Dietary restriction (DR) is believed to be one of the most promising approaches to extend life span of different animal species and to delay deleterious age-related physiological alterations and diseases. Among others, DR was shown to ameliorate acute kidney injury (AKI) and chronic kidney disease (CKD). However, to date, a comprehensive analysis of the mechanisms of the protective effect of DR specifically in kidney pathologies has not been carried out. The protective properties of DR are mediated by a range of signaling pathways associated with adaptation to reduced nutrient intake. The adaptation is accompanied by a number of metabolic changes, such as autophagy activation, metabolic shifts toward lipid utilization and ketone bodies production, improvement of mitochondria functioning, and decreased oxidative stress. However, some studies indicated that with age, the gain of DR-mediated positive remodeling gradually decreases. This may be an obstacle if we seek to translate the DR approach into a clinic for the treatment of kidney diseases as most patients with AKI and CKD are elderly. It is well known that aging is accompanied by impairments in a huge variety of organs and systems, such as hormonal regulation, stress sensing, autophagy and proteasomal activity, gene expression, and epigenome profile, increased damage to macromolecules and organelles including mitochondria. All these age-associated changes might be the reasons for the reduced protective potential of the DR during aging. We summarized the available mechanisms of DR-mediated nephroprotection and described ways to improve the effectiveness of this approach for an aged kidney. Caloric or dietary restriction (DR), which is defined as reducing nutrient intake without malnutrition, is considered one of the most proven approaches to extend life span and to delay deleterious age-related physiological changes and age-related diseases in animals . Positiv+-dependent deacetylases sirtuins, which deacetylated a large number of targets, including transcription factors, thereby regulating its activity  and found that 35% DR provided the maximum protective effect against I/R injury (In this study, young mice underwent 30% DR for 4 weeks prior to I/R that caused an attenuation of the severity of AKI and reduced postoperative mortality. In the kidneys of DR-treated mice, alleviation of I/R-induced acute tubular necrosis and release of lactate dehydrogenase were observed, which was associated with a change in the transcriptional profile . In addiR injury . Later, R injury .In young animals, very short periods of DR also showed protective properties in various models of AKI. For example, fasting for 3 days before I/R injury preserved rats from damage to the tubules and renal functional decline by increasing antioxidant defense and maintaining mitochondrial structure and functions . Short-tStudies in young rats have shown that DR has a protective effect not only against ischemic renal injury but also in models of drug-induced AKI . Thus, DTo date, only some molecular mechanisms of the beneficial DR effects in renal tissue have been proposed. Using novel methods of comparative analysis of microarray data, detailed comparisons of DR-mediated changes in various tissues were carried out resulting in the identification of the 28 most affected genes. These genes characterized common responses to DR and involved both activation and inhibition of stress-response pathways . DR was While the beneficial effects of DR are partially mediated by above-mentioned molecular changes, there are many other protective mechanisms related to DR. For instance, reduced protein intake during DR significantly improves the prognosis of AKI due to normalizing intraglomerular pressure and glomerular hyperfiltration . One morEventually, DR has shown impressive effectiveness in the treatment of experimental kidney pathologies, which makes it possible to translate this approach into clinical practice, especially in conditions when the risk of AKI is increased, for example, during cardiac surgery . In addiWhile the potential of DR to reduce the severity of AKI has been confirmed in experiments with young animals, the largest and most vulnerable group of patients with AKI and CKD is represented by the elderly. The average age of patients with AKI tends to 65 years and steadily decreases every year due to an increase in life expectancy . AccordiOn the other hand, it has been suggested that life-long DR is most effective in preventing the development of age-related changes in the renal tissue meaning dieting should begin at a young age to protect the old kidney. Indeed, DR started at an early age substantially improved age-associated renal histological abnormalities and survival . Life-loHowever, some studies have demonstrated that not only life-long DR but also short-term DR protocols are effective against age-associated abnormalities in kidneys. DR initiated in rats of 6 months of age was as effective as food restriction initiated at 6 weeks of age in slowing the progression of chronic nephropathy . MoreoveTo date, an active investigation of the effects of DR on old animals continues. Transcriptome analysis of renal tissue after life-long DR showed that DR modulates the expression of many genes in old rats and has benefits for kidney function . It was The molecular mechanisms of DR in old organisms look similar to young animals. For instance, DR in both young and old rats reduced the pro-inflammatory response from NF-kB and AP-1 and normalized the network of these transcription factors in the renal tissue of old animals . Old ratL, normalization of mitochondrial ultrastructure, diminished oxidative stress (Unsurprisingly, DR affected energy metabolism and mitochondrial functions. The beneficial effects of adult-onset DR manifested in a decreased accumulation of abnormally folded proteins in the kidney mitochondria in old animals . DR for e stress , abrogate stress .Note that despite a number of positive changes at the molecular level caused by DR, there are only a few studies that describe the effects of DR on kidney function in AKI. Thus, old rats that received 60% of normal food intake for 2 months showed decreased blood urea nitrogen and serum creatinine levels, reduced renal tubular necrosis, and lower incidence of activated caspase-3 and TUNEL-positive cells in kidneys after cisplatin-induced nephrotoxicity . HoweverMost fruitful experimental studies of various DR protocols have been conducted in young animals , while aThe loss of protective effects of therapeutic methods with age is a significant problem not only for DR but also for other treatment approaches. Earlier, a similar loss of positive impact was described when applying ischemic pre- and postconditioning for kidney and heart of old animals . Similarad libitum mice (Thus, not all tissues and systems show improvements during DR with age. For instance, despite the observation that DR ameliorated the state of blood vessels and their response to the vasoconstrictive effect of endothelin-1 in young rats, such positive effects were absent in old rats after short-term DR . Moreovetum mice .Insufficient efficiency of DR in old animals is also observed for the hormone levels. In contrast to the leptin level, which decreased during DR in both young and old animals, the adiponectin concentration increased only in young rats , so DR wThe observed loss of protective properties of therapies can be partially explained by various age-dependent changes that accumulate in all tissues and affect the functioning and tolerance of organs . Thus, iSignificant metabolic shifts accompany aging leading to impaired lipid and carbohydrate metabolism and loss of nutrient-sensing pathways . There aEndocrine functions are also disrupted with age and the kidneys are no exception . In partAn important age-related disorder is the deterioration of cellular quality control systems for proteins and organelles. With age, both the dysfunction of the autophagic-lysosomal system  and the Thus, DR is considered a promising approach for the treatment of various age-related diseases, including AKI and CKD. However, some studies reveal a gradual loss of effectiveness of DR with age, which is alarming given the advanced age of patients with AKI and CKD. The adult-onset DR leads to a number of positive changes, but they affect much fewer pathways, so old organisms after DR cannot develop such high improvements and tolerance as young healthy organisms do . We postNA and EP conceived the manuscript and developed the idea. NA wrote the review. MB and AB helped to collect the data and drafted the manuscript. EP and DZ critically revised and improved the content of the manuscript. All authors contributed to the article 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.


