Prevention and control of infection in dentistry is an essential matter that has gained immense attention in recent years. There exist a lack of scientific data about the cross-transmission and its associated risk, especially in the dental health care setting of Pakistan. This article will evaluate the emerging challenges and threats for the dental community in Pakistan attributable to the COVID-19 outbreak. There is a significant knowledge gap regarding the state- and institutional-level of infection prevention and control (IPC) policies and practices. In addition, not much is known about the development, implementation, and monitoring of IPC policies and its challenges. In recent years, the global burden of oral health disease is 2-fold both for developed and developing nations.2 It is of huge concern that dental care services are not readily accessible to most of the population due to the expensive nature of treatment modalities. In most of the developing countries, the situation is further impacted by the fact that dental care is not well regulated and not even considered as one of the essential components of the primary health care system.3 On top of that, in the state of a recent global pandemic of COVID-19, it is questionable whether the dental practitioners would be consistently utilizing safe infection control practices.Globally more than 3.5 million cases of COVID-19 have been reported . With time, cases in China reduced but the epidemic started to spread rapidly across the world. Pakistan is currently in the midst of this epidemic, which has led authorities to impose social distancing to reduce its spread. It would not be an underestimation to claim that COVID-19 has created havoc across the globe.4During the dental procedures, the use of ultrasonic instruments and high-speed hand-pieces is very common. These instruments aerosolize oral secretions such as saliva and blood into the surroundings. Due to the unique nature of dental procedures, which generates large number of aerosols and droplets, the usual standardized protective measures followed by the dental care workers will not suffice for preventing the spread of COVID-19, especially when the patient is symptom-free, unaware about the disease status, or falsifying infection history. Therefore, the containment of the propagation of the virus would be nearly impossible.5 However, in our context, there is a huge gap with the scientific data for viral and bacterial infection and transmission in dental practices. The cross-infection is underreported in the dental literature. Lack of adherence to standard precautions remains a challenging obstacle. The common examples for noncompliance with the infection control practices in dentistry are never sterilizing dental hand-pieces; never disinfecting impressions/casts; and the occurrence of dried blood on dental instruments such as on hand-mirror heads, on the dental chair, and dental burs.6 Furthermore, it has been exacerbated with the lack of hand hygiene practices while switching patients due to carefree attitudes, never disinfecting the work environment between procedures, lack of provision of protective gears, nonavailability of alcohol-based hand rub, improper dental waste management, and lack of safe water supply in dental units.6 For further understanding of the convolutions, a cause and effect diagram is shown in The oral cavity is the natural habitat for heaps of pathogens and opportunistic microorganisms. These have imposed an immense risk for cross-contamination and infections. In dental practice, the risk of exposure to microorganisms further intensified due to the open and invasive nature of management regimens. There is evidence that in dentistry, hepatitis B virus is a real menace for cross-infection.An effective infection control and prevention program can only be attained when there is a systematic approach for implementing all the vital elements in the dental sector. These core components should be implemented both at nationwide hospitals affiliated with dental institutes and private dental care facilities. The following actions are proposed.A state-level task force should be formed with individuals trained in infection prevention. They would be responsible for developing documented countrywide evidence-based policy procedures and guidelines. It should include guidelines for hand hygiene, use of personal protective equipment, respiratory hygiene/cough etiquette, sharps safety, safe injection practices, instruments sterilization, disinfected environmental surfaces, and dental unit water quality.State-level infection prevention and control key performing indicators should be defined, as well as a mechanism that would allow regular monitoring and evaluation.Introducing regulatory mechanisms for accreditation of dental health care facilities to ensure compliance with infection control standards.Agreed upon international and national policies should be tailored for academic institutions and should be gauged at defined periodic intervals.The hiring of an infection prevention coordinator to ensure compliance of infection control standards.Development and implementation of evidence-based triage process to prioritize and manage infectious patients.Mandatory on-job infection control training of dental providers and students.Identify standard training component for infection control and prevention such as precautionary measures, mode of transmission, and its prevention.There exists a significant gap in the development and implementation of infection control and patient safety policies at dental health care facilities. Without the appropriate infection prevention practices, dental facilities will be the permanent home for transmission of viruses and bacteria within the facilities and to the community, which will further impart resistance. In the past, the understandings from the epidemics such as severe acute respiratory syndrome (SARS), H1N1, Ebola, and the recent COVID-19 demonstrate that health care facilities can amplify newer microorganisms and diseases to the patients, health care workers, and community if there will be no appropriate and effective dental infection prevention and control policies in place.


Silk fibroin has the merits of biocompatibility, biodegradability, ease of processing, and feasibility of modification, which present it as a promising drug delivery material. This review focuses on the structures of silk fibroin, the controlled transformation of secondary structures, and the formation mechanism of silk fibroin-based nanoparticles (SFNPs). We also discuss the intrinsic multi-responsive, surface functionalization, and transgenic modification of SFNPs for drug delivery. Drug delivery is required to deliver appropriate amounts of therapeutic agents to the diseased sites to improve the therapeutic effect of drugs and reduce their adverse effects  by changing their physicochemical properties can maintain the stability of the loaded drugs, prolong the blood circulation time of drugs, realize on-demand drug release in the targeted cells, and reduce the systemic side toxicities  and Ser (12%)  to Silk II (highly ordered β-sheet). Silk fibroin molecules form loose amorphous structures in aqueous solution due to their intrinsic electrostatic repulsion , providing direct evidence of the accelerated release of DOX in the lysosome of tumor cells   through the chemical reaction between the amino groups of silk fibroin and the carboxyl groups of FA molecules. The obtained FA-DOX-NPs could be specifically internalized by FA receptor-overexpressed tumor cells and release the loaded DOX in a controlled manner. They further found that the surface functionalization of FA significantly improved the chemotherapeutic effect and reduced the potential adverse effects of DOX  to acidity, ROS, and GSH, which can facilitate the on-demand release of the loaded drugs from the NPs. Collectively, these SFNPs can be exploited as a promising nanocarrier for drug delivery.Silk fibroin has become an attractive natural polymer for drug delivery due to its versatile merits such as good biocompatibility, modulated biodegradability, large scale production, easy modification, and self-assembling property. Many approaches can be applied to further the application of silk fibroin as a drug delivery material such as optimization of its primary structures, modification with functional chemical groups, adjusting the self-assembling processes, and controlling the interaction between silk fibroin and the loaded agents. It is also critical to endow them with a diseased site-targeting capacity YM wrote the draft of the manuscript. BC, XT, FD, and BX provided suggestions and edited 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.


