect of fluff . This moSome authors have observed a beneficial effect of the fiber’s presence on segregation prevention. Fibers contribute to block segregation of particles in cement, providing they are well dispersed ,124. OneNevertheless, the main benefit of using recycled fibers is the reduction of the environmental impact. Several authors have studied the environmental sustainability of the R-FRC process including Life Cycle Assessment (LCA) ,129,130.This section focusses on hybridization with homogeneous nature fibers, i.e., metallic-metallic, polymeric–polymeric fibers. Therefore, all the combined fibers have a similar affinity for the matrix and their differences are mainly based on the fiber source , the kind of polymer or the fiber morphology. The effect of hybridization with heterogeneous fibers, with a different affinity for the matrix, is more complex and it will be reviewed in Several studies have evaluated the combination of industrial and RMF, mainly obtained from waste tires, in the performance of hybrid R-FRC .Caggiano et al. (2017)  have repIt is well known that the flexural toughness of the FRC can be evaluated by determining both first crack strength and post-cracking flexural behavior  to evaluate the flexural behavior until the first cracks appear and after cracking, respectively. Some studies have reported that the presence of recycled fibers in the hybrid R-FRC has not had an important influence on the first crack strength ,133,134 On the contrary, a significant decay in the post-cracking flexural behavior has been reported by several studies when virgin steel fibers are partial or total replaced by RTSF ,133,134.In general terms, the higher the fraction of recycled fibers, the more significant the reduction in the post-cracking toughness  observed in the four-point bending tests . The mai0 values) were defined as a plastic type. However, the presence of RMF in the composites turned the post-cracking behavior at ultimate state from hardening  to a plastic type [The post-cracking response of all composites  for small crack openings   observedAlthough steel fibers are the most used in the formulation of hybrid metallic fibers R-FRC, there are some studies combining different metals too. For example, Naser et al. (2020)  combined3) was much lower than that of crushed gravel (2.64 g/cm3). However, the replacement of 25%, 50% and 75% of gravel by walnut shell reduced the compression strength by 28.7%, 41.9% and 63.6%, as well as the splitting tensile strength by 28%, 47.93% and 68.8%, respectively. Therefore, Cheng et al. (2017) [Limited studies have been reported on the use of recycled low costs fibers, mainly PET and PP fibers, to partially replace non-recycled fibers in cement composites ; Table 4. (2017)  evaluate. (2017) ,118. Bes. (2017) .Combining fibers with different sizes allows to increase the reinforcing effect too , but it According to Schmidt and Cieślak (2008) , the durFor enhancing the alkali resistance of the rPET fibers and improving the fiber–matrix interfacial chemical and frictional bond, rPET fiber surface could be treated with NaOH solution and a silane coupling agent . RecentlSome researchers have evaluated the use of rPP fibers and recycled coarse aggregate as replacement agents of non-recycled fibers and natural coarse aggregate, respectively, in the production of reinforced concrete beams ,143. In SHCC is a type of engineered FRC with high tensile strength, ductility and enhanced properties due to the fiber-bridging action of fine multiple cracks as a consequence of the even distribution of the fibers. Therefore, they present a tensile strain hardening after the first cracks occur. Some researchers have studied the addition of recycled fibers to partially or even totally replace non-recycled fibers in SHCC to reduce the cost and the negative environmental impact associated with the use of industrial fibers instead of non-recycled materials. For example, Choi et al. (2012)  have stuThe use of fibers with different natures allows getting an advantage from the interesting properties of both types of fibers while minimizing the cost. The different nature of fibers implies different affinities with the matrix and therefore, a more complex integral behavior. Most of the studies about complex hybrid R-FRC involve steel fibers and synthetic polymeric fibers, and in the majority both kinds of fibers are recycled from waste ; Table 62 emissions, 29% water savings and 78% oil equivalent natural resources saving, with respect to the alternative of using virgin PP fibers.One of the first studies on complex hybrid R-FRC was carried out by Meddah and Bencheikh (2009) . They obMastali et al. (2018)  also carKarthik et al. (2015)  observedWaste steel fibers decrease workability of the fresh paste and it affects the product properties or the consumption of superplasticizers. As already mentioned, this effect is related with the non-uniformity of the recycled steel fibers and with the aspect ratio. One of the benefits of hybridization with PP fibers is the improvement of workability by replacing part of the waste steel fibers. This is one of the results obtained by Zhong et al. (2020)  who obse2 saturated suspension or by coating with limestone paste [Waste tires are one of the most studied sources of recycled fibers for hybrid R-FRC because they contain metallic and polymeric fibers in one source and the rubber can be used to replace part of ground aggregates in concrete with the advantage of its lower thermal conductivity. Serdar et al. (2014)  studied ne paste . Rubber ne paste ,52. TherWaste steel fibers can be also obtained from lathes ,97. CombDifferent results were obtained for hybrid composite with lathe waste steel and recycled PP fibers from bags. In this case, the compression strength of the composite was up to 20% lower than that for plain concrete (30 MPa), but flexural strength increased up to 12% . This isOzerkan et al. (2016)  studied Some studies combined industrial or recycled metallic fibers with glass fibers for structural applications. Glass fibers have a better affinity for cement matrix than polymers, but they are rigid. The effect of steel–glass hybrid reinforcement on compressive strength of self-compacting concrete is not significant . HoweverThe use of complex hybrid carbon and glass reinforcement made no sense 10 years ago. However, the increasing use of polymer core composite conductors formed by glass and carbon hybrid fiber made the researchers aware about the recycling difficulties of that waste, which is costly and complex because the harsh methods required to separate both materials can severely degrade the mechanical properties of the fibers. The increase of wastes from the use of this kind of composite materials requires developing new uses and Clark et al. (2020)  proved tStructural Engineering, for repairing and reinforcement buildings and infrastructures ,143,145;Transportation Engineering, in the construction transport infrastructures such as high-speed railways ,146, in Material Engineering, as advanced construction materials ,141 or aConstruction Engineering, as repair mortar , for theTunnel Engineering, for construction of lined tunnels .The results compiled in this review have demonstrated that the use of different recycled fibers from waste  would alIn most of the cases, the content of recycled metallic fibers from waste tires with hooked ends of industrial steel fibers or with industrial PP fibers, increases the impact energy absorption, the chemical resistance in seawater and decreases shrinkage of the R-FRC accomplishing the strict mechanical requirements for structural applications.On the other hand, hybrid R-FRC with recycled glass fibers or recycled plastics, obtained from recycled bottle or carpets, is a good option for applications with high flexural strength and low shrinkage requirements as pavement constructions or design of advanced construction materials with specific properties, e.g., low thermal conductivity.The highest effort in using recycled hybrid reinforcement has been carried out in the framework of structural applications, where FRC must accomplish strict and tough mechanical requirements. For this application, the combination of steel fibers from waste tires with hooked ends of industrial steel fibers or with industrial PP fibers is the most efficient reinforcing approach. This combination (i) improves the final product: increases impact energy absorption, increases chemical resistance in seawater, and decreases shrinkage; (ii) saves costs; and (iii) reduces the environmental impact. On the other hand, the effect of hybridization on compressive strength can be detrimental. In most cases, there is only a slight decrease, but if polymeric fibers are present the decrease is up to a 30%. However, when different steel fibers are used the compressive strength may increase with respect to plain concrete. Therefore, each fiber fraction must be optimized for each application. Liew and Akbar (2020)  have recFor applications with high tensile strength requirements, three good options have been identified: (i) hybrid R-FRC with RGF and unsaturated polyester, both obtained from thermoset composites; (ii) recycled PP fibers combined with acrylic fibers; and (iii) the hybridization of recycled PET with industrial PP fibers. The last can be the best option to manage part of the recovered PET from waste PET bottles in R-FRC, with a notable increase in R-FRC tensile strength compared to plain concrete.Besides the potential valuable of recycled hybrid FRC, there are several challenges that must be solved for the implementation and consolidation of these processes, which require further research efforts in several topics:Challenges related to the optimal morphology of the recycled fibers, because size and shape distributions are too broad to obtain good results at industrial scale. In