Peripheral nerve injury is a common complication in trauma, and regeneration and function recovery are clinical challenges. It is indispensable to find a suitable material to promote peripheral nerve regeneration due to the limited capacity of peripheral nerve regeneration, which is not an easy task to design a material with good biocompatibility, appropriate degradability. Magnesium has captured increasing attention during the past years as suitable materials. However, there are little types of research on magnesium promoting peripheral nerve regeneration. In this review, we conclude the possible mechanism of magnesium ion promoting peripheral nerve regeneration and the properties and application of different kinds of magnesium-based biomaterials, such as magnesium filaments, magnesium alloys, and others, in which we found some shortcomings and challenges. So, magnesium can promote peripheral nerve regeneration with both challenge and potential. Magnesium is the fourth abundant mineral ion in the human body. Magnesium is involved in more than 300 kinds of enzymatic reactions  and variPeripheral nerve injuries are usually caused by inflammation, tumours, and traumatic injuries, accounting for 3–10% systemic trauma . There aAt present, many strategies have been adopted for peripheral nerve injury repair, and autografts are considered to be the “gold standard” clinically. At the same time, there are some insurmountable limitations of autologous nerve graft, such as the risk of donor site lesion, the limited supply and limited therapeutic effect, the risk of pathological changes in the donor site, the limited source of donor nerve and the limited therapeutic effect . To replMagnesium ion is one of the necessary ions for cell metabolism. It is abundant in cells and participates in hundreds of enzyme reactions in the body. In the local microenvironment, magnesium ion has been proved to regulate mitochondrial calcium buffering as the second messenger, also with the effects of anti-apoptosis, anti-oxidation and anti-inflammatory, which is also of great significance for nerve impulse conduction. At present, most of the studies on the nervous system of magnesium ion focus on craniocerebral injury and spinal cord injury , while oThe protective effect of magnesium ions on the central nervous system has been studied. Clinically, magnesium sulfate has been used to prevent cerebral palsy in preterm infants. It is generally believed that magnesium ions can play a neuroprotective role by inhibiting the secondary injury after nerve injury through regulating cell function, antagonizing of N-methyl-D-aspartic acid receptor (NMDA receptor) and calcium ions . In addiInhibition of the inflammatory response promotes nerve regeneration by preventing SCs from apoptosis ,b,c, andL and then down-regulating active caspase-3 and cytochrome expression.Plenty of evidence demonstrates that magnesium ion is closely related to inflammation. Magnesium has been shown to inhibit activated macrophage-induced inflammation and thus promote the differentiation of mesenchymal stem cells . In addiHowever, the underlying mechanisms of magnesium deficiency causing inflammatory response are not fully understood. Possible mechanisms include: (1) Cell entry of calcium and initiation of phagocytes; (2) Calcium channel opening and NMDA receptor activation; (3) Release of neurotransmitters such as substance P; (4) Membrane oxidation and activation of NF-κB.Schwann cells are neuro-gliocytes that constitute the peripheral nervous system. It not only participates in the formation of the myelin sheath but also maintains the growth environment of the axons through its rapid proliferation, division and secretion of various protein molecules after peripheral nerve injury and also promotes the self-repair and regeneration of nerves.After peripheral nerve injury, SCs secrete large amounts of endogenous neurotrophic factor (NTF), including nerve growth factor . NGF plaAppropriate concentrations of magnesium ions in the tissue microenvironment can promote SCs proliferation , as wellIn vivo, magnesium mainly undergoes electrochemical reaction, which is affected by the properties of the material itself and the local microenvironment such as pH and protein. Magnesium mainly undergoes pitting corrosion in vivo, which is more likely to lead to material fracture and is not conducive to nerve regeneration 2, which is deposited on the surface of the material and has a certain protective effect on magnesium; (2) As time goes on, Mg(OH)2 reacts with Cl– in body fluid to form MgCl2 which is more soluble in water, resulting in Mg(OH)2 falling off and magnesium corrosion. In order to have a better application in magnesium promoting peripheral nerve regeneration, the improvement of material properties can provide enough support to maintain sufficient strength and be gradually degraded and absorbed by the human body (The corrosion process of magnesium can be divided into the following two steps: (1) In electrolyte solution, magnesium acts as anode to occur galvanic cell reaction, losing electrons and generating Mgman body .The structural and functional damage of the peripheral nerve could be caused by various factors. The current “gold standard” of clinical treatment of peripheral nerve repair replaces the injury gap with an autograft. However, given the limitations of autografts, including the risk of donor site lesion, the limited supply and therapeutic effect, nerve guide conduit has gradually become a more potential alternative . HoweverBesides, the degradation rate of magnesium filament will also be affected by the filler in the conduit. In conclusion, magnesium metal is widely used for peripheral nerve repair due to the following advantages: (i) Magnesium metal is featured by rapid and complete degradation; (ii) Magnesium metal has good histocompatibility. While other biomaterials may lead to severe inflammation during absorption, magnesium metal has less tissue stimulation and does less damage to the regenerating nerve tissue; (iii) During degradation, soluble magnesium ions and hydrogen are released, which have neuroprotective and antioxidant effects; (iv) Compared with other metal materials, magnesium metal has better flexibility and smoother surface, which are conducive to the adhesion of SCs; (v) The electrical conductivity of magnesium metal may provide electrical stimulation path for the injured nerve and its dominated muscle, thus contributing to nerve regeneration .However, magnesium metal still faces many challenges in clinical application: (i) Magnesium metal is not strong enough or degrades too fast to provide enough mechanical support for nerve regeneration during the whole healing process; (ii) The rapid degradation of magnesium metal results in the accumulation of degradation products and then does harms to tissues. Soluble magnesium ions and hydrogen released will increase pH, thus interfering with nerve generation; (iii) Compressive stress can also affect the degradation rate of magnesium metal and even lead to the fracture of magnesium metal. Therefore, faced with these problems, the magnesium metal to be used in clinical treatment should be improved further to slow degradation rate, which can be achieved by alloying with other metals, altering the surface by anodization or physical treatment and coating with water-resistance substances like polymers .As a new biodegradable bimetallic material, magnesium alloy has been widely studied and has a certain potential in applying nerve guidance conduit (NGC). Compared with pure magnesium, magnesium alloy has the following characteristics: (1) In addition to magnesium ion, other metal ions such as Li, Zn, and Ca can be released to facilitate nerve repair ; (2) TheMetallic glasses, also known as an amorphous alloy or liquid metal, have attracted significant attention. The amorphous structure imparts higher strength, higher wear resistance and corrosion resistance, and good fatigue performance. Magnesium, calcium, zinc, and strontium-based glasses represent a class of biodegradable amorphous alloys. As for magnesium-based glass, many metallic glass systems have been successfully developed, among which the Mg-Zn-Ca metallic glass system possesses a high glass-forming ability and contains the necessary elements of Ca and Zn for the human body . At the 70Zn26Ca4. By impregnation method and potential polarisation method, the result indicates that the relaxed ribbon had higher corrosion resistance. Biocompatibility was studied by MTT assay. The survival rates of the relaxed ribbons and crystallised ribbons were above 75% after 1, 3, and 7 days, indicating their good biocompatibility with the potential for nerve regeneration. However, the cell viability of the relaxed ribbons was higher than that of the crystallised ribbons at all time points, which could be attributed to the fact that the crystallised ribbons had more degradation rate than the relaxed bands. Because the concentration of ions released by the glass system exceeds the optimal concentration, the crystal ribbon released more ions into the medium and exerted toxic effects on cells. The results showed that the corrosion resistance of the relaxed band was better than that of the crystalline band, and it had good cell compatibility with SCs.Many experiments have demonstrated that the promoting effect of magnesium ion on peripheral nerve regeneration is not positively correlated with the concentration, but there is an optimal concentration. The release rate of magnesium ions in the magnesium-based glass system prepared in this experiment is still beyond the optimal concentration, suggesting that further improving the preparation process and optimising the performance will be the direction of future research.in vivo still needs to be considered, and its corrosion resistance also needs to be further improved. Therefore, the surface modification of magnesium and its alloys become the focus of