Changes in lifestyle and demographics, rising consumer incomes, and shifting preferences due to advanced knowledge about the relationships between food and health contribute to generate new needs in the food supply. Today, the role of food is not only intended as hunger satisfaction and nutrient supply but also as an opportunity to prevent nutrition-related diseases and improve physical and mental well-being. For this reason, there is a growing interest in the novel or less well-known plant foods that offer an opportunity for health maintenance. Recently, interest in plant foods and underutilized fruits is continuously growing, and agrobiodiversity exploitation offers effective and extraordinary potentialities. Plant foods could be an important source of health-promoting compounds and functional food ingredients with beneficial properties: the description of the quality and physicochemical traits, the identification and quantification of bioactive compounds, and the evaluation of their biological activities are important to assess plant food efficacy as functional foods or source of food supplement ingredients. It is known that specific foods confer additional health benefits to human beings as treatment and/or prevention of several diseases . For thiNutraceuticals are detailed as food products purified, produced, or extracted from an animal or plant source , or produced from pressed, powdered, or dried plant material and demonstrated to present a health-promoting benefit or to protect against several chronic diseases ,4. DietaIn the plant biochemistry, secondary metabolites , produced in the plants, are not directly involved in the normal organism growth and development, but they act as defense compounds against predators, diseases, parasites, ultraviolet radiation, and oxidants to facilitate the reproductive processes . These sToday, nutraceuticals on the market consist of both traditional foods  and non-traditional foods . . In receThis Special Issue provides readers with a good overview of the status and exciting developments in this field. It includes papers focused on modern analytical instrumentation and new methods and biological tests applied to the evaluation of underutilized plants and phytochemical characterization of innovative natural sources of bioactive compounds and relative health-promoting properties.Tasmannia lanceolata, Backhousia citriodora, and Syzygium anisatum by ultra-high-performance liquid chromatography and the mechanism of action against food spoilage yeasts together to their antioxidant and antimicrobial activities. The extracts showed broad-spectrum antifungal activity against weak-acid resistant yeasts in comparison to the standard antifungal agents. Polygodial, citral, and anethole were the main bioactive molecules identified in Tasmannia lanceolata, Backhousia citriodora, and Syzygium anisatum, respectively. The ethanol and methanol extracts showed the highest polyphenolic content and antioxidant properties, while the hexane extracts contained the highest amount of total bioactive compounds and demonstrated the strongest antimicrobial activities.Fahad Alderees et al. investigated the bioactive composition of different extracts of Clitoria ternatea L. flowers on the inhibition of pancreatic α-amylase and the starch in vitro enzymatic digestibility and predicted the glycemic index of different flours, such as potato, rice, wheat, glutinous rice, corn, and cassava flours. Moreover, the application in a bakery product, prepared from the studied flours and extracts, was also determined. The results showed that the extracts inhibited the pancreatic α-amylase activity together to a significant reduction in the glucose release, hydrolysis index (HI), and predicted glycemic index (pGI) of the considered flours.Charoonsri Chusak et al. studied the influence of the extracts from Buchanania obovata Engl., evaluating its potential as a functional ingredient in innovative food products. The seed and flesh contained several polyphenols, such as ellagic acid, p-coumaric acid, gallic acid, trans-ferulic acid, quercetin, and kaempferol, that may be responsible for the biological activities. In particular, the seed, eaten as bush food, presented a delphinidin-based anthocyanin.Selina A. Fyfe et al. investigated the health-promoting properties , functionality, and phytochemical composition of the Australian Native Green Plum, Terminalia ferdinandiana (vernacular name: Kakadu Plum), as a novel nutritional source. The food industry processes the T. ferdinandiana fruits into puree generating seeds as a by-product that is generally discarded. This study was aimed to process the Kakadu Plum seeds separating the kernel and determining its nutritional composition. T. ferdinandiana kernels presented the potential to be used as a new protein source for dietary purposes and non-conventional supply of palmitic, oleic, and linoleic acids.Saleha Akter et al. showed the chemical and nutritional composition of the kernels of a native Australian fruit, Yang Cao et al. presented a review on the phytochemical composition, biological properties, and nutrigenomic implications of yacon as a potential source of prebiotic, evaluating the current evidence and future directions. Yacon is an underutilized plant consumed as a traditional root-based fruit in South America and it mainly contains fructooligosaccharides (FOS) and inulin. Therefore, it has bifidogenic benefits for gut health because FOS are not easily broken down by digestive enzymes. Scientific studies on the bioactive molecules and nutrigenomic properties of the extracts and isolated compounds from yacon may help in further research to investigate yacon-based nutritional products.Underutilized and alternative fruits represent an excellent opportunity for local growers to gain access to special or niche markets where consumers appreciate exotic traits and the presence of nutrients able to prevent degenerative diseases. The creation of specific horticultural models for fruit production may be an important opportunity to obtain a high-standardized raw material and produce high-quality fresh or derived-products. Additionally, the phytochemicals extracted from these fruits could have an excellent application in the food industry for increasing the shelf life and stability of the commercial products. Several strategies should be applied to study: (i) the toxicological traits of bioactive extracts, (ii) the metabolism of bioactive compounds (including their bioaccessibility and bioavailability), and (iii) the sensory and nutritional traits of the food products added with biologically active molecules from underutilized fruits . The ecoStudies on the isolation and characterization of bioactive compounds using complementary analytical methods and on their influence on biological status in animal/human models are needed for the evaluation of their potential benefits. Finally, it is important to further confirm the lack of toxicity of these sources together to their natural bioavailability .