most studies, researchers have cut or selected the fibers manually, which is not possible in a large scale FRC production. The broad size and shape distribution of fibers reduces workability in excess and favors their mechanical entanglement, increasing the consumption of superplasticizer and challenging the homogeneous distribution of the fibers in the matrix;The way to extend the limits of the reinforcing effect of recycled polymers;The optimal dispersion of polymers and the improvement of their interaction with the matrix, which is limited due the polymer hydrophobic nature, to decrease air entrapment in the fresh mixture;The rubber attached to polymeric and steel fibers from waste tires is another issue that requires deep study. It is true that it contributes to increase notably the impact energy absorption at first crack and at ultimate stage, but rubber particles reduce the fiber-matrix interactions, decreasing the compressive and flexural strengths compared to those of industrial steel FRC;The durability of hybrid R-FRC could be affected if the specific surface of recycled fibers is higher than that of industrial fibers. This is especially relevant in the case of recycled steel fibers because steel corrosion would be faster. On another hand, rubber attached to steel fibers would protect them from corrosion. Therefore, durability must be further studied in these cases;The interest and consolidation of 3D printing of concrete is increasing fast. Reinforcement of concrete structures made by 3D printing can be manually placed, for example, in form of steel bars. However, a better alternative is reinforcement by means of fiber dispersion, which need to be further explored . In thisResearch on the use of recycled reinforcing fibers for producing more sustainable hybrid fiber cement-based materials is very widespread in the last few years. Although current findings prove the valuable use of recycled fibers in hybrid FRC, the knowledge on the potential enhancement of different properties is fragmented. This critical review compared and grouped the different results, to provide a deep understanding on the use of different recycled fibers. Furthermore, the effects of using different recycled fibers, alone or in different combinations, on the different properties of the final cement products as a function of the dosage are quantified. Thus, the use of reinforcing fibers can be optimized according to different final product requirements. From the analysis of the results compiled in this review, it is concluded:In summary, the use of recycled fibers in hybrid R-FRC is a promising way to not only enhanced the product properties but also to improve sustainability and to reduce FRC costs. However, research is still need it to overcome the identified challenges related to fiber dispersion, quality and workability. Overcoming these challenges could open new application fields for hybrid R-FRC.


Immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis , are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis-associated neoplasia. Only 40–60% of patients respond to currently used standard-of-care immunotherapies. In addition to this limited long-term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is considered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the progressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures. Immune-mediated inflammatory diseases (IMIDs) comprise a large number of chronic inflammatory conditions such as inflammatory bowel diseases , chronic inflammatory arthritis , and multiple sclerosis. The clinical course of these debilitating diseases is typically marked by relapsing exacerbations, causing lifelong morbidity, disability, and heightened risk of disease-associated mortality . OptimizThe beginning of the 21st century marked a new chapter for genomic research; next-generation sequencing (NGS) technology made it possible to routinely generate billions of reads and to quantify millions of transcripts in parallel. It first started with the analysis of cell mixtures, but further technological developments; protocol optimizations; and, above all, the increasing commercialization with upcoming simplifications and standardizations of the experimental procedures enabled the generation of datasets on a single-cell level . This deScRNA-seq was first established in 2009 . VariousInDrop, Drop-seq, and 10× Genomics Chromium are the three most frequently used systems until now. Besides differences between the systems with regard to bead manufacturing and barcode design, the cDNA conversion distinguishes in particular the systems . WhereasBesides understanding the composition of the inflammatory niche, single-cell transcriptomic analysis can guide successful therapeutic interventions for patients with IMIDs. Kim et al., recently described the successful use of tofacitinib in a patient with drug-induced hypersensitivity syndrome after performing an scRNAseq analysis of the patient’s skin and blood . ScRNAseDespite an increasing number of studies employing scRNA-seq in IMIDs, spatial information of the tissue context is missing. However, spatial gene expression heterogeneity does not only play an essential role during organ development but also in various pathological processes of IMIDs. Macrophages are able to protect tissue niches but also cause the migration of further immune cells to open up the niche for inflammatory responses . FibroblOn the protein level, mass cytometry has evolved as a valuable high-throughput assay for single cells and is recently also available for the analysis of tissue sections (imaging mass cytometry (IMC)). Mass cytometry/IMC is a technique that resembles flow cytometry but uses rarely abundant metal-coupled antibodies to stain for proteins instead of fluorescent dyes. Since these metals are usually not present in biological specimens, mass cytometry usually has a minimal background and a good signal-to-noise ratio. Technically, single cells are ionized with inductively coupled argon plasma, and then the ions are separated by mass (TOF mass spectrometry) and quantified. Mass cytometry allows for the generation of high-throughput data in a very short period of time. In IMC, FFPE or frozen tissue sections are stained with metal-labeled antibodies. The resolution is about 0.5–1 µm, allowing for subcellular localization of protein expression. Currently, panels including about 40 different antibodies are feasible for IMC and mass cytometry. IMC is a powerful tool to detect proteins in a directed manner but is limited by the availability and applicability of the metal isotopes. Furthermore, other macromolecules such as lipids or small metabolites cannot be detected. Unbiased approaches are based on mass spectrometry, e.g., matrix-assisted laser desorption ionization (MALDI) imaging, which takes advantage by measuring metabolites but does not reach single-cell resolution . Yet, unNon-invasive imaging modalities such as CT, PET, and MRI have been extensively used in clinical practice and greatly facilitate diagnosis and evaluation of treatment of autoimmune diseases. However, their imaging lateral resolution is within the range of 50–100 μm . TherefoConfocal microscopes focus a laser beam on a small focal spot that scans through the sample and detects fluorescent light emitted by the sample. The use of a detection pinhole permits light only from the focal plane to reach the detector, and therefore enables optical sectioning. Consecutive imaging at different depths allows for three-dimensional (3D) volumetric imaging of samples . Under oSome of these imaging disadvantages can be mitigated by multiphoton laser scanning microscopy (MPLSM), in which a fluorophore absorbs two or three photons emitted by a pulsed infrared laser source. The infrared excitation light penetrates tissue deeper than visible light at shorter wavelengths used in confocal microscopy due to less tissue scattering. In addition, MPLSM restricts the fluorophore excitation in a very small focus and thus results in optical sectioning without the need of a pinhole used in confocal microscopy to block the light out of focus. Together, MPLSM enables the deep tissue penetration depth, the lack of out-of-focus bleaching, and the reduced photo-damage while maintaining very good spatial and temporal resolution. Two-photon laser scanning microscopy (TPLSM), the most popular form of MPLSM, is therefore widely used for 3D imaging and intravital imaging of immune cells in vivo . In expeThe generation of a nonlinear optical process, named harmonic generation (HG), is another advantage of MPLSM imaging. Photons simultaneously interact with biological materials and convert into one photon in HG. Secondary harmonic generation  and third harmonic generation  are the most common forms of HG used for label-free imaging by MPLSM, as signals come from the optical property and the structure of the material. For biomedical applications, HG is very useful in the imaging of connective tissue, collagen fibers, muscle, inflammatory cells, and blood vessels in vivo and in vitro . For insWhile CLSM and MPLSM enable imaging with great spatial resolution and penetration depth, the acquisition speed of both microscopies is limited because the image is built up one voxel at a time. In order for this limitation to be addressed, light-sheet fluorescence microscopy (LSFM) was developed. The concept of LSFM was introduced more than 100 years ago  and has An inherent drawback of fluorescence microscopy is its spatial resolution, which is limited by the diffraction of light. The diffraction limit is about 200–300 nm in the lateral direction and 500–700 nm in the axial direction. Many subcellular structures will be too small to be resolved under this resolution. The diffraction limit was bypassed by the invention of several SRM technologies, such as stimulated emission depletion (STED) microscopy ,67, struThe combination of molecular omics data profiling and improved imaging techniques provides unique advantages for clinical diagnosis, monitoring, and therapy of IMIDs, which could lay the basis for the optimized care of patients with IMIDs. However, these high-end technologies are of limited utility without complementary methods for interpretation of the collected data to decipher the inherent complexity of the investigated diseases. To extract detailed information and draw conclusions with wider applicability to biological processes, datasets have to be integrated and analyzed as a holistic system. For example, the Standardization of Clinical Testing (Nex-StoCT) and the U.S. Centers for Disease Control and Prevention (CDC) have collaborated to establish measures to ensure that analytical approaches of NGS data are valid, and that tests based on NGS meet existing standardized clinical laboratory requirements . The conBioinformatics challenges also explain why omics technologies are yet to gain broad clinical applicability. Taking the context of RNA sequencing, one major challenge includes the fact that there is currently no harmonized body to lay down standards that will ensure the analytical quality of RNA sequencing analysis pipelines. Another challenge has to do with the abundance of software tools and their combinations for the analysis of RNA sequencing data, and in third place, highly complex pipelines consisting of the chaining together of tools that are largely independently developed, maintained, updated, and licensed . Very feThe advances in gathering omics data that are scaled down to a single cell led to enormous, to some extent even boundless amounts of information that is impossible to comprehend without developing dedicated tools and methods. The desire to use this rich information and uncover new, yet unknown dependencies, regulatory mechanisms, and patterns greatly influenced the development of the new research field of Systems Biology. Not pretending for the generality of the definition , SystemsThe initial step of the bottom-up approach of Systems Biology is the collection and import of datasets on transcriptome, proteome, and metabolome , previously acquired in the contexts relevant to a concrete problem or medical condition in question, frequently also for multiple species  . AlreadyThere is a good number of recent studies employing the systems biology approach in the context of immunology and inflammation. A network of signal transduction pathways for inflammatory macrophages, containing 1122 molecule species (nodes) and 2705 reactions (links), was manually constructed and annotated . By consThus, the principal tools and methods of Systems Biology are in place to be applied also to the problem of inflammatory diseases, while the computational algorithms and database integration continue rapid development. The major challenges still exist, as for example in combining different layers of datasets . Importantly, the experimental validation of network analysis predictions still remains a crucial step within this approach.The integrated analysis of protein–protein, gene regulation, and coexpression network models, alongside gene expression data, can lead to the discovery of the most relevant genes and pathways in IMIDS, as well as causal mechanisms and their topological properties ,102,103.Taken together, the synergistic competence in molecular biology, bioinformatics, biostatistics, bioethics, computer sciences, mathematics, and medicine might enable the expansion of our understanding of the underlying disease mechanisms in the clinical fields of IMIDs and could lead to advancements in inflammation research. Artificial intelligence (AI) and machine learning (ML) are additional techniques that have the capacity to identify and uncover clinically relevant patterns and interdependencies amongst the acquired information and take confounding factors into account ,108. The


Telehealth has emerged as a model of modern technology for health care services in Vietnam during the COVID-19 pandemic. To actively prevent the outbreak of COVID-19 by using a national digital transformation program, the Vietnamese Ministry of Health launched project 2628/Quyet dinh-Bo y te, which approved a scheme for remote medical examinations and treatments for 2020 to 2025. The project aims to connect 1000 hospitals to strengthen the quality of medical services by using the expertise of central hospitals to support rural areas via provincial hospitals. Phutho General Hospital (PGH) is one of leading provincial hospitals that participated in and applied the early telehealth systems in Vietnam. By using telehealth systems, PGH can offer valuable support to doctors’ activities by streamlining and facilitating their work. Telehealth was demonstrated to be feasible, acceptable, and effective at PGH in Vietnam, and it resulted in considerable improvements in health care outcomes. The COVID-19 pandemic has facilitated the acceleration and enhancement of telehealth in Vietnam. The success of telehealth in Phutho may be a useful reference for other parts of the world. However, this telehealth system focuses on the connectivity among doctors rather than the connectivity between doctors and patients, which is an area that needs further assessment. Since the outbreak of COVID-19, which originated in Wuhan, China, in 2020, the disease has spread widely across the world ,4. The pA method for controlling the transmission of SARS-CoV-2 is social distancing, which is made possible by the reduction of person-to-person contact ,11. In tThis paper aims to present the results of applying telehealth in Vietnam at Phutho General Hospital (PGH), which is the largest provincial hospital in the northwest region of Vietnam, as well as the advantages and challenges of early-stage telehealth in Vietnam.PGH, the largest public hospital in the northwest region of Vietnam, has over 1500 beds, 20 departments, and 9 centers. Currently, PGH is a satellite hospital that consists of 8 national hospitals. Hospital facilities and equipment are being enhanced, and many advanced medical technologies and techniques are being applied to medical examinations and treatments. Recognizing the importance of advancements in technology, PGH implemented telehealth technologies, which has allowed the hospital to connect with national hospitals via information technology systems. PGH has registered and signed agreements with 8 national hospitals  as part On June 22, 2020, given the complex issues resulting from the COVID-19 pandemic, the Vietnamese government comprehensively reviewed its epidemic prevention plan and decided to approve a scheme for “remote medical examination and treatment for 2020 - 2025.” The scheme has rapidly received strong support from the medical community, doctors, and citizens. After nearly 3 months of preparation, on September 24, 2020, the Ministry of Health of Vietnam officially launched the remote medical examination and treatment program, thereby connecting 1000 hospitals, including 20 central hospitals. The project aims to reduce the burden on central hospitals, increase the quality of medical examination and treatment in primary health care facilities, save costs, and improve patients’ experiences and satisfaction while ensuring the safety of medical staff, doctors, and patients during the COVID-19 pandemic. The program receives financial support from the Vietnamese Government for both inpatients and outpatients, regardless of whether patients have insurance or not, and telehealth services are provided free of charge. The medical specialties include the cardiology, oncology, respiratory and musculoskeletal fields.As one of the earliest hospitals to participate in the project, PGH launched a telehealth clinic on November 14, 2020. Teleconsultations were one of the applications that physicians in PGH used commonly to consult with specialists from Bach Mai hospital, Viet Duc Hospital, the National Hospital of Tropical Diseases, and the Vietnam National Cancer Hospital . The telAnother breakthrough of telemedicine in PGH was successfully applying telemedicine in surgery. For example, on August 6, 2020, PGH organized a telemedicine cardiovascular surgery program for PGH and Hanoi Heart Hospital for the case of a 55-month-old child with a ventricular septal defect hole under 2 aortas . Before The COVID-19 outbreak has changed the way that people contact and communicate with PGH and national hospitals. Telehealth is a model that uses electronic information and telecommunication technologies to support and promote long-distance clinical health care, patient and professional health–related education, public health care facilities, and health administration agencies. Telehealth technology helps doctors connect patients with physicians through video calls, emails, and web-based patient portals and enables real-time consultations between specialists. A quick web-based visit can improve diagnosis and treatment efficiency, help with improving patients’ experiences, and reduce the number of complications and hospital admissions. Recently, many researchers have indicated that using telehealth for specialty visits connects primary care physicians, specialists, and patients, resulting in the enhanced coordination of care and speedy diagnoses . This seTelemedicine has changed the approach of health care services and how they are delivered. Telemedicine has also offered many advantages for doctors and patients in PGH, as shown in the following sections.Doctors and physicians in remote, rural areas of Phutho province can learn from experienced doctors. This is an opportunity for PGH to receive professional support remotely and gradually improve the quality of medical services. Often, using smartphones to transmit images and videos is much more convenient than using formal videoconferencing