research and application of peripheral nerve regeneration now.Although magnesium alloy and Mg-based metallic glass can significantly improve the corrosion resistance of magnesium and slow down the degradation rate, the long-term neurotoxicity of zinc, calcium, and other ions released from magnesium alloys Surface modification methods of magnesium and its alloys mainly includes conversion coating, anodization, micro-arc oxidation and others. In contrast, in terms of biomedical and neural application, the frequently used way of surface modification of magnesium and its alloys is polymer coating by electrospinning, electrochemical deposition, dip-coating, spray-coating, spin-coating, and other ways. Moreover, it will lead to differences in the coating performance if different coating ways are applied .Poly  (PEDOT) is an ideal coating material with excellent conductivity and biocompatibility, which has been used in nerve implantation . Many ty70Zn26Ca4 ribbons  with tannic acid (TA)/poly(N-vinylpyrrolidone) (PVPON). They investigated the corrosion resistance, and biocompatibility was higher than the uncoated and significantly higher than pure Mg. What is more, SCs had an excellent initial attachment with typical morphology on the surface of coated ribbons in vitro.There are some other coatings to be studied. in vivo. Hydroxyapatite (HA) coated magnesium alloy (WE43) in vitro improved the adhesion and proliferation of adrenal pheochromocytoma cells (PC12). However, those of SCs were not significantly improved, while in vivo, it showed controlled degradation and reduced gas production, but only a little regeneration of sciatic nerve tissue  (PGSM) into PGSM-Mg and investigated the properties improvement. PGSM-Mg showed suitable biodegradability and sustained release of Mg2+. It could promote SCs adhesion and proliferation better and expressed more neural-specific genes than several kinds of scaffolds, showing great potential to promote peripheral nerve regeneration.2+-improved biomaterial will hold great promise for applications in promoting peripheral nerve regeneration. If the study explored which concentration of MgOl can better promote SCs growth and proliferation, the study would be more valuable for peripheral nerve regeneration. Moreover, it lacked biodegradability tests, which is also essential for clinical application.2+ will enrich the pathways and fields of promoting peripheral nerve regeneration. Additionally, in order to make Mg2+ released at an appropriate rate at the site of the peripheral nerve injury and reduce the toxicity of magnesium, it will be an effective measure to explore how to control the binding and release of Mg2+ through biomaterials for the applications of magnesium to promote peripheral nerve regeneration. At the same time, it is necessary to detect and improve the degradability and plasticity of Mg2+-improved biomaterials.The variousness of peripheral nerve injury makes difficulties regenerating peripheral nerves, so exploring different biomaterials depending on the injury situation and combining with MgBased on the existing literature, our review not only expounds the importance of magnesium ion to the nervous system and the mechanism of magnesium ion promoting peripheral nerve regeneration but also summarises the application of magnesium-based biomaterials to promote peripheral nerve regeneration by improving the corrosion resistance and biocompatibility . Above a(1)The research on the effect and mechanism of magnesium on the peripheral nervous system has not been fully clarified, such as the toxic effect of magnesium. However, its effect and mechanism still play a crucial role in providing effective theoretical guidance for promoting peripheral nerve regeneration.(2)in vitro. However, it is still necessary to investigate its role in promoting peripheral nerve regeneration in vivo and further confirm the improvement of corrosion resistance and biocompatibility.The research on the properties of modified magnesium needs to be improved. At present, the research mainly focuses on its corrosion resistance and biocompatibility (3)The methods to study the properties of magnesium and its alloys are similar and systematic in research, while the methods to study the properties of coatings are relatively fragmentary and immethodical. However, various experimental methods have accumulated rich and valuable experience, which lays a good foundation for improving the coating performance testing system in the future.(4)Magnesium alloy, its surface coating and other biomaterials modified by magnesium are the main forms to promote peripheral nerve regeneration. So, on the one hand, it is necessary to develop new alloys, coatings or biomaterials, and explore their properties and peripheral nerve promoting effects. On the other hand, in addition to further optimisation on the properties of the alloys, coatings or biomaterials, it is also necessary to consider the cost, efficiency, stability, and other issues, which is expected to play an important role in clinic widely.(5)The ability of magnesium to promote bone regeneration and vascular regeneration has been widely recognised and has been used in the clinic . CombineThe research on magnesium to promote peripheral nerve regeneration is rising in recent years, but research is relatively deficient. There is still great potential in this field where opportunities and challenges coexist, which needs the joint investment and efforts of many researchers, promoting the development of the research and putting it into clinical use in the future for the benefit of patients!JXZ, BZ, and JLZ summarized the related literature and wrote the manuscript. WL checked and polished the language. SZ contributed to conception, design, and critically revised the manuscript. All authors contributed to the article 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.


Rehabilitation of atrophic maxilla with dental implants is still a challenge in clinical practice especially in cases of alveolar bone resorption due to peri-implantitis and pneumatization of the maxillary sinuses. Several surgical approaches have been employed to reconstruct the lost tissues allowing the proper tridimensional position of the implants. In this context, the aim of this case report is to describe a surgical and prosthetic approach to fully rehabilitate the atrophic maxilla with dental implants. The patient presented with unsatisfactory functional and esthetical implant-supported prosthesis with some of the implants already lost by peri-implantitis. The remaining three implants were also affected by peri-implantitis. Reversal prosthetic planning was performed, and a provisional prosthesis was fabricated and anchored in two short implants. Sinus floor augmentation procedure and onlay bone graft were then accomplished. After a healing period of 8 months, digital-guided surgery approach was performed to place the implants. Finally, a definitive prosthesis was installed. One-year follow-up has revealed stabilization of the bone tissue level, successful osseointegration, and a pleasant esthetic and functional result. A proper diagnosis and careful planning play an important role to enhance precision and to achieve patient esthetic and functional outcomes. Dental implants have been extensively used to rehabilitate partial or total edentulous patients in the recent decades , 2. To oWhen teeth are lost due to periodontal disease, dental cavities, or trauma and the oral rehabilitation is not performed in a reasonable amount of time, the alveolar process tends to resorb. In this regard, the reduction in bone density, resorption of the alveolar ridge, and pneumatization of the maxillary sinuses are characteristics that usually affect patients that have lost their teeth for a long time , 6. In tTrying to overcome the disadvantages of autogenous bone graft, guided bone regeneration with bone substitute materials and growth factors (recombinant human bone morphogenetic protein-2 (rhBMP-2), plasma-rich platelets (PRP), and leukocyte- and platelet-rich fibrin (L-PRF)) have been proposed and tested , 24. AltFinally, implant design, implant abutment connections (implant platform), and physical-chemical surface characteristics play pivotal role in the osseointegration process enhancement (implant microtopography) and in primary implant stability (macrotopography) especially in patients requiring immediate implant loading and in patients with poor bone quality and quantity –33. ThusA 45-year-old Caucasian female patient sought for dental treatment in the Department of Periodontology with the main complaints of dissatisfaction with the use of a total upper denture Figures . PatientBased on her medical history and clinical and radiographic analyses, the treatment plan was proposed in different stages. The first treatment phase encompassed new provisional prosthesis, surgical removal of the implants affected by peri-implantitis followed by the installation of two short implants with immediate loading, and provisional prosthesis installation. In the second phase, the surgical approaches included maxillary sinus floor augmentation bilaterally with concomitant graft with DBBM plus PRF membranes, autogenous block bone graft, implant placement, and definitive prosthetic rehabilitation. The planned surgical reconstruction in different phases of the treatment was intended to allow the patient to use provisional prosthesis during her treatment without functional and esthetic complaints. Written informed consent was obtained prior to initial treatment.The first step of treatment involved the confection of new provisional prosthesis previous to implant removal. In this moment, all the expectations of the patient regarding her tooth characteristics  and all the necessary changes in her prosthesis were taken into account to achieve all the patient's functional and esthetic requirements. The prosthetic procedures are represented by Figures The next step in the