Our access to computer-generated worlds changes the way we feel, how we think, and how we solve problems. In this review, we explore the utility of different types of virtual reality, immersive or non-immersive, for providing controllable, safe environments that enable individual training, neurorehabilitation, or even replacement of lost functions. The neurobiological effects of virtual reality on neuronal plasticity have been shown to result in increased cortical gray matter volumes, higher concentration of electroencephalographic beta-waves, and enhanced cognitive performance. Clinical application of virtual reality is aided by innovative brain–computer interfaces, which allow direct tapping into the electric activity generated by different brain cortical areas for precise voluntary control of connected robotic devices. Virtual reality is also valuable to healthy individuals as a narrative medium for redesigning their individual stories in an integrative process of self-improvement and personal development. Future upgrades of virtual reality-based technologies promise to help humans transcend the limitations of their biological bodies and augment their capacity to mold physical reality to better meet the needs of a globalized world. The rapid development of digital technologies has transformed societies across the world ,2. AccesThe interaction between the human mind and virtual realities has been demonstrated to improve cognitive functions ,20,21,22In this present review, we will first portray different types of virtual reality (VR) employed in biomedical practice and will concisely describe their measurable impact upon brain structure and cognitive performance. Then, we will explore important medical applications of VR technologies that significantly improve the quality of life in patients with neurological deficits. Lastly, we will conclude with the promises VR use offers healthy individuals for self-improvement and personal development.Computer-generated worlds provide digital experiences, which are referred to as virtual realities. Depending on the intensity and quality of feelings elicited by the computer-generated world, several main types of virtual realities can be differentiated.In this type of reality, the person is not fully immersed in the virtual world . It is tIn this type of reality, the person is fully immersed and has the feeling of presence in the virtual world ,49. The A characteristic feature of augmented reality is that some components of the virtual world are superimposed on the surrounding world ,52. The This type of hybrid reality is a form of augmented reality in which the real elements and the virtual elements are able to interact with one another, thereby granting the user the ability to interact with both real and virtual objects ,54,55. FExtended reality (XR) is a general term that encompasses all immersive technologies, including present-day technologies, such as the aforementioned augmented reality (AR), VR, or mixed reality (MR), plus future technologies that are still to be created. The application of such advanced technologies in the context of health emergencies deserves further consideration as this will create opportunities for effective non-human interaction.The seat of human consciousness is located in the brain cortex, which forms the outer layer of the cerebrum ,57,58. IKnowledge of the cortical anatomy is essential for the accurate description of the localization of cognitive functions and proper understanding of the localized nature of observed changes in gray matter volumes or EEG power spectra after VR exposure. With an interdisciplinary audience of biomedical engineers, computer scientists, health professionals, and neuroscientists in mind, we briefly outline the characteristic anatomical features of the human brain cortex and summarize their relevance to cognition.Structurally, the cerebrum consists of two cerebral hemispheres, designated as left and right respectively. Each hemisphere has an outer layer of gray matter, referred to as the cortex, and an inner layer of white matter. The cortex is further divided by large grooves into four lobes: frontal lobe, temporal lobe, parietal lobe, and occipital lobe. Each lobe contains ridges, referred to as gyri, specialized in the execution of specific cognitive functions.The frontal lobe is located at the front of the head  Figure . In VR aThe temporal lobe is located on the side of the head above the ear  Figure . In VR aThe parietal lobe is located in the middle-upper part of the head above the temporal lobe  Figure . In VR aThe occipital lobe is located at the back of the head  Figure . In VR aBrain injury is a serious medical condition that disrupts the normal functioning of the brain and severely impacts a person’s life. Two major causes of brain damage are mechanical trauma, which is the most common type of brain injury seen in younger adults (<45 yo) , and vasVR provides a safe, controlled environment for performing customizable, engaging rehabilitation activities that promote learning of motor skills . FurtherThe main therapeutic effect of VR on upper limb motor activity is to increase the active range of motion (AROM) of the shoulder, elbow, and wrist ,122. SigBrain injuries that affect motor cortex areas innervating the lower limb may result in impairments in the gait, maintenance and adaptation of balance, or postural control for a range of activities of daily living . BecauseThe use of VR allows for a reproducible, objective assessment of cognitive processes underlying attention, memory, information processing, logical sequencing, and problem-solving ,129. VR Brain injury often leads to anxiety, depression, emotional lability, and mood swings. Medication with antidepressants  or mood Sensory deficits, including pain, may persist as long-term symptoms of traumatic injuries. In such cases, immersive VR could be used as a form of distraction analgesia alone or in combination with a pharmacological intervention (such as opioid administration) . MaladapSevere brain injuries, which cause irreversible damage to neural tissue, may result in permanent loss of motor or sensory function. However, because the seat of human consciousness is located in the brain cortex, it is possible to replace lost functions with the use of BCIs, provided that the damage involves only the peripheral nervous system or the peripheral effector organs. In other words, the brain cortex can be directly connected to bionic devices, which are engineered to perform the lost functions of the damaged peripheral organs.Severe paralysis may be caused by different pathogenetic mechanisms, such as spinal cord trauma , neurodeDirect electric stimulation of the brain cortex is able to elicit conscious experiences in awake subjects  . This faVR shapes modern life, including entertainment and digital health. As with every tool, the quality of its use depends on the intentions of the user. Augmented reality provides easy access to vast amounts of computer-stored data, which is an ideal way to enhance users’ creative problem-solving and decision-making ,205,206.VR presents a breakthrough in the capability of technology to recreate reality and so it embodies the philosophical concept of the virtual  into a pVR promises a plethora of experiences to people who engage in it and induces states of mind ranging from simplified to overwhelming. The scale of these states goes from pure excitement or fear ,237 to mContemporary use of VR goes far beyond entertainment. It can be beneficial for training, for research purposes, and for neurorehabilitation. BCIs may assist the replacement of lost functions, such as moving or speaking, thereby restoring severely paralyzed or locked-in patients’ ability to communicate with the surrounding world. VR may additionally support the perception of an embodiment for precise control over bionic devices that extend the capabilities of the human body.


Due to the ongoing nationwide lockdown in Nepal, women and children face a greater risk of malnutrition and eventually leading to mortality and morbidity. To harness the progress made so far in improving the nutritional status of women and children, a focus on nutrition should be a part of the COVID-19 response plan. As the threat of COVID-19 pandemic is expanding, numerous nations have confined development or actualized lockdowns to give their public health strategies more opportunity to focus on prevention and management of COVID-19 infections. The Government of Nepal has imposed nationwide lockdown from March 24 until June 14 in 2020 and might extend beyond [The impact of the COVID-19 on nutrition outcomes has not been acknowledged at this point in Nepal but studies have shown that large scale emergencies have increased morbidity and often mortality in infants and young children –5. TheseCommunities and vulnerable groups like women and children dealing with malnutrition are doubly susceptible to compromised health due to COVID-19 pandemic. That is because, malnutrition can weaken the immune system and they may be more vulnerable to acquiring COVID-19. In addition, the lockdown has resulted in a decrease in household incomes leading to less availability and reduced access to food, and restriction in receiving essential health care services. Nutrition services like vitamin A and deworming campaign, supplementation of micronutrient powders, treatment of malnourished children through the outpatient therapeutic center, and nutrition rehabilitation homes have also been affected as a result of the priority shift of health sector towards COVID-19. Alternatively, the pandemic could force people to take on behaviors like consumption of unhealthy food, inadequate intake of nutritious food, and poor hygiene and sanitation practice. Insufficient breastfeeding practices, due to fear and anxiety of transmission of COVID 19 from breastfeeding mothers, result in decreased feeding and caring practices for children. The predictable outcomes of such situations might decrease the immune function, increase the susceptibility to severe diseases, and lead to a high incidence of wasting and stunting among children.Food insecurity and hunger is one of the top issues of malnutrition in Nepal. COVID-19 could further induce malnutrition due to people losing their jobs mainly informal sector and those in foreign employment. Similarly, it might also affect the agricultural production due to shortage of seeds, fertilizers and manpower, further plunging the population into poverty and malnutrition. According to Global Hunger Index 2019, Nepal experiences a serious threat of hunger, with a score of 20.8 standing at rank of 73 among 117 countries , there iThe possible ways to ensure better nutrition among women and children in resource-constrained settings like Nepal could be a combination of different measures. This includes developing and implementing mitigation strategies to reach out to those most affected by the crisis and activation and functionality of nutrition clusters at the sub-national level to ensure predictable, timely, and effective nutrition response. Similarly, program and service to protect, promote and support optimal breastfeeding and age appropriate and safe complementary feeding and feeding practices should remain a critical component of the response for women and children in the context of COVID-19. Continuity of safe motherhood services along with maternal and child nutrition interventions are required including vitamin A and deworming tablets supplementation, screening and treatment of children with acute malnutrition, distributing fortified flour to pregnant women and children above 6 months, supplying micronutrient powder, and ensuring proper counseling on infant and young child feeding practices. Similarly, mass awareness campaigns on the importance of breastfeeding, complementary feeding, and feeding during pregnancy and breastfeeding children should be done through various sources of media including mobile text messages. Counseling and psychological support to mothers and caregivers of under 5-year children is also required to promote nutrition, health, and wellbeing. Continuation of services through outpatient therapeutic centers to treat malnourished children by applying the simplified treatment approach like reducing the number of visits and by increasing the ratio of ready to use therapeutic food to be taken to the home is required to minimize the risk of contamination. Equally important is ensuring nutrition commodities are available and accessible, market supply should not be disrupted and promotion of the locally available nutritious foods should be done. In food-insecure areas where communities have limited access to adequate food, strategies such as the distribution of specialized nutritious food (e.g. supply of fortified flour) can be done.Being an issue of serious concern, it would be appropriate for Nepal and other similar resource constrained settings to focus its efforts on addressing the nutrition of women and children for building healthier societies. Focusing only on COVID-19 might bring forward other health consequences which could strain the capacity of the health system and country’s socio-economic potential. Nutrition should thus be a core component of the COVID-19 response plan, integrated into each aspect of prevention, treatment, and recovery.