technology and is often preferred by doctors .Patients can easily receive consultations and prescriptions from leading physicians in national hospitals without having to travel long distances, which saves time and money. From a psychological perspective, rural patients in Vietnam always want to be examined and cared for by central medical staff who are believed to have more experience, knowledge, and skills than lower-level medical teams. Therefore, telemedicine increases patients’ access to care when it involves extended specialist and physician access. This results in telemedicine improving patient engagement and satisfaction.Telehealth is an effective option for supporting the fight against the outbreak of COVID-19, as it reduces the risk of coming into contact with people with SARS-CoV-2 infection . HospitaTelehealth and telemedicine have emerged as new models of health technology and have been applied in many hospitals in Vietnam during the COVID-19 outbreak. However, there are some limitations.First, telemedicine may not suit every person or situation. Second, medical data maybe at risk of being violated by hackers and being accessed by other criminals, especially if a patient accesses telemedicine services on a public network or via an unencrypted channel. Third, care may be delayed when a person needs emergency care, as accessing telemedicine services first may delay treatment, particularly since a doctor cannot provide lifesaving care or conduct laboratory tests digitally. Fourth, technological concerns can be challenging; a weak internet connection can make it especially difficult to offer quality care. Fifth, not all hospitals are equipped for telemedicine, particularly those that lack computer terminals, which are necessary for implementing telemedicine services.The data reported in this paper can be made available by the corresponding author upon request from qualified investigators.Telehealth has emerged as a model of modern technology for health care services in Vietnam during the COVID-19 outbreak. This report is the first to provide the early results of counseling and support activities of remote examination and treatment activities in Vietnam. It is expected that these remote examination and treatment consultancy activities, which are based on an information technology platform, will increasingly promote and ensure the efficiency and sustainability of telehealth in Vietnam.The results from PGH show the advantages of using telehealth in remote examinations that adhere to the treatment system standards of the Ministry of Health. By integrating modern data transmission technology and using high-speed internet, the system is capable processing data in real time and supporting the remote delivery of surgery. Doctors at higher-level hospitals can directly guide surgeons of lower-level hospitals, thereby shortening the process of treating patients in emergencies.The COVID-19 pandemic has allowed unprecedented opportunities for telemedicine to develop. These opportunities require heightened engagement from the government to make sure that a regulatory foundation is implemented. A synchronized telemedicine system should be built in Vietnam in the future.


The fertility of sows mainly depends on the embryo losses during gestation and the survival rate of the post-farrowing piglets. The selection of highly-prolific sows has been mainly focused on the selection of genotypes with high ovulatory quota. However, in the early- and post-implantation stages, the rate of embryo losses was increased with the increase of zygotes. Among the various factors, placental growth and development is the vital determinant for fetal survival, growth, and development. Despite the potential survival of fetuses with deficient placental development, their life-conditions and growth can be damaged by a process termed intrauterine growth retardation (IUGR). The newborn piglets affected by IUGR are prone to increased morbidity and mortality rates; meanwhile, the growth, health and welfare of the surviving piglets will remain hampered by these conditions, with a tendency to exacerbate with age. Functional amino acids such as glycine, proline, and arginine continue to increase with the development of placenta, which are not only essential to placental growth (including vascular growth) and development, but can also be used as substrates for the production of glutathione, polyamines and nitric oxide to benefit placental function in many ways. However, the exact regulation mechanism of these amino acids in placental function has not yet been clarified. In this review, we provide evidence from literature and our own work for the role and mechanism of dietary functional amino acids during pregnancy in regulating the placental functional response to fetal loss and birth weight of piglets. This review will provide novel insights into the response of nutritionally nonessential amino acids (glycine and proline) to placental development as well as feasible strategies to enhance the fertility of sows. During the last two decades, the number of total born piglets per litter has been increased through genetic selection. Meanwhile, with the increase of litter size, the incidence of stillbirth increased and individual pig birth weight decreased, thus reducing the reproductive efficiency of sows , 2. The Pigs exhibit the most severe (up to 25%) naturally occurring intrauterine growth retardation (IUGR) among livestock species , 11. At Studies over past few years have attempted to clearly delineate the causality related to spontaneous fetal loss and low weight of live-born piglets , 15–17, For the survival of conceptuses to term, we must coordinate the development of placentae and the specific adaptation of pregnancy to growth and development. For conceptus attachment and establishment or placental development, a series of events must proceed to ensure the uterine receptivity of the developing conceptuses, which include blastocyst hatching, hormone secretion, elongation into a filamentous conceptus and implantation and attachment , 15.After fertilization, the zygote undergoes time-dependent mitotic divisions, resulting in embryos at different cleavage stages. A pig embryo enters the uterus between the four- to eight-cell stage and develops into a blastocyst shortly thereafter (around day 5). Between day 11–12 of pregnancy, the blastocyst secrets estrogen, changing the endometrial secretion of prostaglandin F2 alpha, allowing it to directly enter the uterine capillaries and release into the uterine lumen, eventually preventing the luteolysis of the corpus luteum and maintaining the progesterone secretion essential for a successful pregnancy , 28. BetImplantation is the process for the attachment of the blastocyst to the uterus for the juxtaposition of embryonic and maternal circulation, leading to the establishment of a functional placenta and successful pregnancy, with the initial attachment process starting around day 12 during gestation . Peri-imBetween day 15 and 20 of pregnancy, trophoblastic and uterine membranes come close together, enabling the interdigitating microvilli to develop between the apical domes of the uterine epithelium and the trophoblast to cover the entire placenta except for the openings of uterine glands, leading to the transition from primarily histotrophic to hemotrophic nutrition . Along tPlacentae develop earlier than fetuses in gilts. Between day 20 and 60 of pregnancy, the porcine placenta begins to grow rapidly, with a significant increase in weight, size and surface area, followed by near-maximum development and vascularization at day 70 of pregnancy . During The swine placenta is a typical diffuse epitheliochorial organ without invasion , i.e., wAmong the nutrients required by pregnant sows, amino acids play the most important role in placental growth due to their involvement in the synthesis of sufficient proteins to support the proliferation of trophectoderm and endothelial cells . Amino aGlycine, the most abundant amino acid in oviductal, uterine and follicular fluids, plays a vital role during oocyte maturation, fertilization, and early embryonic development in pigs . The catOxidative stress can impair the female reproductive physiology by altering the affectivity of antioxidant defense system in humans and animals. There is growing evidence that pregnant sows suffer from elevated levels of oxidative stress in late pregnancy and lactation –57, due Available evidence shows that the amount of glycine synthesized in vivo is insufficient to meet the metabolic demands  in humans, pigs, rodents, and other mammals, thus unable to support their maximal growth , 63. It Proline serves not only as the building block of proteins, but also as a nitrogenous substrate for endogenous synthesis of arginine, glutamate, and polyamines in mammals . EspeciaPrevious study has indicated that supplementation with putrescine promotes the proliferation of porcine trophectoderm cells by increasing protein synthesis via activation of the mechanistic target of the rapamycin (mTOR) signaling pathway . HoweverMoreover, compelling evidence from animal studies shows that reduced placental and fetal growth is associated with a reduction in placental proline transport in gestating dams with either naturally occurring or malnutrition-induced growth retardation . During Arginine serves as the physiological precursor for synthesis of protein and other biological molecules, including ornithine, polyamines, proline, glutamine, creatine, and NO . ArgininGenerally, pregnant pigs are fed a restricted diet during gestation to avoid excess weight gains and associated farrowing and locomotion issue, and reduce lactational feed intake –93. Thus4) as an essential cofactor for all NO synthetases (NOSs) [4 concentration in the porcine placenta, thus playing a synergistic role in promoting placental NO synthesis [Arginine is a common substrate for the synthesis of NO and polyamines, both of which affect angiogenesis and thus fetal growth. However, the porcine placenta lacks arginase and arginine decarboxylase and therefore cannot synthesize ornithine from arginine . Arginins (NOSs) . NO synts (NOSs) . Of partynthesis . The argynthesis , and theynthesis , 98. Addynthesis . Additioynthesis . Collectynthesis , 101.FiIt has been widely accepted that arginine promotes the growth of skeletal muscle and reduces the accretion of white adipose tissue . Apart fAs an endogenous activator of arginine, N-carbamylglutamate (NCG) also has a similar effect on fetal growth and placental development. NCG, a safe and metabolically stable functional analog of N-acetylglutamate, can activate the key enzyme (carbamylphosphate synthetase-1) of the arginine-synthetic pathway and increase the endogenous synthesis of arginine , 105. StAlthough its beneficial effect on pregnant sows has been confirmed by a large number of experiments, the supplementation of 0.8–1% arginine to the diet was reported to greatly increase the feed cost due to the high price of arginine, thereby restricting its wide use . AccordiIn the last decade, the selection for high prolificacy in modern sow herds has led to a marked increase in litter size. The consistent outcomes of this strategy are an increase of the embryonic losses during early gestation and the number of less vital and less mature low-birth-weight piglets at farrowing. The important contributors to this result seem to be aberrant placental development and functional impairment (deficits in vasculature) in early gestation and inadequate uterine capacity at all periods of gestation. Among nutrients, amino acids play the most important role in placental growth because they are absolutely required for synthesis of sufficient proteins to support the proliferation of trophectoderm and endothelial cells. Moreover, amino acids are not only the building blocks of proteins in cells, but also the precursors for synthesis of nitrogenous substances  essential for placental growth and angiogenesis, conceptus development or scavenging free radicals to prevent placental oxidative damage. The requirements of amino acids in placentae differ markedly as gestation advances, but the amount of amino acids, especially glycine, proline, and arginine, is reduced due to the widespread practice of restricted feeding programs in sows during the entire gestation period to prevent excessive maternal body gains. Simply increasing the total crude protein content in the maternal diet is not an effective option because its oxidation generates high levels of ammonia and is extremely toxic to embryos and fetuses. Thus, adding specific amino acids that are deficient in the dietary supply is an attractive strategy to enhance placental growth and function, which in turn promotes fetal growth and development. As mentioned earlier, adding glycine, proline, arginine and their derivatives or endogenous synthesis promoters in the diets of pregnant sows will potentially promote the sow’s reproductive performance, fetal growth, and placental development. However, there is still a paucity of information on the effects of dietary functional amino acids on placental and conceptus development in swine except for arginine. This review has laid a theoretical basis for facilitating the translation of the basic research on glycine and proline biochemistry and physiology into feeding practice, and provided a reference for the nutritional strategy to improve the reproductive performance of sows.


Empirical evidences reveal that prices of healthcare and food are cointegrated with COVID-19 cases and lockdown measures in all the selected countries except Italy. Equally, healthcare and food prices reinforced itself in the long-run in the US, the UK and France. Furthermore, COVID-19 cases lead to significant increases in food and healthcare prices in the US, whereas, food and healthcare prices in France and UK declined significantly as COVID-19 cases mount. Conversely, food and healthcare prices declined significantly in the US and soar in France and the UK in reactions to COVID-19 new cases. Likewise, government stringency measures and containment health measures contributed significantly to healthcare and food price hike in the US and France respectively. Meanwhile, healthcare and food prices in the other selected countries remained unaffected even as the pandemic ravages. Following this empirical discoveries, relevant policy guidelines have been communicated.The pervasive effects of the novel coronavirus (COVID-19) have put the world to test. Its effects permeate all facets of life including healthcare services and food supplies. However, most empirical studies failed to investigate its effects on the prices of food and healthcare services, which by all standards, are essential commodities. On this background, this study evaluates the impact of COVID-19 reported cases and lockdown stringency measures on the food and healthcare prices in the six (6) worst-affected countries. For empirical purposes, daily prices of food and healthcare services between 22 COVID-19, Food prices, Healthcare prices, Government stringency measure, Containment health index, Dynamic ARDL. As exposed in several studies, including  among otpandemic . Consequst December, 2020th, November 14th, November 20th, December 19th, December 19th and December 24th respectively. The number of covid-19 reported cases soared to 20,000,595  in the US as at 31st December, 2020 making her the most affected among others. Coming behind the US in terms of COVID-19 reported cases as at 31st December, 2020 is Russia , France , the UK , Italy  and Turkey . The reported cases of transmissions and deaths continued rising amid varying degrees of lockdown policies including government stringency measure and containment and health measures adopted by individual countries.In the worst-affected countries, including the US, Turkey, Italy, the UK, Russia and France, the recorded cases of the novel virus exceeded 2 million as at 31As earlier highlighted, available evidences eloquently revealed that previous studies, except In the light of this backdrop, the objective of the present study is to critically evaluate empirically, the effects of COVID-19 reported cases and lockdown stringency measures On account of its guiding objectives and mindful of extending the trajectory of existing knowledge, the current study differs from existing literature in several respects. First, unlike previous studies, the current study considers the relative effects of COVID-19 and its induced lockdown stringency measures on both food and healthcare prices in the selected worst-affected countries. Secondly, as against panel aggregated study which may suffer aggregation bias, the current study provides country specific estimations leading to country unique policy directions devoid of aggregation bias. Equally, the inclusion of the containment and health index in the model makes the study unique noting that previous studies did not consider its effects on macroeconomic variables. Moreso, the application of the recently developed Dynamic Autoregressive Distributed Lag (DARDL) model makes the current study exceptional considering its unique capacity in revealing the simulative counterfactual effects of the explanatory variables on the explained variable . To the The remaining part of the study is concisely organized thus: literature review is presented in part-2, followed by methodology presented in part-3. The empirical analysis and discussions of findings are outlined in part-4, while the study is summarized with some policy recommendations in part-5.2The review is focused on the Grossman's theory of demand for healthcare developed in 1972. Grossman  a key component of the consumer price index during the COVID-19 period is affected by same exogenous factors in 1 and Ӽk are sets of independent variables, Based on the aforementioned objectives of this research and following insights gained from Following the DARDL pathway represented in Model 1:Model 2:4I(2). Second, a test of cointegration must be performed to ascertain whether the variables share a common long-run relationship. When a long-run relationship exists among the variables, the dynamic simulations of the variables henceforth becomes appropriate and applicable (I(0) while some are integrated of order-one I(1). Accordingly, the evidence of mutual integration of the data sets cut across all the sample countries. Having confirmed the maximum order of integration among the series (order-one), moreso, that the series are mutually integrated between orders-zero and one, the study therefore, proceeds with the test of cointegration through the enablement of the PSS bounds test cointegration technique.Before the implementation of the DARDL procedure, two important pre-estimation requirements must be satisfied. First, all the variables entering the model must be stationary at most after first difference. That is, none of the variable is expected to be integrated of order-two plicable . AccordiThe summarized results of long-run cointegration test as displayed in 4.1The study proceeds with the estimation of both long- and short-run relationship among the enlisted data sets in all the relevant countries. However, due to the absence of cointegration among the data sets, the long-run coefficients were not reported for Italy. Likewise, the study reported only the short-run estimates of health care and food prices for Russia and Turkey respectively. The estimated results of both long- and short-run are summarized in LCVC) have positive and significant effects on both prices in the USA which supports the submissions of (LCVNC) on both prices are negative and insignificant in the USA, while it is positive and significant only on food prices in the