process of rehabilitation was to perform the maxillary sinus floor augmentation. This procedure was completed four months after short implant placement. The surgical procedure consisted by a midcrestal and vertical releasing incisions alongside the remaining alveolar bone to reveal the lateral sinus wall . A laterAfter four months of the maxillary sinus augmentation procedure, it was planned to increase the bone thickness in the maxillary anterior area with autogenous block bone graft. The autogenous bone graft was harvested from the mandibular ramus. For this, an access preparation was carried out with a crestal and vertical releasing incision in the retromolar region. Then, a mucoperiosteal flap was obtained by exposing the buccal wall and the oblique line. The osteotomy was performed with rotating instruments and the cortical block was obtained with a hammer and chisel, as described . The mucThe implants were placed with the aid of guided surgical approach after a 4-month onlay graft healing. Initially, the provisional prosthesis was filled with proper acrylic material  and was adjusted to allow precise adaptation to the augmented area, with ideal occlusion, fitting, and esthetics. The prosthesis was then duplicated to be used as multifunctional guide. Four vestibular gutta-percha fillings assisted as radiographic markers. A silicone interocclusal record was made to maintain the denture in a stable interarch position, during the cone beam computed tomography (CBCT) scan. A cone beam technique  was used to scan the patient. A second scan was made of the prosthesis extraorally. Virtual planning was performed with seven implants in the posterior area of the maxilla (three in the right side), as described . Three gAfter the healing period of 3 months, the implants were exposed and the cover screws were removed Figures . A minicRehabilitation of maxillary deficiencies with dental implants can be a challenge for most of the clinicians and surgeons, and in many instances, a multidisciplinary approach with the involvement of several disciplines is mandatory to achieve satisfactory functional and esthetic outcomes. The increased expectation for a pleasant esthetic result from the patient is something that increases the challenge for a successful oral rehabilitation. In this context, the advancements in tissue engineering, bone regeneration, bone substitute biomaterials, implant surface, and design have promoted the development of new materials and techniques for the successful treatment of complex cases. Moreover, the introduction of new technologies, such as cone beam computed tomography, guided implant surgery, and new software, allow the achievement of more predictable and safe surgical procedures. Although interdisciplinary treatments usually result in better clinical outcomes, the increased treatment duration, costs, and miscommunication between clinicians should be taken into account when planning a complex oral rehabilitation.In the case presented, it was chosen to perform the treatment in several steps. The initial treatment plan, i.e., the confection of provisional prosthesis supported by two short implants, was selected to allow the proper rehabilitation of the patient without affecting the masticatory functions, esthetics, and social behavioral. As the previous prosthesis was not adequate in terms of esthetics and functions due to the loss of the implants by peri-implantitis , the proThe placement of conventional length implants (>10 mm) in the posterior maxilla in the presence of insufficient bone height usually requires sinus floor augmentation procedures. Several studies in the literature have demonstrated successful results with dental implants in maxillary sinus grafted with autogenous, bone substitute materials, and combinations thereof. Thus, after a healing period of 4 months, it was decided to perform the sinus floor augmentation procedure using a combination of DBBM and L-PRF. This approach was chosen because previous studies have demonstrated beneficial effects when the maxillary sinus is graft with combination of DBBM and growth factor, allowing early implant placement and more new natural bone formation , 37, 38.During the follow-up visits, it was decided to graft the anterior alveolar crest with an onlay autogenous bone graft to increase the width of the alveolar bone. This surgical procedure is aimed at correcting horizontal deficiencies in the maxillary area allowing the installation of implants in an ideal tridimensional position. According to Buser et al. , an imprAfter the healing period, the placement of implants was planned by means of computed guided surgery. After CBCT scan of the patient and denture, the virtual planning was performed and the files were sent to Bioparts  to manufacture the surgical templates. The conical implants were installed with the flapless approach, which facilitates would healing and decreased postoperative pain . VirtualDespite the fact that the present treatment approaches have led to a satisfactory functional and esthetic result, it also presents some disadvantages that need to be taken into account. The virtual planning of the implants is time-consuming and comes with a higher cost due to multiple CBCT scans and template fabrication. This method necessitates good communication with the dental technician. Moreover, implant graft (maxillary sinus and onlay autogenous bone) increases the treatment duration and costs and might lead to postoperative discomfort.In summary, this case report illustrates an efficient surgical-prosthetic approach for the management of a complex case of peri-implantitis, which required surgical reconstruction of the maxillary bone, dental implants, and prosthetic rehabilitation. A proper diagnosis and careful planning play an important role to enhance precision and to achieve patient esthetic and functional outcomes. Moreover, bone regenerative procedures by means of onlay autogenous bone graft and maxillary sinus augmentation allowed implant placement in an ideal tridimensional position, which favored the manufacturing of a proper prosthesis regarding function, esthetics, and biological properties, known as periodontal prosthesis.


The objective of this review is to illustrate the state of the art in high-power ultrasound (HPU) application for olive oil extraction with the most recent studies about the effects of HPU treatment on oil yield, quality, chemical composition, as well as on the consumer’s perception. All the examined works reported an increase in oil yield and extractability index through the use of HPU, which was ascribed to reduced paste viscosity and cavitation-driven cell disruption. Olive oil legal quality was generally not affected; on the other hand, results regarding oil chemical composition were conflicting with some studies reporting an increase of phenols, tocopherols, and volatile compounds, while others underlined no significant effects to even slight reductions after HPU treatment. Regarding the acceptability of oils extracted through HPU processing, consumer perception is not negatively affected, as long as the marketer effectively delivers information about the positive effects of ultrasound on oil quality and sensory aspect. However, only a few consumers were willing to pay more, and hence the cost of the innovative extraction must be carefully evaluated. Since most of the studies confirm the substantial potential of HPU to reduce processing times, improve process sustainability and produce oils with desired nutritional and sensory quality, this review points out the need for industrial scale-up of such innovative technology. Mediterranean Diet (MD) as a concept and lifestyle emphasizes a specific dietary pattern that is typical of the Mediterranean basin, and particularly of the countries where the growth of olive trees is widespread, such as Greece, Crete, and Southern Italy . The posOlive oil, its composition and, its positive effects on human health as a major component of MD have been thus extensively documented and reviewed in the literature ,7,8,9,10Within the process flow of EVOO extraction, malaxation is crucial in determining both the yield and the overall quality of the product, especially in terms of micro-components, i.e., phenolic compounds and tocopherols concentration. This step consists of continually kneading the olive paste under controlled temperature and time conditions, which allows for a significant reduction of olive paste viscosity, facilitating the subsequent separation in the decanter ,17,18. RAmong the various innovative technologies, ultrasound is particularly promising, with various applications in the food industry, such as improving process speed, the possibility to assist food drying, cutting, and emulsification, improving the extraction of bioactive compounds, inactivating food pathogens, and spoilage microorganisms, and to enhance or inhibit enzymatic activity depending both on processing parameters and type of enzymes ,31,32,33The olive oil industry has also been adapting the application of ultrasound technology within the field of oil production, thanks to its effects on cell disruption. Among the various frequency ranges of ultrasound, high-power ultrasound (HPU) treatments in the frequency range of 18–40 kHz are observed to cause cell wall mechanical damages and disruption in vegetable tissues, thus promoting the release of soluble components and enhancing mass transfer ,35. The However, to the best of our knowledge, no attempts have been made to review recent literature on the effects of HPU on olive oil extraction and processing. Thus, the aim of this review is to summarize the main studies performed in the past five years (2016-till date) on the application of HPU in the extraction of olive oils and its effects on oil yield, legal quality, chemical composition, sensory attributes, and consumer perception.The review consists of three sections: [i] the first section examines the effects