Cachexia, a severe multifactorial condition that is underestimated and unrecognized in patients, is characterized by continuous muscle mass loss that leads to progressive functional impairment, while nutritional support cannot completely reverse this clinical condition. There is a strong need for more effective and targeted therapies for cachexia patients. There is a need for drugs that act on cachexia as a distinct and treatable condition to prevent or reverse excess catabolism and inflammation. Due to ghrelin properties, it has been studied in the cachexia and other treatments in a growing number of works. However, in the body, exogenous ghrelin is subject to very rapid degradation. In this context, the intranasal release of ghrelin-loaded liposomes to cross the blood-brain barrier and the release of the drug into the central nervous system may be a promising alternative to improve its bioavailability. The administration of nose-to-brain liposomes for the management of cachexia was addressed only in a limited number of published works. This review focuses on the discussion of the pathophysiology of cachexia, synthesis and physiological effects of ghrelin and the potential treatment of the diseased using ghrelin-loaded liposomes through the nose-to-brain route. Cachexia is a multifactorial syndrome characterized by the continuous loss of skeletal muscle mass (with or without loss of fat mass) that cannot be entirely reversed by conventional nutritional support, leading to progressive functional impairment ,2. CacheThe nasal route has been, successfully, exploited for the continuous release of drugs, including macromolecules, to the central nervous system (CNS) . The olfkakos (bad) and hexis (condition). In Greece, in the fourth century BC, Hippocrates accurately described the central pathogenesis of cachexia, saying: “meat is consumed and becomes water”, considering cachexia as a sign of death [Etymologically, cachexia is derived from the Greek of death ,18. Cachof death ,19. Weigof death . Cachectof death .The disease is characterized by the continuous loss of skeletal muscle mass, fat and bone . HoweverCachexia is a significant and growing public health problem . It is aCachexia is described in association with many chronic conditions , such asData from 2014 in industrialized countries, such as countries in North America, Europe and Japan, showed that the general prevalence of cachexia is growing and has reached about nine million patients . Data arCachexia can be qualified as a global public health problem. For a person to be classified as such, comorbidity must: (i) have a high burden in terms of morbidity, mortality, quality of life and costs; (ii) be unfairly distributed, affecting disadvantaged population groups to a greater extent; (iii) there is some evidence that public health strategies can substantially reduce the burden of the disease and, finally, that these preventive strategies are not yet fully installed . BesidesAdequate nutritional support remains one of the pillars of the treatment of cachexia ; howeverThe additional weight loss is due to processes related to metabolic changes, mediated by the excessive release of proinflammatory cytokines and the increased activity of the sympathetic nervous system. Both catecholamines and proinflammatory cytokines promote catabolic processes .Proinflammatory cytokines decrease the effectiveness of growth hormones (GH) and act on the central nervous system as mediators of inflammation and as catabolic factors that stimulate proteolytic pathways, leading to muscle atrophy and the increased breakdown of adipose tissue .Proinflammatory cytokines, including interleukin-6 (IL-6), IL-10 and IL-1β and tumor necrosis factor-alpha , stimulate the breakdown of muscle proteins, cause contractile dysfunction and inhibit myogenesis, in addition to promoting the waste of adipose tissue, the inhibition of adipocyte differentiation, stimulation of lipolysis and increased apoptosis in adipocytes .The negative energy balance related to cachexia is associated with the inflammatory signaling in the hypothalamic melanocortin system; the regulation of the central inflammatory signaling of the metabolism is related to melanocortin signaling. Neurons that express pro-opiomelanocortin peptide (POMC), orexigenic peptide associated with agouti (AgRP) and neuropeptide Y (NPY) in the presence of proinflammatory cytokines generate a decrease in the release of AgRP/NPY and increase the release of POMC .POMC is cleaved to produce melanocyte-stimulating hormone . Alpha-MSH, released at synapses, is linked to melanocortin 4 (MC4R) receptors, leading to an increase in the basal metabolic rate, a reduction in lean body mass and a decrease in food-seeking behavior. AgRP/NYP, a natural MC4R agonist, when decreased, increases the effects of POMC, leading to reduced appetite, resulting in appetite restriction generated by the decreased expression of AgRP/NYP , associated with an increase in the effects of POMC .The TNF-alpha content also decreases carbohydrate reserves, inhibiting insulin receptor activity and a decrease in the expression of the glut-4 transporter, which should play a key role in impaired glycemic homeostasis .The increased activity of the sympathetic nervous system resulting from increased plasma concentrations of neurotransmitters also results in a loss of body mass and increased energy expenditure, stimulation of lipolysis, decrease in lipogenic enzymes and stimulation of apoptosis in skeletal muscles . CatechoWhen starting an inflammatory process, the body adopts an increase in the systemic activity of the sympathetic nervous system. One of the goals of inflammation is to stimulate dendritic cells, which participate in the immune response . Immune As cachexia is associated with complex pathophysiological processes, pharmacological treatments, such as calcium supplementation or appetite stimulants, such as medroxyprogesterone acetate; megestrol acetate; cyproheptadine and corticosteroids, such as prednisolone, methylprednisolone and dexamethasone, are used in the current treatment and present only limited success . The phaThere is an increase in observations and discussions by scientists about cachexia being seen as a common final metabolic pathway, regardless of the underlying disease being a distinct and treatable condition . ResearcThe administration of ghrelin in patients with cachexia results in the decreased release of proinflammatory cytokines and reduces sympathetic nerve activity . The useGhrelin is a 28-amino acid hormone  producedAcylation may not be necessary for all actions of ghrelin . Some evIn the acylation of ghrelin, GOAT uses dietary triglycerides, including C6-C10 fatty acids, with a strong preference for C8 . The ghrGOAT seems to act also to detect and communicate to the brain about the availability of peripheral nutrients and, also, for energy storage . GOAT isThe discovery of ghrelin represents an important turning point in the study of stomach-brain interactions and has made enormous contributions to our understanding of systemic homeostasis .One of the mechanisms of action proposed for ghrelin assumes that this hormone regulates the metabolism through the activation of orexigenic neural circuits, such as the central melanocortin system . In addiAdditionally, to decrease in the expression of POMC expression, inflammatory IL-1 beta signaling in the melanocortin system is strongly associated with the negative energy balance related to cachexia. Ghrelin has decreased POMC expression and inhibits proinflammatory cytokines, such as IL-1alpha, IL-1beta and TNF-alpha ,42.Most animals, including humans, have standardized eating patterns in which meals are eaten based on learned and/or environmental factors. The signaling of ghrelin with ventral hippocampal neurons (vHP) is physiologically relevant for conditioned feeding behaviors. The activation of neurons by ghrelin-vHP still communicates directly with neurons in the lateral hypothalamus (LHA) expressing neuropeptide orexin . TogetheThe synthesis of ghrelin and routes involve ghrelin signals in the hypothalamus. In X/A-like cells located in the stomach, it is where the pro-ghrelin is acylated. Two routes were proposed to transmit the signals of ghrelin derived from the stomach to the hypothalamus: the afferent vagal nerve and the blood circulation. The vagus nerve is the tenth cranial nerve, contains both efferent and afferent fibers and transmits information from the viscera to the brain. Ghrelin binds to GHS-R1a and suppresses the electrical activity of the vagal afferent nerve. This electrical signal reaches the NTS, (nucleus tractus