UK. This implies that new recorded cases of COVID-19 leads to increases in food prices in the UK, and price reductions in healthcare and food prices in the USA, whereas it remains neutral on both prices in all the other countries. The empirical findings of this study in terms of the effects of COVID-19 cases on healthcare and food prices in the USA contradicts the findings of From the estimated results reported in LGSI) and the containment health index (LCNHI), the empirical evidences indicate that government stringency measure (LGSI) has a positive and significant impacts on healthcare and food prices in the USA and only on food prices in the UK. Meanwhile, a significant negative relationship exists between government stringency measure and healthcare and food prices in France in the long-term. For the case of containment health index (LCNHI), it is established that contrary to the effects of government stringency index (GSI), a significant negative/positive relationship exists between containment health index (LCNHI) and healthcare and food prices in the USA and France respectively. The above outcomes imply that the US and UK (food only) residents paid direly for healthcare services and food supplies as government stringency measures gets tougher, whereas their counterparts in France had to pay a little less for healthcare and food as the lockdown measure tightens. Conversely, containment health measure (LCNHI) ensured that US residents accessed healthcare services and food supplies at relatively cheaper prices as against France residents that paid more for healthcare services and food supplies. This further reflects major differences in policy directions and inclinations in the two countries which only country specific studies can elicit. For the other selected countries, including Russia and Turkey, except Italy, where long-run relationship was not established, prices of healthcare and food supplies remained unaffected despite the degree of COVID-19 induced lockdown measures. This demonstrate that the government of Russia and Turkey were able to shed their citizens from the pervasive effects of COVID-19 and its induced lockdown measures. However, it is noteworthy to mention that among the six (6) most affected countries specified herein, the Russian federation and Turkey are the least affected leading to the minimal effects of the virus and the lockdown measures on healthcare and food prices as revealed by the empirical evidences.Considering the impacts of COVID-19 induced lockdown measures, including the government stringency index (LCVC) and COVID-19 new cases (LCVNC) had negative significant effects on both healthcare and food prices in Italy. Implying that Italian residents paid less for healthcare services and food supplies as COVID-19 cases persists within the immediate time. Also, COVID-19 induced lockdown measures  did not impair residents accesses to healthcare services and food supplies within the immediate time. This suggests that within the immediate time and as the lockdown measures persists, Italian government ensured that her citizens did not suffer untold hardship in terms of access to healthcare services and food supplies. Accordingly, the F-statistics which shows the overall significance of the model demonstrates that the overall regressions are significant for the countries studied. However, the speed of adjustment (ECT) shows very slow adjustments to long-run equilibrium after initial short-run perturbations in all the countries especially in Italy, Russia and Turkey. Also, the adjusted (R2) which shows the goodness of fit between the explanatory variables and the explained variable shows high degree of predictability in most of the countries except for Russia and Turkey thereby reflecting the earlier observed effects.Furthermore, the short-term effects largely reflect the long-run effects for other countries except Italy where long-term relationship were absent. However, the prevailing empirical evidences demonstrate that both COVID-19 cases  on healthcare and food prices in the USA are clear opposite of the effects of COVID-19 new cases (LCVNC). Likewise, opposite effects are equally conspicuous between government stringency measure (LGSI) and health and containment measure (LCNHI) on both prices. Meanwhile, for brevity, the simulation graphs of COVID-19 and its induced lockdown measures on healthcare and food prices for other selected countries are presented only in the supplementary pages as appendix. However, due to the lack of long-run cointegration, the simulation graphs were not available for Italy. Equally not available are the simulation graphs of COVID-19 and its induced lockdown measures on healthcare and food prices in Russia and Turkey respectively due to lack of cointegration among the series.Figures 2 graphs, it is ascertained that the results, by all standards, are robust for policy moderations. However, for brevity, we presented the CUSUM and CUSUM2 graphs for the US only. The plots for other enlisted countries are available in the supplementary documents which can be made available on request.Expectedly, the robustness and reliability of every empirical investigation, to a large extent, depends on the consequential post estimation/diagnostic tests. On this background, the empirical outcomes of the DARDL for all the enlisted countries were subjected to several post estimation enquiries. Amongst such tests are the Breusch-Godfrey and Durbin's alternative autocorrelation tests, White homoscedasticity test, and the recursive as well as OLS stability tests. Based on the outcomes of all the tests reported in 5The severe impacts of the novel corona virus (COVID-19) on the global economy necessitated several studies that sought to provide relevant theoretical and empirical explanations about its links and with the notion of informing knowledge-based policy directives. Surprisingly, amid the overwhelming empirical studies, only but a few studies considered the potential link between the pandemic and food and healthcare prices. That is, most previous studies did not consider it necessary to investigate how COVID-19 and its induced lockdown stringency measures impaired access to food supply and healthcare services. On this background, the present study set for itself the task to fill this obvious lacuna in extant literature by probing the potential effects of daily COVID-19 cases and lockdown stringency measures on daily prices of food and healthcare services in the world's six worst-affected countries. In the same vein, and with the notion of providing unique empirical evidences, the study employed the newly introduced dynamic autoregressive distributed lag (DARDL) model of LGSI) restricted residents access to healthcare services and food supplies in the US and food supplies in the UK, whereas, it was the containment health index that hampered consumers access to healthcare services and food supplies in France. Accordingly, to reduce the severe implications of the lockdown measures on the citizenry in terms of rising prices of healthcare services and food supply, the US and the UK government should pay more attention and reconsider her stringency measures (LGSI), while the government of France has to reconsider her stance on containment and health measures. Conclusively, the study, to a large extent, suggests the acceptance of the hypothesis that COVID-19 cases and its induced stringency measures leads to rising food and healthcare prices in the enlisted countries with minor variations in some countries as pointed out earlier.The empirical evidences from the analysis demonstrate that prices of healthcare services and food items follow an autoregressive function. Implying that their current prices even during the pandemic are being influenced by their prices in the past. Such being the case, to shield the citizens from the severe effects of COVID-19 case and its induced lockdown measures, efforts should be made to contain and control such spillover effects arising from past prices mostly during the pandemic. Equally noted is that COVID-19 cases affected consumers access to healthcare and food supplies in the USA in terms of rising prices, whereas, it is the new recorded cases that affected citizens access to food supply in the UK. This requires that the US and the UK government pay more attention to COVID-19 cases and COVID-19 new cases respectively to alleviate the sufferings of her citizens. However, for the other selected countries, both prices remained unaffected despite the magnitudes of COVID-19 cases and new cases. Meanwhile, the government of these countries need to keep a close watch on these prices to ensure that they remain unaffected and stable even amid the second wave of the pandemic and beyond. Furthermore, the study discovered that government stringency index  are still evolving. Therefore, more studies with similar orientation are required to confirm the findings of the present study using the adopted modelling technique (DARDL) or other relevant procedures. Furthermore, the inclusions of other related macroeconomic variables like the exchange rate, inflation as so on, and the enlistment of other affected countries could elicit better understandings of the effects of the pandemic on the global economic landscape leading to wider ameliorative policy options.Emmanuel Uche: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper.Samuel Nnamdi Marcus: Conceid designed the experiments; Analyzed and interpreted the data; Wrote the paper.Lionel Effiom: Analyzed and interpreted the data; Wrote the paper.Chijioke Okoronkwo: Performed the experiments; Analyzed and interpreted the data; Wrote the paper.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data associated with this study has been deposited at Our world in data.The authors declare no conflict of interest.No additional information is available for this paper.