of HPU on olive oil yield and extractability; [ii] the second one discusses HPU impact on olive oil quality and chemical composition, with a focus on oil legal quality parameters, phenolic content, lipid stability, volatile compounds, and sensory attributes, while [iii] the third section concerns consumer perception of olive oils extracted with the use of HPU.Many studies have investigated the potential application of HPU to olive paste immediately after olive crushing and before the malaxation step  with thep ≤ 0.05) both oil yield and oil extractability index of 1.2 and 6.5%, respectively, compared to samples extracted through conventional malaxation. This improvement of oil extraction efficiency was probably related to HPU-driven lysis of cell membranes due to acoustic cavitation. In another study [Rigane et al.  underliner study , the samBejaoui et al. ,39 obtaiMoreover, HPU processing can be combined and applied simultaneously with other novel technologies like microwave, which significantly improves heat exchange and oil yield .In conclusion, the examined literature indicates that the application of HPU to the olive oil production processing, and in particular, to assist malaxation, tends to significantly improve oil yield and increase the oil extractability index due to the coupled effects of both higher processing temperature and cavitation phenomena. However, considering the advantages and potential effects on chemical constituents, the HPU treatment should be tailored to achieve the best oil yield, without negatively affecting olive oil quality.The objective of this section is to review the main literature on the impact of HPU treatment on olive oil parameters related with legal quality and chemical composition.232 and K270 concerning primary and secondary lipid oxidation, respectively) are the most relevant in the literature concerning HPU processing of olive paste. None of these parameters seem to be affected by the treatment [Olive oil legal quality is determined by a series of parameters, as defined by International Olive Council , which areatment ,44,51,52reatment .Phenolic compounds present in olive oil are responsible for potent effects on health, as well as improvement of sensory aspect by enhancing bitter and pungent notes ,53,54 anIn this regard, the results on comparison between phenolic content of oils produced through conventional and HPU-assisted extraction published in literature are conflicting. In fact, most studies reported an increase in the concentration of phenols achieved through HPU treatment ,55,56; wThe increase of total phenolic compounds observed by Almeida et al. , who appAnother main factor that could account for the improvement of phenolic content through olive paste HPU treatment is the inactivation of poly-phenoloxidase (PPO), which is responsible for the oxidative losses of phenolic compounds during malaxation . HoweverIqdiam et al.  noted a However, where observed, the increase in phenols concentration did not involve all phenolic compounds, but mainly some secoiridoid derivatives such as p-HPEA-EDA and 3,4-DHPEA-EA, which are strictly related to hydroxytyrosol ,57,58. TThe effect of temperature is particularly debatable: on one hand, higher temperatures might determine the degradation of phenolic compounds and enhance PPO activity leading to phenols degradation whereas, on the other hand, high temperatures could improve the diffusion and solubility of polyphenols resulting in enhanced extraction rates . UltrasoFurthermore, there are other factors not connected with HPU application that might determine important differences in the phenols content of the extracted oils. The most important factor above all is the oxygen concentration in the headspace during malaxation since it plays a key role in many enzymatic and non-enzymatic oxidation reactions . The varFinally, the different analytical techniques used for total phenols determination should be considered since they could affect the final result. In fact, in some of the cited studies, total phenolic content was determined through the Folin-Ciocalteu method, while in others as a sum of the areas of the chromatographic peaks found through HPLC analysis. This is clearly a significant factor because it is possible that not all phenolics were included. Moreover, some interferents were highlighted in the case of Folin-Ciocalteu assay, such as ascorbic acid , possiblLipid oxidation is the principal factor limiting the shelf life of olive oils, which are generally quite stable to autoxidation phenomena due to the high content of monounsaturated fatty acids and minor compounds, i.e., phenolics and tocopherols showing antioxidant activity ,63. HPU HPU treatment of high-unsaturated fatty acid foods is generally problematic since those fatty acids are more susceptible to autoxidation . NeverthWith regard to olive oil fatty acid composition, it is generally not affected by HPU treatment ,63. BejaMost of the volatile compounds that characterize olive oils are produced during malaxation due to the activation of specific pathways, among which the lipoxygenase enzyme (LOX) takes on great importance generating a wide range of C6 aldehydes, alcohols, and esters, accounting for most of the positive sensory notes of olive oils. Such modifications are triggered when olive fruit tissues are damaged, thus facilitating the release of endogenous enzymes such as lipoxygenase and hydroperoxide lyase .In this regard, Bejaoui et al. ,57 studiOther studies pointed out some differences between the volatile and sensory profiles of oils obtained through conventional and HPU-assisted extraction. Almeida et al.  observedA decrease in the concentration of volatile compounds after HPU treatment could also occur, depending on processing conditions, i.e., ultrasound power and treatment time. A decrease in C5 and C6 aldehydes of approx. 5% following HPU treatment was reported by Taticchi et al. , which wRegarding total tocopherols, some studies report an increase achieved with HPU treatment (approx. 20%), mainly involving α-tocopherols (up to 50%) ,55. ThisThe concentration of pigments  is positively affected by HPU application ,51,55 wiIn conclusion, the impact of HPU on olive oil quality and chemical composition is not univocal, especially in the case of micro-components, i.e., polyphenols, tocopherols, and volatile compounds. However, these contrasting results primarily depend on the complexity of physical and biochemical mechanisms involved in the transformations occurring during olive oil production and on the wide variety of processing parameters, such as ultrasound power, temperature, and time of treatment, as well as on variables that are not strictly related with HPU application, such as oxygen concentration in the headspace during malaxation, olive variety and climate. Thus, a HPU treatment could be designed in order to improve the final content of antioxidants and volatile compounds through enhanced extraction, limiting oxidative and thermal losses. As many discrepancies were found in the literature regarding the effects of HPU on olive oil nutritional and sensory quality, The traditional character of EVOO is probably the main factor limiting the introduction of innovative technologies in this field, such as HPU processing. The objective of this section is to determine whether consumers could be open to such innovation and willing to pay more to obtain a more sustainable product that naturally contains a higher concentration of micro-components which could benefit human health and improve oil shelf-life.As highlighted by Guerrero et al. , when inAnother study carried out by Roselli et al.  attempteIn the light of the literature research, it seems clear that the most important aspect to achieve a higher acceptance rate for HPU-extracted olive oils is to create a positive perception of the product, highlighting the positive effects of such technology, in terms of waste reduction and improvement in antioxidants content. HPU-extracted olive oils should be addressed to a specific market segment (niche market), with consumers of higher awareness levels and open to innovation, since it is much more likely that they are also willing to pay more to get a higher quality product.The reviewed literature confirms that HPU treatment could be successfully implemented in EVOO processing to enhance, shorten or substitute malaxation step, or eliminate olive paste pre-heating. There is evidence that HPU-driven extraction of olive oil leads to higher yields and improves oil extractability index through reduced paste viscosity and acoustic cavitation phenomena provoking cell membrane damages. Such treatment might also affect the development of phenolic and volatile compounds and consequently olive oil health properties, oxidative stability, and sensory aspect . Nevertheless, the treatment should be carefully designed to produce olive oils with the desired characteristics since too high ultrasound power and/or too long treatment times might detrimentally affect the stability of EVOO components. Further research is needed to better highlight the main processing parameters to modulate for obtaining oils with tailored physico-chemical, chemical, and sensorial properties. As for the consumer perception, olive oils extracted through HPU are generally accepted, but only a small proportion of consumers are willing to pay an additional price for such a high-quality product. This percentage largely depends on the ability to deliver information regarding the advantages of the innovative process, i.e., health benefitting properties (phenols enrichment) and sustainability (waste reduction), which could help to overcome the skepticism generated by the non-traditional process. In view of this, the costs of the innovative extraction process should also be analyzed and compared to the traditional one to determine whether a significant competitive advantage provided by the HPU application can be highlighted.