solitarius) which synapses with NPY (neuropeptide Y) neurons in the ARC. . The circulating ghrelin is transported through the BBB and binds to neurons in the vicinity of capillaries .GHS-R1a in the hypothalamus is predominantly expressed in ARC. ARC contains orexigenic neurons expressing NPY and AgRP and anorexigenic neurons expressing POMC. Both NPY/AgRP neurons and POMC neurons project to vHP. The high activity of POMC neurons increases the release of alpha-MSH in vHP, which, in turn, acts on neurons expressing MC4R to suppress the food intake. NPY acts by stimulating the food intake, while AgRP antagonizes MC4R. The action of ghrelin on vHP stimulates feeding also with the activation of the neurons LHA  and orexin release. Ghrelin induces the food intake by activating the NPY/AgRP neurons. Ghrelin stimulates the release of GH by activating the somatotrophs in the anterior pituitary .Ghrelin also suppresses systemic inflammation through its sympatho-inhibitory functions. Central ghrelin receptors that involve an NPY receptor-dependent pathway mediate ghrelin inhibitory properties on norepinephrine release. The modulation of overstimulated sympathetic nerve activation may result in the inhibitory effect of ghrelin on TNF-alpha production . In sympGHS-R1a is also expressed in the vagus nerve ; the vagThus, the action of ghrelin depends on the accessibility of the hormone to its cerebral targets  but, alsIn inflammation, GHS-R1a is expressed on lymphocytes, and ghrelin has been shown to decrease the expression of inflammatory cytokines in monocytes and T cells  and suggIn the cardiovascular system, GHS-R1a is expressed in the heart and aorta. It is also reported that the GHS-R1a gene can be detected in the cardiomyocyte cell line in culture and human vascular endothelial cells . GhrelinGhrelin exhibits gastroprokinetic activity , becauseThe administration of ghrelin in rats has been reported to prevent muscle atrophy by increasing the phosphorylation of protein kinase B ; decrease the myostatin pathway ; activate myogenin (a transcription factor involved in myogenesis and repair) and activate myoD  .In adipose tissue, ghrelin stimulates the expression of genes encoding fat storage-promoting enzymes such as lipoprotein lipase (LPL), fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACCα) and stearoyl-CoA desaturase-1 (SCD1), which can provide important reserves of energy for the organism. In brown adipocytes, ghrelin decreases the expression of thermogenic-related proteins, thereby decreasing the metabolic process during which the body burns calories to produce heat .Due to the benefits, the ghrelin pharmacological approach is considered a promising and valuable approach for the treatment of a variety of metabolic complications, including cachexia ,63.Treatment with ghrelin has drawbacks, which include a short half-life and the need for infusion or in bolus parenteral administration, with multiple side effect events like somnolence, a warm feeling, facial warmth, abdominal pain emesis and vertigo ,11.The limitations of treatments with exogenous ghrelin have led to the investigation of alternatives such as anamorelin, a ghrelin agonist that is potent and highly specific ,65,66, aAs stated above, the action of ghrelin depends on the accessibility of the hormone to its cerebral targets. However, the actions of ghrelin pertinent to cachexia are not limited to these central effects ,52. ThusThe brain is isolated and protected by various mechanisms from the external environment. The physiological barrier has properties such as the control of influx and efflux transporters, expression of narrow junctions or by the metabolizing enzyme present in endothelial cells ,69,70. TNose-to-brain may be advantageously used for the chronic brain administration of large and sensitive compounds, such as biotherapeutics . The nosIntranasal administration is an alternative to oral and intravenous routes and is useful in systemic drug administration and a potential alternative for invasive methods to overcome the BBB/blood-cerebrospinal fluid barrier and deliver drugs to the central nervous system .Current formulations for ghrelin are being planned for parenteral administration . HoweverDrugs delivered intranasally are transported along olfactory sensory neurons to produce significant concentrations in the CSF and olfactory bulb. The olfactory region of the nasal mucosa that provides a connection between the nose and the brain is used to target drug molecules that act on the central nervous system .Then, the mechanisms of nose-to-brain drug transport were described: (i) the systemic route is characterized by absorption of the drug through the nasal mucosa, systemic distribution and passage through the BBB, similar to the intravenous route; (ii) the olfactory pathway in which the drug may permeate the olfactory epithelium to the olfactory bulb from which it has access to the central nervous system; (iii) the trigeminal pathway, the pathway of most significant interest in our study, in which the drug avoids the BBB, is carried by the trigeminal nerve pathway .The systemic pathway is primarily responsible for the transcellular release of low molecular weight lipophilic substances, which can be absorbed more readily into the bloodstream, exhibiting a profile similar to that of an intravenous injection . The sysThe olfactory pathway can be subdivided into two pathways: neural and epithelial ,79,80. IThe trigeminal nerve is the major cranial nerve; although the trigeminal nerve endings are not directly exposed in the nasal cavity, it is assumed that the initial entry point is probably the ophthalmic and maxillary branches of the trigeminal nerve, which innervate the dorsal nasal mucosa together with the anterior part of the nasal cavity and the lateral walls of the nasal mucosa ,84. NumeNose-to-brain delivery suffers from limitations, such as mucociliary clearance, enzymatic metabolism and permeation limited by particle size. Therefore, liposomes may be able to protect ghrelin from nasal enzymes, and liposome functionalization may increase the permanence time in the nasal cavity, improving permeation and, consequently, increasing the bioavailability of ghrelin, which may be promising in the treatment of cachexia .Nasal drugs circumvent the gastrointestinal and hepatic first-pass effect. However, they may be significantly metabolized in the lumen of the nasal cavity or during passage through the nasal epithelial barrier, due to the presence of a wide range of metabolic enzymes in the nasal tissues. Even though the first-pass nasal metabolism is weaker than the hepatic and intestinal metabolisms, it has a significant importance in drug bioavailability.The mucociliary clearance system plays an essential role in the defense of the respiratory tract. Mucus collects foreign particles and lashes and provides the driving force by preventing airborne xenobiotics from being inhaled. Xenobiotics adhere to mucus and are transported to the nasopharynx. This mucociliary clearance significantly influences nasal drug absorption .To overcome these difficulties, from nasal metabolism and mucociliary clearance, strategies such as liposome loading can be followed. The use of functionalized liposomes may promote prolonged contact between the drug and the site of absorption, facilitate direct absorption through the nasal mucosa and protect against enzymatic metabolism.Liposomes are self-organizing vesicles of nanometer range consisting of concentric lipid bilayers with an internal aqueous phase ,87. ManyThe main composition of the liposomes is the phospholipids, which are amphiphilic molecules formed by a hydrophilic head and hydrophobic chains. By these characteristics, when the phospholipids are dispersed in aqueous solutions, they tend to form membranes . Their pAs drug carriers, liposomes are widely used because of their ability to encapsulate hydrophilic, amphiphilic and lipophilic molecules . In addiThe protective phospholipid layer that is usually resistant to pH, body free radicals and enzymatic actions protects ghrelin from degradation until release occurs . LiposomLiposomes have gained attention as promising strategies for the treatment of neurological diseases . The devCationic nanostructures are more efficient vehicles for the release of drugs into the central nervous system than the neutral or anionic ones . The eleThe addition of polyethylene glycol (PEG) protects the liposome from plasma protein binding, thus forming a protective layer on the surface and avoiding the opsonization process and subsequent elimination of liposomes . Then, PCachexia is associated with many chronic