The human gut microbiome is a huge microbial community that plays an irreplaceable role in human life. With the further development of research, the influence of intestinal flora on human diseases has been gradually excavated. Gut microbiota (GM) dysbiosis has adverse health effects on the human body that will lead to a variety of chronic diseases. The underlying mechanisms of GM on human diseases are incredibly complicated. This review focuses on the regulation and mechanism of GM on neurodegenerative diseases, cardiovascular diseases, metabolic diseases and gastrointestinal diseases, thus providing a potential target for the prevention and treatment of disease. Firmicutes/Bacteroidetes ratio is an important parameter to reflect GM disorder (The human gut microbiota (GM) is a complex, dynamic, and spatially heterogeneous ecosystem inhabited by a myriad of microorganisms interacting with each other and with the human host, including bacteria, fungi, archae, and viruses. The collection of all intestinal microorganisms genes represent a genetic repertoire, which is one order of magnitude higher than that of human genome . To somedisorder . In addiOnce the GM disorder occurs, the structure and function of the intestinal flora will change and even cause the occurrence or development of some diseases. The underlying regulatory mechanisms are complex. In recent years, with the rapid development of molecular biology, genomics, bioinformatics analysis technology, and high-throughput sequencing technology, the research of GM has made rapid progress. A great deal of research has produced evidence that GM disorder and its metabolites play a key role in maintaining host intestinal homeostasis and influencing the development of many diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and gastrointestinal diseases.The imbalance of GM will affect the health of the host through many ways, such as energy absorption, choline, short chain fatty acids (SCFAs), gut-brain axis, bile acids (BAs), and so on. However, the mechanism of GM on human diseases has not yet been completely elucidated. In this paper, we review the latest findings related to the regulation and mechanism of GM on human diseases, then summarized the characteristics of intestinal microflora changes associated with various diseases  and Alzheimer disease (AD) .Bifidobacterium, Pasteurella, and Enterococcus in intestinal microorganisms of PD patients increased significantly , such as hypertension, atherosclerosis and heart failure, are a major cause of death worldwide . A growiFirmicutes/Bacteroidetes ratio is remarkably increased , which can act on the 5-HT3 receptor of intestinal vagus nerve and inhibit the afferent activity of vagus nerve from intestine to brain. 5-HT released into blood can lead to vasoconstriction. Then 5-HT and SCFA can affect blood pressure through blood circulation and blood brain barrier damage caused by hypertension . In addiFirmicutes/Bacteroidetes ratio, which then attenuates high blood pressure  and glucagon-like peptide 1 (GLP-1), thus reduce blood pressure and inhibit the occurrence of atherosclerosis . Bile acGM composition varies significantly among atherosclerosis patients and healthy people. Further research revealed that GM was involved in the development and progression of atherosclerosis, as bacterial DNA was detected in atherosclerotic plaques. Intestinal microorganisms and their metabolites can influence the development of atherosclerosis. Microorganisms metabolized some alkaloids into harmful substances, which further activate pro-inflammatory cytokines, thereby promoting the formation of atherosclerosis. Overall, these studies illustrate that GM and its metabolic products can regulate the occurrence and development of atherosclerosis through multiple pathways. Regulating GM can be one of the therapeutic strategies for cardiovascular health.Although the incidence of metabolic diseases is related to genetic and environmental factors, the incidence of metabolic diseases in people with the same genetic background and energy intake is correlated with the presence of intestinal flora. In recent years, increasing studies have suggested that GM dysbiosis is closely associated with many metabolic disorders including obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD).Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bacteroides decreased, while the abundance of Phylum Firmicutes increased significantly , type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM). There is accumulating evidence that GM is a risk factor in the occurrence and development of diabetes.Clostridium and Prevotella  and an increase in the number of pathogenic bacteria . The pathogenic bacteria secrete toxic chemicals that damage intestinal epithelial cells and cause a chronic inflammatory response, which contributes to the development of CRC  is one of the most common malignancies in the digestive system. Studies have shown that GM dysbiosis is related to CRC. Intestinal microbial Dysbiosis in CRC patients is characterized by a decrease in the species of intestinal probiotics  is significantly enriched in feces samples and colon tumor tissues of patients with CRC, which can promote the abnormal proliferation of colon cells  and the Natural Science Foundation of Zhejiang Province (No. LY21C110001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.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.


Neuroplasticity following deafness has been widely demonstrated in both humans and animals, but the anatomical substrate of these changes is not yet clear in human brain. However, it is of high importance since hearing loss is a growing problem due to aging population. Moreover, knowing these brain changes could help to understand some disappointing results with cochlear implant, and therefore could improve hearing rehabilitation. A systematic review and a coordinate-based meta-analysis were realized about the morphological brain changes highlighted by MRI in severe to profound hearing loss, congenital and acquired before or after language onset. 25 papers were included in our review, concerning more than 400 deaf subjects, most of them presenting prelingual deafness. The most consistent finding is a volumetric decrease in gray matter around bilateral auditory cortex. This change was confirmed by the coordinate-based meta-analysis which shows three converging clusters in this region. The visual areas of deaf children is also significantly impacted, with a decrease of the volume of both gray and white matters. Finally, deafness is responsible of a gray matter increase within the cerebellum, especially at the right side. These results are largely discussed and compared with those from deaf animal models and blind humans, which demonstrate for example a much more consistent gray matter decrease along their respective primary sensory pathway. In human deafness, a lot of other factors than deafness could interact on the brain plasticity. One of the most important is the use of sign language and its age of acquisition, which induce among others changes within the hand motor region and the visual cortex. But other confounding factors exist which have been too little considered in the current literature, such as the etiology of the hearing impairment, the speech-reading ability, the hearing aid use, the frequent associated vestibular dysfunction or neurocognitive impairment. Another important weakness highlighted by this review concern the lack of papers about postlingual deafness, whereas it represents most of the deaf population. Further studies are needed to better understand these issues, and finally try to improve deafness rehabilitation. In case of severe to profound deafness, especially if speech intelligibility with conventional hearing aids is poor , cochleaThe aim of this systematic review and coordinate-based meta-analysis is to summarize the current knowledge on gray and white matter changes as revealed by structural MRI in subjects with severe to profound hearing loss. Plastic changes in deaf humans are compared with those in deaf animals and in human blind subjects. We end with some perspectives and further possible directions of investigation.Several animal models of deafness have been used to study neuroplastic changes following loss of audition. The most widely used animal model is the congenitally deaf white cat . These aThe modifications of the auditory pathways in animal models of deafness are discussed below according to structural or functional criteria.Structural changes have been described at the different relays of the auditory pathway . StudiesAt the level of the auditory cortex, studies in deaf cats showed an overall trend to a decrease in size, in particular in early-deaf cats . In bothBerger and co-workers compared the laminar organization of the auditory cortex in congenitally deaf and hearing cats. Although the auditory cortex preserved its six-layered cortical structure, the granular (IV) and infragranular (V–VI) layers were thinner in both A1 and the dorsal zone (DZ), which is part of the secondary auditory cortex . The thiImproved visual and tactile functions in both early- and late-deaf animals are well-documented . For exaLocal field potential recordings after intracochlear electrical stimulation showed that synaptic activity is preserved in the supragranular layers of the PAC in deaf cats, but is decreased in the infragranular layers . This isDifferent mechanisms have been proposed to explain the above described functional and structural cortical changes. A first mechanism is the strengthening of existing cortico-cortical connections by the development of new synapses