As a highly dynamic tissue, the endometrium is periodically shed in response to the secretion of estrogen and progesterone. After menarche, the endometrium of healthy women proliferates and differentiates under the action of steroid hormones  that are secreted by the ovaries to provide appropriate conditions for embryo implantation. Polycystic ovary syndrome (PCOS), a prevalent endocrine and metabolic disorder in reproductive-aged women, is usually associated with multiple cysts within the ovaries and excess levels of androgen and is characterized by hirsutism, acne, menstrual irregularity, infertility, and increased risk of insulin resistance. Multiple factors, such as anovulation, endocrine-metabolic abnormalities, and inflammation, can disrupt the endometrium in PCOS patients and can lead to endometrial hyperplasia, pregnancy complications, or even cancer. Despite many recent studies, the relationship between PCOS and abnormal endometrial function is still not fully understood. In this review, we investigate the correlation of PCOS patient endometrium with anovulation, hyperandrogenemia, insulin resistance, progesterone resistance, and inflammatory cytokines, aiming to provide a theoretical basis for the treatment of disorders caused by endometrial dysfunction in PCOS patients. Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disease that affects 4–21% of adolescent and childbearing women worldwide . Its patFor PCOS patients who do not want to become pregnant, the incidence of endometrial carcinoma increases substantially due to the long duration of irregular menstruation. The study conducted by Meczekalski et al. showed that the risk of endometrial carcinoma in PCOS patients is approximately three times higher than that of healthy women . The endPolycystic ovary syndrome patients’ ovaries synthesize too much androgen, resulting in the recruitment of numerous pre-ovulatory small follicles. These follicles do not respond to the normal concentration of follicle stimulating hormone, and this hinders the formation of dominant follicles. In PCOS patients, the endometrium cannot be periodically shed due to the associated follicular development disorders and long-term lack of ovulation, and under estrogen stimulation the endometrium continues to thicken leading to atypical hyperplasia or even to carcinogenesis. A study conducted by Zhang et al. showed that about 97% of the enrolled PCOS patients did not ovulate, and 41% of them had endometrial hyperplasia, which suggested that endometrial hyperplasia in PCOS was induced by anovulation and continuous estrogen stimulation . Han et In the ovary, the production of steroid hormones is governed by gonadotropins and ovarian cell signaling. Androgen, a steroid hormone, converts to dehydroepiandrosterone (DHEA) and androstenedione in ovarian follicle cells and in the adrenal cortex through the activity of cholesterol side chain lyase CYP11A; . ApproxiAndrogen can inhibit the growth and differentiation of endometrial cells and the decidualization of the endometrium, thereby interfering with embryo implantation . Studiesin vitro decidual response of human endometrial stromal fibroblasts , and changes in DHEA can alter the bio-availability of endometrial androgen and the endometrial microenvironment. Gibson et al. found that DHEA can enhance the roblasts , and HA roblasts . Eaglesoroblasts . Meanwhiroblasts .In addition, studies have shown that HA in PCOS patients stimulates oxidative stress as evidenced by the over-generation of reactive oxygen species ROS; . ROS canInsulin resistance occurs when the effect of insulin on cells, such as fat, muscle, and liver, is lower than normal, resulting in decreased glucose utilization, increased liver gluconeogenesis, and increased blood glucose concentration and compensatory hyperinsulinemia. Studies have shown that about 50–70% of PCOS patients also have IR and compensatory hyperinsulinemia, and the risk of type 2 diabetes is significantly increased in PCOS patients .Since the discovery of insulin in 1921, its mechanism of action has been widely debated . In 1985In vitro studies have found that inhibition of serine/threonine phosphorylation can antagonize or terminate insulin signaling and thus is an important mechanism of IR  is an important mediator of inhibiting the effect of estrogen in the progesterone signaling pathway . Mig-6 iThe endometrium contains a variety of resident and transient immune cells, which together with cytokines and chemokines maintain the normal function of the endometrium . NumerouUterine natural killer cells, which are part of the endometrial cell population, not only promote embryo implantation, but also protect the embryo from pathogens . UNKs arp < 0.05; C-reactive protein, an acute-phase protein mainly produced by hepatocytes, is a sensitive indicator of tissue injury and inflammatory response . NumerouIsolated endometrial cells from PCOS patients show altered gene expression, including IL-6 and TNF-α, indicating changes in the status of inflammation . TNF-α, Clarifying the specific mechanisms  of endometrial lesions caused by the various phenotypes of PCOS will provide new treatment strategies for improving clinical pregnancy outcomes in patients with PCOS and for reducing the risk of endometrial lesions. Future research should focus on screening more molecular targets of therapeutic drugs for PCOS and endometrium-related diseases.YZ: funding acquisition. ZX, JL, and JF: conceptualization and writing – original draft preparation. HH, JinZ, and JiaZ: editing. YH, XW, and YZ: supervision. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (grant numbers 81774136 and 82074259), the Cultivation Project of the Outstanding Youth Fund of the Heilongjiang University of Chinese Medicine (grant number 2018jc02), and the “Outstanding Young Academic Leaders” Scientific research project of Heilongjiang University of Chinese Medicine to YZ.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.


Neglected Tropical Diseases (NTDs) are a group of infectious diseases that disproportionally affect impoverished countries. NTDs, because of their severity, negatively impact the disability-adjusted life year (DALY), a measure of overall disease burden on a country. This metric quantifies the potential years of life lost due to premature death as well as potential years of healthy life lost due to chronic states of illness and disability. NTDs, thus, transform the health of individuals and whole societies.The world health organization estimates that NTDs affect more than one billion people in 149 countries and cost developing economies billions of dollars every year. In 2012, NTDs accounted for approximately 22 million DALYs globally. People suffering from these diseases often lose their abilities to contribute socially and economically, forgo educational opportunities, and are burdened with exorbitant expenses for treatment. NTDs are, therefore, a primary driver of the poverty cycle in many countries.“Chemoinformatics has become an integral part of the drug discovery process, accelerating the search for novel chemicals with desired physicochemical, pharmacological, toxicological, and pharmacokinetic properties.”This special issue of Frontiers in Chemistry is devoted to cheminformatics approaches in drug discovery for neglected tropical diseases. The papers that are included in our special issue cover a variety of research questions related to different aspects of computer-assisted drug discovery for NTDs. A brief description of these papers is provided below.Choudhury and Bhardwaj report a dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets. Mtb-DapB, a validated mycobacterial drug target, was used as a basis for model systems to explore the effectiveness of DHPMs to screen novel unexplored compounds. The model systems were subjected to 200 ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid molecules occupying both binding sites. A huge library of 1,563,764 publicly available molecules was screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice, and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength, and drug-like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.Vasconcelos and Rezende propose the use of integrated computational methods capable of evaluating the druggability of the predicted proteomes of Leishmania braziliensis and Leishmania infantum, species responsible for the different clinical manifestations of leishmaniasis in Brazil. The protein members of those proteomes were assessed based on their structural, chemical, and functional contexts applying methods that integrate data on molecular function, biological processes, subcellular localization, drug binding sites, druggability, and gene expression. These data were compared to those extracted from already known drug targets (BindingDB targets), which made it possible to evaluate Leishmania proteomes for their biological relevance and treatability. Through this methodology, the authors identified more than 100 proteins of each Leishmania species with druggability characteristics, and potential interaction with available drugs. Among those, 31 and 37 proteins of L. braziliensis and L. infantum, respectively, have never been tested as drug targets, and they have shown evidence of gene expression in the evolutionary stage of pharmacological interest. Also, some of those Leishmania targets showed an alignment similarity of <50% when compared to the human proteome, making these proteins pharmacologically attractive, as they present a reduced risk of side effects. The methodology used in this study also allowed the evaluation of opportunities for the repurposing of compounds as anti-leishmaniasis drugs, inferring potential interaction between Leishmania proteins and ∼1,000 compounds, of which only 15 have already been tested as a treatment for leishmaniasis.Winkler reviewed the use of artificial intelligence and machine learning for the discovery of drugs to treat neglected tropical diseases. He discussed how computational methods are starting to make significant inroads into the discovery of drugs for neglected tropical diseases due to the increasing availability of large databases that can be used to train ML models, the ever-improving accuracy of these methods, the lower entry barrier for researchers, and widespread availability of public domain machine learning codes. He also summarized the application of artificial intelligence, largely the subset called machine learning, to modeling and prediction of biological activities and discovery of new drugs for neglected tropical diseases. The pathways for the development of machine learning methods in the short to medium term and the use of other artificial intelligence methods for drug discovery were discussed as well. The current roadblocks to, and likely impacts of, synergistic new technological developments on the use of ML methods for neglected tropical disease drug discovery in the future were also reviewed.Kleandrova et al. report the first multi-target model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mt-QSAR-MLP) to virtually design and predict versatile inhibitors of proteins involved in the survival and/or infectivity of different pathogenic parasites. The mt-QSAR-MLP model exhibited high accuracy (>80%) in both training and test sets for the classification/prediction of protein inhibitors. Several fragments were directly extracted from the physicochemical and structural interpretations of the molecular descriptors in the mt-QSAR-MLP model. Such interpretations enabled the generation of four molecules that were predicted as multi-target inhibitors against at least three of the five parasitic proteins reported here with two of the molecules being predicted to inhibit all the proteins. Docking calculations converged with the mt-QSAR-MLP model regarding the multi-target profile of the designed molecules. The designed molecules exhibited drug-like properties, complying with Lipinski’s rule of five, as well as Ghose’s filter and Veber’s guidelines.