conditions, infectious diseases and seen in patients after extensive traumatic injuries or sepsis. Cachexia results in a compromised quality of life, increased mortality and greater susceptibility to treatment-related toxicities. With an increasing number of individuals in cachectic conditions associated with the absence of an effective drug intervention, the awareness of cachexia and advances in the development of treatments are urgently needed. We understand that highlighting the practical approaches of the multimodal management of cachexia and its comorbidities is one of the most essentials actions. However, new alternatives for the targeted administration of drugs, therapeutically effective and with biological safety, can reverse the findings of cachectic syndrome completely. The studies considered in this review report is that ghrelin is a promising therapeutic option and may play a role in improving the symptomatic burden of cachexia. Further studies are, however, still needed to overcome the limitations of the administration of exogenous ghrelin and to determine its usefulness in improving the patient’s experience with cachectic syndrome. The use of drug-loaded liposomes to target the central nervous system is still restricted to initial experimental work in cell and animal models or follows preclinical development, with a few now entering clinical trials in humans and requiring further studies. There is still insufficient evidence to support or refute the use of ghrelin in people with cachexia. Further studies are needed to select the appropriate administration route, with a focus on assessing the safety and efficacy. An intelligent drug management system to improve the bioavailability of exogenous ghrelin in people with cachexia can be a suitable alternative to overcome the limitations encountered in the current parenteral administration. Due to biphasic properties, liposomes are the nanostructures most studied for delivering macromolecules like peptides or proteins. Then, liposomes like drug delivery systems have been the proposal to protect ghrelin from physiological instability, increase the retention time and improve its permeation. The naso-cerebral pathway presents itself as a good alternative for ghrelin administration, using a direct connection between the nose and the brain, which can enable its action on the central nervous system. The development of a ghrelin-based cachexia treatment may offer the opportunity to meet the needs of cachectic patients. The naso-cerebral pathway can be one pathway for adherence. However, preclinical developments and clinical trials in humans are needed to establish criteria for the use of liposome-loaded ghrelin and naso-cerebral administration in the treatment of cachexia.


Early hospital readmission (EHR), defined as all readmissions within 30 days of initial hospital discharge, is a health care quality measure. It is influenced by the demographic characteristics of the population at risk, the multidisciplinary approach for hospital discharge, the access, coverage, and comprehensiveness of the health care system, and reimbursement policies. EHR is associated with higher morbidity, mortality, and increased health care costs. Monitoring EHR enables the identification of hospital and outpatient healthcare weaknesses and the implementation of corrective interventions. Among kidney transplant recipients in the USA, EHR ranges between 18 and 47%, and is associated with one-year increased mortality and graft loss. One study in Brazil showed an incidence of 19.8% of EHR. The main causes of readmission were infections and surgical and metabolic complications. Strategies to reduce early hospital readmission are therefore essential and should consider the local factors, including socio-economic conditions, epidemiology and endemic diseases, and mobility. The term EHR first appeared in the medical literature in 1953 examining the causes of readmission of psychiatric patients to the York Clinic, Guy's Hospital in London,In 1988, the Health Care Financing Administration, a body created in 1977 to administer and supervise Medicare in the United States, required an audit of all readmissions within 30 days of discharge to determine whether the discharge was premature or whether other quality issues could be identified. This audit process was extended to hospitals serving Medicare beneficiaries and poor people, considering the lack of association between social-demographic factors and hospital readmission,In 2009, the Center for Medicare and Medicaid Services (CMS) begin to evaluate hospital readmission rates in public institutions as part of the Annual Update Program of Data and Quality of the CMS Reporting Hospital.Agencia Nacional de Saude Suplementar (ANS),,In Brazil, there is no government policy linked to the Ministry of Health to verify hospital readmission in public hospitals. In the private healthcare sector, the a new hospitalization in the same hospital within a certain period of time after initial hospital discharge”The Ministry of Health (MS) defines hospital readmission as “,EHR is a well-accepted measure of hospital care quality. A critical analysis to search for preventable causes at the time of readmission is recommended. Therefore, complications of the first hospitalization, adequacy of diagnoses and medical treatment, missing medication, proper patient education to support adherence, premature discharge, and inadequate outpatient follow-up have to be assessedThe advantage of using EHR as a hospital care quality measure is the continuous monitoring of EHR rates and causes. These rates are valuable healthcare indicators used to identify and develop corrective measures for further improvements. Patients with complex and severe diseases are at higher risk for EHR, requiring a well-coordinated in- and outpatient monitoring,EHR has been associated with an increased risk of mortality. Adverse events, infections, and medication errors are the predominant risk factors,The risk of EHR is two times higher for patients with chronic kidney disease on hemodialysis compared to the general population,The first studies addressing EHR of kidney transplant recipients were published in 2008 in the United States when the CMS began evaluating hospital readmission rates at public institutions as part of the Annual Data and Quality Update Program of the CMS Report Hospital.---,,Using data from a cohort of 32,961 kidney transplant recipients treated by the Medicare system from 2000 to 2005 extracted from the US registry, EHR was 31%, ranging from 18 to 47% across transplant centersEHR should not be seen only as an indicator of healthcare quality but also as a surrogate for mortality and graft loss during the first year post-transplantIn Brazil, according to data from the Brazilian Registry of Transplants, about 5000 kidney transplants are performed every yearIn a recent single-center Brazilian study, the incidence of EHR was 26.6% among 1175 recipients of kidney transplant between January 2011 and December 2012. The independent risk factors associated with EHR were recipient age, CMV pretransplant negative serology, induction with rabbit antithymocyte globulin, acute rejection treated during index hospitalization, and length of stay. The median time of the index hospital admission was 9 days, during which the incidence of delayed graft function was 40.2%. The high incidence of delayed graft function and the inability to discharge patients until they become dialysis-free affect EHR. Prolonged initial hospitalization provides time to diagnose and treat various complications associated with EHR. On the other hand, it increases the risk of infections, medication errors, and accidents.,,,The main reasons for EHR were infections, surgical complications, and metabolic disturbances. Among infectious complications, CMV infection was the main causeStrategies and protocols have been developed to reduce EHR in the general population. Parker and colleaguesAmong kidney transplant recipients, EHR is a surrogate marker for morbidity and mortality, regardless of the demographic characteristics of the population. This marker includes not only comorbidities but also socioeconomic status, access to care, fragility level, and limited health literacy. Patients identified as vulnerable based on EHR could benefit from additional or individualized monitoring strategies, including frequent outpatient visits, phone calls, laboratory tests, monitoring of adherence, and family educationIn the general population, EHR is a well-established measure of healthcare quality and is a robust predictor of morbidity and mortality. In the kidney transplant population, EHR is associated with mortality and graft loss as well. Measures to reduce EHR should consider multi-professional interventions considering the local demography, discharge protocols, comprehensiveness, and reimbursements of health care for the local clinical and epidemiological situation. Effective interventions will certainly reduce morbidity, mortality, and costs, increasing the quality of life of kidney transplant recipients.