in the core and belt auditory cortex, both in early and late-onset deafness . For exade novo connections. The responsiveness of PAC neurons to non-auditory sensory inputs may underlie the improved tactile and visual skills in deaf animals.To summarize, there is ample evidence for a reduction of the size or the number of neurons at different levels of the auditory pathways and in the PAC, especially in case of early deafness. However, the global pattern of thalamo-cortical and cortico-cortical connections seems mainly preserved, with some strengthening but very few Enhancement of non-auditory sensory skills has also been reported in human deafness. For example, improved visual functions have been described in congenitally deaf individuals, including distinguishing emotional facial expressions and local facial features, peripheral visual field tasks and attention to the peripheral visual field . ActivatIn order to improve our understanding of the structural correlates of deafness associated functional plasticity, we conducted a systematic review and coordinate-based meta-analysis of the anatomical MRI studies conducted in subjects with severe to profound hearing loss.We performed a systematic review of the literature on studies published in English language peer-reviewed journals and comparing gray matter (GM)/white matter (WM) volume, cortical thickness, and cortical curvature between severe to profound deaf and normal hearing subjects. We followed the PRISMA guidelines . The seaWe classified the papers using the Oxford Center for Evidence-based Medicine (OCEBM) levels of evidence . Level 1We also performed an Activation Likelihood Estimation (ALE) meta-analysis of the literature of structural changes in deafness, based on the reported stereotactic coordinates. ALE was initially developed for meta-analysis of functional data , but thep < 0,01 (cluster forming threshold) and 0,05 for cluster-level family-wise-error (FWE) with 1,000 thresholding permutations.To be included, the studies have to use Voxel-Based Morphometry (VBM), to provide the coordinates of the peaks in MNI or Talairach space, and to give significant results after correction for multiple comparisons. All the coordinates were transformed in MNI space, using SPM in GingerALE. Two datasets were built, the first one with the coordinates of the peaks where deaf subjects showed greater volume than the normal hearing control subjects, and the other one with the peaks where deaf subjects showed lower volume than their controls. For the paper from A total of 555 studies were identified and screened from all database searching see . All papIn total, 427 deaf individuals and 539 normal hearing controls were included see . The ageModifications of GM in the temporal lobe were present in only five out of 19 studies. In deaf babies, one study reported a GM volume increase in the anterior part of Heschl’s gyrus (HG) ; in deafThere are also reports of GM changes outside the occipital and temporal brain areas. Three studies in deaf adults reported increased GM volume in the bilateral  or left per se  and left uncinate fasciculi , but theIn summary, the main modifications in WM in deaf individuals occurred in the temporal lobes, and more specifically around the STG which hosts the auditory cortex.Only two studies investigated changes in cortical curvature in the auditory cortex. One study reported a steeper slope of the posterior Sylvian fissure , whereasTen studies met the inclusion criteria for ALE, including the recent study of McCullough and Emmorey, for a total of 239 deaf subjects (68 children and 171 adults) compared to 289 normal hearing controls (82 children and 207 adults). All deaf participants except 30 presented with prelingual onset of deafness. The first dataset that we built gathers the coordinates of the peaks where deaf subjects showed greater volume than the normal hearing control subjects. They concern 30 foci from five studies . The secThe three most consistent findings in deaf subjects derived from our review are (1) a volumetric decrease in WM in auditory cortex; (2) a volumetric decrease in GM and WM in visual cortex, particularly in babies and children; and (3) a GM increase in the right cerebellum. Cortical thickness and curvature have been studied sparsely in comparison with GM and WM volume, making it difficult to draw firm conclusions with respect to these measures.Unlike a recent meta-analysis , we haveper se induces brain modifications, especially in the hand motor region, and in regions involved in visual processing of faces and hands during SL comprehension (see in subsequent sections for more details). Furthermore, the age of SL acquisition also plays a central role in brain morphology, corroborating the idea of a critical period of language acquisition, such as for the development of the auditory brain. For example, the lack of early SL access in case of deafness is responsible for a GM decrease within the occipital lobe , and vermal lobules I and II (lingula) receive afferents from the vestibule . TherefoFinally, the cerebellum is also involved in many cognitive processes such as verbal working memory, phonological storage, sound and speech recognition, attention, spatial tasks, visual perception of motion, speed and direction, and affective regulation . Some ofThe reported volumetric changes in the insula vary considerably and range from a GM increase in the posterior left insula  to an ovIt has been hypothesized that the strong reliance of deaf individuals on lip-reading and articulatory-based representations of speech could impact the structure and the function of the insula . For insOne third of the studies did not find any significant modifications in brain anatomy. Several hypotheses can be put forward to explain these negative findings. First, more than half of the included studies have a sample size of less than 20 subjects per group, resulting in low statistical power . This isBrain modifications in deafness have been more consistently reported in animal studies than in human studies. Some similar changes have been described in both animal and human studies. For instance, at the level of the cochlear nuclei, a decrease in the size of the cell bodies has been reported in histological studies in both animals and humans . MRI stuBrain structural and functional changes following loss of vision have been studied in far greater detail than those following auditory deprivation [see Some GM volume increases were also demonstrated outside the visual areas, for example in hippocampus , sensoriSeveral hypotheses can be put forward to explain why structural changes are less prominent in case of deafness. A first explanation is that the visual system takes a much more prominent role in the human brain compared to audition. An estimated 30–40% of the cortical mantle is devoted to processing visual information, compared to only 8% for audition . A seconThe included papers suffer from some limitations which should be considered in future investigations. First, the included papers attributed the reported brain modifications to deafness, omitting the possibility that other factors which can interact with cerebral morphology, such as etiology of the deafness , SL and hearing aids use, vestibular dysfunction, neurocognitive skills, etc. For example, the use of hearing aids may by itself induce functional and structural brain changes in auditory and language-related areas, the associative regions and the cerebellum . Second,This review has also its proper limitations. First, the existing literature meeting our inclusion criteria concerned almost exclusively studies in prelingually deaf subjects, at the detriment of the postlingually deaf population. The study of prelingually deaf population presents some advantages linked to the homogeneity of this population with respect to the age of onset of deafness, the severity of the hearing loss, and the use of SL as primary language in absence of effective hearing aids. Mild to moderate hearing loss in the aging population has been more frequently studied, but studies of severe to profound hearing loss are lacking. This is more surprising since this population is larger than the prelingually deaf population , and wilThis review demonstrates that severe to profound prelingually deafness is responsible of structural brain modifications mainly but not limited to the temporal lobe. Our results are also of clear clinical interest, since brain plastic changes can facilitate, or complicate, CI auditory rehabilitation [for example Severe to profound deafness induces modifications of both brain GM and WM characteristics. The major modifications are a WM decrease around the auditory cortex, the occipital lobe and the cerebellum, a GM decrease in the occipital lobe of the deaf pediatric population, and a GM increase of the right cerebellum. Different measures  and methods  should be combined to create a more comprehensive view of the brain modifications. Deaf subjects must be better categorized to dissociate brain changes due to deafness from those of sign language use, age of SL acquisition, lip-reading abilities, etiology of deafness, use of hearing aids, and vestibular dysfunction. More attention needs to be paid to structural changes in postlingual deafness which affects the vast majority of the deaf and aging population in western countries.The original contributions presented in the study are included in the article/AG did the literature review and wrote the first draft of the manuscript. AG, ND, and RK wrote the final version of the manuscript. All authors contributed to conception and design of the study, 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.