COVID-19 is imposing massive health, social and economic costs. While many developed countries have started vaccinating, most African nations are waiting for vaccine stocks to be allocated and are using clinical public health (CPH) strategies to control the pandemic. The emergence of variants of concern (VOC), unequal access to the vaccine supply and locally specific logistical and vaccine delivery parameters, add complexity to national CPH strategies and amplify the urgent need for effective CPH policies. Big data and artificial intelligence machine learning techniques and collaborations can be instrumental in an accurate, timely, locally nuanced analysis of multiple data sources to inform CPH decision-making, vaccination strategies and their staged roll-out. The Africa-Canada Artificial Intelligence and Data Innovation Consortium (ACADIC) has been established to develop and employ machine learning techniques to design CPH strategies in Africa, which requires ongoing collaboration, testing and development to maximize the equity and effectiveness of COVID-19-related CPH interventions. What is already known about this subject? The still ongoing COVID-19 pandemic is generating massive health, social and economic costs, amplifying existing inequalities and disparities and creating new ones.What are the new findings? Big data and Artificial Intelligence machine learning techniques and collaborations can be instrumental in an accurate, timely, locally nuanced analysis of multiple data sources to inform clinical public health decision-making related to COVID-19, vaccination strategies and their staged roll-out.What are the recommendations for policy and practice? Ongoing collaborations between African countries and other countries, such as Canada, relying on big data and Artificial Intelligence machine learning techniques, can enhance testing and development to maximize the equity and effectiveness of COVID-19 related clinical public health interventions.The COVID-19 pandemic is a global public health emergency with immediate and secondary health, social and economic impacts, as well as cascading and compounding crisis effects that are global in nature, and that cannot be solved by any one country acting alone. More than 190 million people have been infected, more than four million people have died, and SARS-CoV-2 and its variants of concern (VOCs) continue to spread globally with differing morbidity and mortality patterns nationally and regionally . This COThese measures include hand washing, use of masks, physical distancing, case finding, testing, contact tracing, isolation, quarantine, border controls, and restricted movement and gatherings . While tWith unprecedented and ongoing clinical public health and scientific global collaboration in the year since the emergence of the COVID-19 pandemic, some new vaccines have been approved and are now being used under emergency use provisions by some nations and are pending emergency use approvals in many other nations. At least 230 other vaccine candidates are in varying stages of preclinical and clinical development, and some of these will likely be available for national emergency use approvals .While many economically developed countries have already started immunizing, securing for themselves more than half of the world’s doses, most African nations are still waiting for vaccine stocks while preparing their vaccination campaigns. At the time of writing, a global average of 1.89 per 100 people has been vaccinated, while the continent of Africa is in last place with the number vaccinated at 0.04 per 100 people [Deploying and administering effective and safe vaccines against COVID-19 to large populations at a fast pace is, indeed, a nontrivial task, given the factors above, the high transmissibility of the virus and its speed of spread, the variable feasibility of public health mitigation and prevention strategies, the infrastructure and logistics requirements, including cold chain, supply, distribution and delivery related issues, real-time monitoring and determination of vaccine efficacy, and vaccine production, as well as vaccine hesitancy, which is particularly high in the African continent ,12.Due to the logistical challenges in Africa, an assessment of different vaccination scenarios and roll-out strategies, that take into account national and local realities, is of paramount importance for public health policy and decision making, in order to maximize and track staged progress towards the achievement of herd immunity. The Africa-Canada Artificial Intelligence and Data Innovation Consortium (ACADIC) has been leveraging big data and AI-based techniques to respond to these policy questions in nine African countries.The COVID-19 pandemic has been and is a catalyst for innovation, profoundly modifying the way vaccine products are conceived, manufactured, tested, and delivered. Many unprecedented collaborative innovation efforts to inform vaccination strategies at the global level are underway, which rely on recent scientific advancements, including big data and Artificial Intelligence (AI)-based techniques . In partACADIC is also assisting with the design of vaccination strategies to help keep the number of COVID-19 cases requiring hospital care  below the maximum hospital capacity and maximize the impacts of available supply of vaccines, given the limited dose of vaccines that Africa may receive. We are building on the experience we have gained from South Africa, where ACADIC has designed and is piloting Artificial Intelligence-based techniques to model prioritization strategies in the COVID-19 vaccine roll-out in the Gauteng Province, the most populous of the nine provinces in South Africa.In South Africa the national government is responsible for COVID-19 vaccine procurement and distribution to the nine provinces where provincial governments are responsible for storage, distribution to designated vaccination sites, and administration of vaccine to the population. An ACADIC team member is part of the Gauteng province premier’s COVID-19 Advisory Committee and is leading the COVID-19 related modelling initiatives in the committee.In order to identify and prioritize target groups who can benefit most from vaccination, in the Gauteng Province a pilot study has been conducted, multi-dimensional data have been provided by the Gauteng Department of Health (GDOH) and are being used to characterize variables associated with severe illness. Fourteen dimensions of individual-specific characteristics have been modelled and include: age; eleven relevant co-morbidities; gender and ethnicity; information pertaining to the type of hospitalization  and whether the subject was discharged alive or died in care is also provided. This allows for implementation of a supervised machine-learning classification procedure. Multi-dimensional survey data are also available and provide representative data samples with a large number of inputs pertaining to social vulnerabilities. A subset of these inputs accords with the data inputs from the GDOH and matching between the two data sets has been performed. The data sets from the GDOH contain co-morbidities as an index of vulnerability that covers co-morbidities relevant to COVID-19. These include diabetes, hypertension, emphysema, bronchitis, asthma, pneumonia, heart disease, stroke, HIV/AIDS, and tuberculosis. The data sets provided by the GDOH contain about 5000 points of complete patient records for the period of the first wave of COVID-19 and the beginning of the second, where the remainder of the data are becoming available. This limited data set is sufficient to train smart algorithms with relatively high efficiency.A deep neural network (DNN) has been trained to separate two classes of data sets: severe illness  and less severe illness . A training sample with 70% of the data has been used, where a testing sample with 30% of the data has been used to validate results and with which to estimate potential over-training. The corresponding DNN weights have been applied to the population data provided by the Gauteng City-Region Observatory . Figure The DNN output provides a dimensionless number between 0 (highest risk of severe illness) and 1 (lowest risk of severe illness). Ideally, the population is classified according to the DNN output, which can be easily achieved through an electronic system. Further, AI-derived recommendations can be elaborated, as in Several highly transmissible COVID-19 variants of concern (VOCs)—such as the South Africa VOC B.1.351, or the United Kingdom VOC B.1.1.7—have emerged and have spread internationally, with variable virulence and antigenicity relative to immune responses to infection with the resident strain, and relative to currently available vaccines.The genomic characteristics and human immune response to resident and VOC strains of SARS CoV-2 must be matched with the antigenicity of currently available and soon to be available vaccines, and this data must be incorporated into big data AI applications. For both resident and VOC strains of the SARS-CoV-2 virus, big data AI applications can aid in the targeted identification and analysis of emergent hotspots or outbreaks; in the strategic choices for rapid, highly targeted and staged delivery of effective vaccines, as well as in ongoing monitoring for the efficient delivery and effectiveness of currently available vaccines and for vaccines that may become available in the future.Since the required quantities of vaccines to reach herd immunity at national levels will not be immediately available to Africa, national allocation plans, and prioritization-based strategies are urgently needed to maximize clinical public health effectiveness and equity. To be effective, these strategies and plans must be locally informed and evidence-based and ensure staging and roll-out that achieves optimal health and health system and broader social and economic benefits with a gradually increasing supply of vaccines.For instance, heterogeneous responses to the spread of COVID-19 are driven by a variety of factors, notably individual-specific characteristics , and characteristics specific to an individual’s behaviors and routine . These factors can contribute to the emergence of epidemiological hot spots and understanding these, and their geo-locations is critical to deciding on how to most effectively and equitably prioritize the staged distribution of vaccines to critical demographic or vulnerable population categories . Prioritization-based strategies must also be informed to address local obstacles and challenges, including that an adequate number of doses are procured and equitably distributed, according to a sustainable supply-chain output based on manufacturing and logistics capacity.Indeed, a convergence of these issues has led to the cancellation in South Africa of the use of the Oxford AstraZeneca vaccine because of poor efficacy in reducing mild disease from the South Africa VOC B.1.351 ,17. HoweWhereas more detailed data are available for South Africa , the ACADIC Consortium is developing networks and methodologies to transfer this pilot study, the knowledge gained and developed modelling techniques, to other African countries in a manner that accounts for differences in demographics and prevalence of co-morbidities and re-weighting the DNN algorithm initially developed for South Africa. We have already done this with Botswana, and we are doing this for seven other African countries. Validation and further correcting procedures will be implemented in order to ensure that the assumptions of the model are consistent with the specific features of the selected country. We are also specifically seeking to expand understanding of social vulnerabilities, which are paramount to model development and interpretation of the data. A range of sources—such as detailed geo-spatial maps of social vulnerabilities—will be utilized as inputs to our models. Further, gender is a major variable impacting COVID-19 in terms of risk of developing the communicable disease, disease severity, response to treatments, adverse reactions to medications and magnified social vulnerability  and is bBig data and AI machine learning techniques, tools and collaborations can be highly instrumental in maximizing the equity and effectiveness of COVID-19 related CPH interventions. COVID-19 is a global public health emergency and has catalyzed international collaboration that brings diversified expertise to integrate big data and Artificial Intelligence-based techniques to inform clinical public health containment, control, and mitigation strategies in a rapidly evolving global pandemic, including optimal allocation of resources such as vaccines when global supply is unequally distributed. As manufacturing capacity is aligned with global demand for approved vaccines, national staged vaccine access allocation plans, and prioritization-based strategies are needed. Vaccine scarcity and the emergence of VOCs mandate novel decision support tools to develop vaccination priority and roll-out strategies to maintain critical public health and frontline service capacity, reduce the hospitalization and mortality and safely reopen essential business, and the economy. In conclusion, big data and AI machine learning techniques, tools and collaborations can be highly instrumental in a more accurate, timely, locally nuanced analysis of multiple sources of changing data to inform clinical public health decision making, including vaccination strategies and their staged roll-out, social vulnerabilities, gender, and strategies to identify and respond to VOCs.