Microglia play an essential role in maintaining central nervous system (CNS) homeostasis, as well as responding to injury and disease. Most neurological disorders feature microglial activation, a process whereby microglia undergo profound morphological and transcriptional changes aimed at containing CNS damage and promoting repair, but often resulting in overt inflammation that sustains and propagates the neurodegenerative process. This is especially evident in multiple sclerosis (MS), were microglial activation and microglia-driven neuroinflammation are considered key events in the onset, progression, and resolution of the disease. Our understanding of microglial functions in MS has widened exponentially in the last decade by way of new tools and markers to discriminate microglia from other myeloid populations. Consequently, the complex functional and phenotypical diversity of microglia can now be appreciated. This, in combination with a variety of animal models that mimic specific features and processes of MS, has contributed to filling the gap of knowledge in the cascade of events underlying MS pathophysiology. The purpose of this review is to present the most up to date knowledge of the dynamic responses of microglia in the commonly used animal models of MS, specifically the immune-mediated experimental autoimmune encephalomyelitis (EAE) model, and the chemically-induced cuprizone and lysolecithin models. Elucidating the spectrum of microglial functions in these models, from detrimental to protective, is essential to identify emerging targets for therapy and guide drug discovery efforts. Microglia play an essential role in maintaining homeostasis in the central nervous system (CNS), as well as responding to injury and disease  model, and the chemically-induced cuprizone and lysolecithin models. Elucidating the spectrum of microglial functions in these models, from detrimental to protective, is essential to identify emerging targets for therapy and guide drug discovery efforts.Known as the resident immune cells of the CNS, microglia are a highly specialized population of mononuclear phagocytes whose origin has been traced to yolk sac progenitors colonizing the neuroepithelium during developmental hematopoiesis  containing more microglia than the gray matter , increased cell proliferation, and functional modifications that include the production of soluble mediators. These processes can result in both detrimental and protective effects depending on timing and location and together influence the neurological outcome. Moving away from the classification that labeled damaging microglia as M1 and reparative microglia as M2, single-cell transcriptomic studies have unequivocally established that, Multiple sclerosis is a chronic inflammatory disease of the CNS, whose onset and progression have been attributed to the interplay of aberrant immune system activation (both innate and adaptive), genetic susceptibility, and environmental factors  signatures  lesions, where microglial activation has been associated with cortical demyelination and neurodegeneration , which play a role in the recruitment of T cells and monocytes into the CNS, are also produced by microglia  that dynamically change as the disease evolves  in MS. Indeed, ROS producing enzymes such as myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits have been found upregulated in microglia within and in the proximity of MS lesions, both in WM and GM , myelin basic protein (MBP), and proteolipid protein (PLP). Peptides are injected emulsified in Complete Freund’s Adjuvant (CFA) to boost immune activation and are usually accompanied by administration of pertussis toxin, which is thought to favor BBB breakdown and facilitate immune cell extravasation into the CNS parenchyma. Being T cell-mediated, EAE is especially suited to mimic the pathological hallmarks of the acute and relapsing-remitting phases of MS and has paved the way for the development of first-line disease-modifying therapeutics currently in clinical use. Similar to MS, EAE features profound immune-inflammatory activation sustained by the synergistic action of immune cells trafficking into the CNS and resident glia, especially microglia  analysis, at least four disease-associated microglia subsets were identified following EAE, three of which showed high upregulation of inflammatory and proliferative genes  and were localized to demyelinating lesions  chemokines , complement factors  and nitric oxide  is essential for microglial survival and proliferation. Microglia depletion induced pharmacologically by inhibition of CSF1R in a mouse model of EAE reduced neuroinflammation and increased myelin preservation, suggesting that the presence of microglia contributes to an environment that prevents remyelination and CNS recovery -M is selectively expressed by microglia in the CNS and has been associated with shifting microglia towards an anti-inflammatory phenotype by inhibiting TLR4 signaling  signaling pathway. Microglia-targeted ablation of TNFR2, which is activated by the transmembrane form of TNF, resulted in the early onset of EAE with exacerbated demyelination  delayed microglial recruitment and reduced gene expression of TNF limiting demyelination , which is elevated during demyelination  shifted microglia to an anti-inflammatory phenotype and prevented demyelination, while a deficiency in the OSM receptor (expressed on microglia and astrocytes) exacerbated demyelination in the cuprizone model , is a demyelinating and inflammatory phospholipid that acts as a membrane-dissolving detergent. When delivered by injection into white matter tracts, LPC induces highly reproducible focal demyelinating lesions. Injections are typically targeted to the thoracic and lumbar regions of the spinal cord or the corpus callosum  and remyelinating phase (10 days post-injury), showed that in the demyelinating phase microglia have a predominantly proinflammatory transcriptome, typically associated with damaging functions, while in the remyelination phase microglia display a reparative/pro-regenerative profile. Interestingly, the necroptotic death of proinflammatory microglia is necessary for the replenishment of the cell pool with regenerative microglia which drives the remyelination process  and upregulate genes associated with oligodendrocyte differentiation and myelin formation  and their anatomical location in the brain and spinal cord . While detrimental functions are highly associated with MS onset and acute disease, protective functions have been attributed to microglia in facilitating the repair process. Thus, to be successful in uncovering the underlying pathological mechanisms of MS and, consequently, identifying novel drug targets, it is paramount that animal models to study MS accurately reflect the complexity and diversity of microglia responses. What emerges from the numerous studies in the EAE, cuprizone, and LPC models is that microglia indeed display signatures and responses highly representative of the various stages of lesion formation and resolution in the human disease. Generally speaking, in all models detrimental microglial activation is maximal at the acute phase of the disease , whereas microglia-dependent reparative functions best correlate with sub-acute and chronic EAE, or the remyelination phase in cuprizone and LPC models. While T cell involvement is significant in the EAE model, and present to some extent in the LPC model, with cuprizone administration T cells are of minimal to no consequence. This makes the cuprizone model the “cleanest” to appreciate microglial-dependent innate immune mechanisms and to explore avenues to directly affect oligodendrocyte survival and differentiation and promote remyelination. In summary, this overview of the breadth of microglial responses provides validation of the usefulness of the models commonly utilized to recapitulate the different aspects of MS immunopathology, thus a degree of confidence that findings with these tools may be translated to MS therapy.MP and HD equally contributed to drafting the manuscript and the figures. RB identified the topic, drafted the manuscript and the figures. 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.