The formulation of additives with combinations of compounds previously characterized is recommended to avoid bacterial resistance. To improve the delivery of phytogenics and overcome limitations associated to compounds volatility and susceptibility to degradation, the use of encapsulation is advisable. Besides, newer approaches and dedicated methodologies are needed to elucidate the phytogenics pharmacokinetics and mode of action in depth.Aquaculture growth will unavoidably involve the implementation of innovative and sustainable production strategies, being functional feeds among the most promising ones. A wide spectrum of phytogenics, particularly those containing terpenes and organosulfur compounds, are increasingly studied in aquafeeds, due to their growth promoting, antimicrobial, immunostimulant, antioxidant, anti-inflammatory and sedative properties. This trend relies on the importance of the mucosal barrier in the fish defense. Establishing the phytogenics’ mode of action in mucosal tissues is of importance for further use and safe administration. Although the impact of phytogenics upon fish mucosal immunity has been extensively approached, most of the studies fail in addressing the mechanisms underlying their pharmacological effects. Unstandardized testing as an extended practice also questions the reproducibility and safety of such studies, limiting the use of phytogenics at commercial scale. The information presented herein provides insight on the fish mucosal immune responses to phytogenics, suggesting their mode of action, and ultimately encouraging the practice of reliable and reproducible research for novel feed additives for aquafeeds. For proper screening, characterization and optimization of their mode of action, we encourage the evaluation of purified compounds using  Allium sp. are among the most commonly studied and administrated plant-based additives  serving only as proxies, that only provide a snapshot of the effects of the evaluated feed additive on the organism. These approaches do not allow elucidating their mode of action at cellular and molecular levels. This is of special relevance when dealing with functional feed additives with potential pharmacological properties, as their standardized use mainly depends on the proper understanding of their regulatory properties in the immune system.Since outbreaks of fish diseases are one of the main constrains for the progress of the aquaculture sector , the incvice versa, an interaction that plays a determinant role in the maintenance of the mucosal integrity and functionality , harboring diverse myeloid and lymphoid cells that are responsible for the host protection against pathogens and antigens, while tolerating beneficial symbiont colonization to maintain mucosa homeostasis –21. Six + T cells expressing antigen-specific T cell receptors (TCR) in their surface. Recognition of this complex stimulates the dedicated CD4+ cells activation and differentiation into T helper cell subsets possessing inflammatory cytokines secreting capacity that further coordinate the adaptive response together with B cells  a downstream signaling response mediated through pattern recognition receptors (PRRs) immediately takes place. So far, several piscine PRRs have been identified, being the toll-like receptors (TLR), NOD-like receptors (NLR) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) the best characterized , 25. Epi B cells , 28. Intunocytes –31.+ T-cells, produce IgM, IgT, and eventually IgD plasmablasts -a major lymphocyte population in the gut, gill and at some extent the skin-, have just been recently addressed   . InteresAlthough characterized by common cellular components, immune mediators and immune mechanisms, the different composition, organization and functions of MALTs may vary according to each tissue intrinsic and external environmental factors , changesThe mucosal tissues are intrinsically characterized by mucus secreting cells, such as goblet cells . Beside In nature, plant secondary metabolites have functional roles independent from plant growth and development; thus, protecting plants from herbivore and pests, or acting as chemoattractants for pollinators . These bAllium sp. are among the most widespread administrated plant-based additives in aquaculture  are particularly present and traditionally consumed in the Mediterranean area and appreciated in terms of human nutrition and therapy  and thyme (Thymus vulgaris)  , 110. Thulgaris) . This baTogether with their well-studied bactericidal potential, these phenolic compounds are described to potentially improve the integrity of the mucosal tissues due to their observed antioxidant, anti-inflammatory and consequent immunomodulatory properties in the gastrointestinal mucosa of several animal models . The repkB and MAPK pathways, modulating the expression of pro-inflammatory and anti-inflammatory cytokines  and onion , are sulfur‐containing compounds. This group of bioactive substances comprises alliin, allicin and its derived bioactive compounds like ajoene, diallyl trisulfide (DATS), diallyl disulfide (DADS), diallyl sulfide (DAS) and allyl methyl disulfide, commonly termed as organosulfur compounds. These organosulfur compounds are the responsible for the recognized antioxidative, antimicrobial, antifungal and antiparasitic properties of garlic  , exertinpathways , 137. Sorception . In accocrobiota . In addicrobiota , 141.2+ flux in neutrophils augmenting their phagocytic function and consequent ROS production. In parallel, other compounds are able to inhibit spontaneous ROS production by neutrophils  a combination of garlic and essential oils from plants of the Lamiaceae family promoted skin mucus lysozyme activity and fish survival against V. anguillarum when exposed to a confinement stress (Seriola dumerili), the same additive induced an up-regulation of a set of immune related genes in the skin in response to a monogenean parasite Neobenedenia girellae infection (Sparus aurata) skin mucus in terms of bacterial inhibition capacity against fish pathogens and decrease of stress markers, whereas the transcriptional analysis suggested the stimulation of the secretory pathway possibly associated to humoral immune molecules secretion into mucus and activation of phagocytic cells , who might be also modulated by the antimicrobial properties of these compounds, may facilitate the activation of TLR and TRP signaling pathways; thus, amplifying the mucosal immune responses. Moreover, the bioactive compounds are also suggested to passively diffuse across the cell membrane, scavenging ROS that contribute to the inflammatory pathways, and interacting with TRP channels of the endoplasmic reticulum, potentially stimulating the secretory pathway. The above-described mode of action of phytogenics derived from Lamiaceae family and Allium sp. at the level of the main mucosal lymphoid tissues in fish is depicted in According to the above-described studies and the acknowledged properties of these phytogenics’ bioactive compounds, we suggest that the mechanisms of cell activation that may be responsible for the mucosal immune-related responses are mediated by the activation of TRP cation channels in both immune and epithelial cells of mucosal tissues. The bioactive compounds may activate TRP channels leading to intracellular CaIn addition, a summarized representation of the potential mucosal immune responses induced by the dietary administration of terpene and/or organosulfur based phytogenics and their effects against fish pathogenic organisms is suggested in Feeding the projected world population by 2050 in a sustainable way is a great challenge, in which aquaculture is predicted to supply the majority of aquatic dietary protein. For that, the implementation of novel policies and production system approaches targeting effective health management and animal welfare are mandatory . MoreoveAlthough limitations in testing and reproducing studies using dietary immunostimulants have been pointed out since long ago –155, thein vitro under variated settings, before moving forward to in vivo trials. However, it is important to consider that the biological activities of essential oils or extracts cannot be attributed to a single compound or to a unique specific mechanism, since their multi-component properties exert greater biological activity when compared to the major components alone, whose function is probably regulated by the synergy with limiting compounds .The remaining 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.