The basic theoretical assumptions of Exercise Physiology and its research directions, strongly influenced by reductionism, may hamper the full potential of basic science investigations, and various practical applications to sports performance and exercise as medicine. The aim of this perspective and programmatic article is to: (i) revise the current paradigm of Exercise Physiology and related research on the basis of principles and empirical findings in the new emerging field of Network Physiology and Complex Systems Science; (ii) initiate a new area in Exercise and Sport Science, Network Physiology of Exercise (NPE), with focus on basic laws of interactions and principles of coordination and integration among diverse physiological systems across spatio-temporal scales (from the sub-cellular level to the entire organism), to understand how physiological states and functions emerge, and to improve the efficacy of exercise in health and sport performance; and (iii) to create a forum for developing new research methodologies applicable to the new NPE field, to infer and quantify nonlinear dynamic forms of coupling among diverse systems and establish basic principles of coordination and network organization of physiological systems. Here, we present a programmatic approach for future research directions and potential practical applications. By focusing on research efforts to improve the knowledge about nested dynamics of vertical network interactions, and particularly, the horizontal integration of key organ systems during exercise, NPE may enrich Basic Physiology and diverse fields like Exercise and Sports Physiology, Sports Medicine, Sports Rehabilitation, Sport Science or Training Science and improve the understanding of diverse exercise-related phenomena such as sports performance, fatigue, overtraining, or sport injuries. The human organism comprises various multicomponent physiological systems that interact through various feedback mechanisms across a range of nonlinear feedback mechanisms, operating across spatio-temporal scales to generate complex transient dynamics that continuously adapt to intrinsic and external perturbations. The traditional reductionist approach, employed to investigate physiological systems and their regulatory mechanisms based on classical cybernetics, is insufficient to provide a comprehensive understanding of the structure and dynamics of individual systems and how systems and subsystems coordinate their dynamics across various levels of interaction to generate integrated functions at the organism level. Synchronization and integration among physiological systems is essential to generate distinct physiological states  and, therefore, unraveling the underlying principles of physiological systems integration as a network is crucial to understand how various physiological functions emerge as a result of interaction among such systems. Recent research has shown that physiologic states emerge as a result of a very particular network organization, network topology, and network dynamics of interaction among systems and subsystems . This dyThere is an epistemological gap in the scientific research of physiological systems in the field of Sports and Exercise. The prevalent approach is the mechanistic one , which aAlthough integrative physiology recognizes the importance of interconnectivity across physiological systems , its resA new field, Network Physiology, has recently emerged to fill in this gap , 2017 anDisrupting organ communications and their dynamic coordination as a network can lead to dysfunction in individual systems or the collapse of the entire organism during exercise  in the cardiovascular system , the resIn recent years, the Network Physiology framework has been utilized in various fields of basic Physiology and Clinical Medicine, including multiple organ failure and sepsis in critically ill patients , neonataThe aim of this article is to provide a vision and a new programmatic framework for basic research and practical applications of Network Physiology to Exercise and Sports Science. We propose a new theoretical framework for investigations in Exercise Physiology based on principles and approaches based on Network Physiology and Complex Systems Science. We discuss early works and provide a vision for future research directions in a new emerging field, Network Physiology of Exercise (NPE), utilizing examples of exercise prescription for health and disease, where we focus on exercise recommendations for healthy population and clinical patients , and we point toward the practical perspectives and future developments in NPE.The network science-based vision of NPE is in contrast with that of current Exercise Physiology, strongly influenced by reductionism. In this section, we contrast the theoretical assumptions of both approaches focusing on some main misconceptions that affect the understanding of diverse exercise-related phenomena: the adaptive properties of the human organism, the understanding of the physiological states of health and fitness, the objective and principles of exercise training, the assessment of the physiological status, and the role of exercise professionals and users/patients. Exercise Physiology, the most influential discipline in exercise and sports training, has remained resistant to the introduction of the science of complex systems in biology . ReductiInstead of the usually assumed causal bottom-up effects from micro‐ to macro-structures and processes, the NPE approach, applying the principle of circular causality, assumes a bottom-up/top-down relationship between micro and macro-components . For insThe understanding of human organisms as complex adaptive systems (CAS), instead of complicated systems , has several theoretical and practical implications on exercise prescription. Contrary to what is usually assumed in Exercise Physiology, in CAS, the behavior emerges from the interaction among components and cannot be explained (or reduced) to any single component. Studying elements of complex systems in isolation is by definition incomplete, as interactions generate novel information that determines the future of elements and thus of the system itself . This doThis means that their interactions change in time, and not only quantitatively but also qualitatively. For this reason, there are neither clearly separable cause-effect or dose-response relations among components nor time-invariant mechanisms and regulation profiles. In Exercise Physiology, the integrative functions are studied within the framework of the traditional control theory, and concepts such as homeostasis, feedback loops and central programmers are usually evoked to describe system regulation during exercise . The behIn NPE, as exercising individuals interact nonlinearly with their environment, the exercising unit is the performer-environment system . This meAs nonlinear and history-dependent systems, physiological networks present hysteresis, a phenomenon that explains the delay in a system’s recovery of its initial state after a perturbation . The stuQualitative changes occurring in CAS are the product of a widely ignored property in Exercise Physiology: self-organization. Physiological components and processes acting at multiple levels (from molecules to systems) are spontaneously coupled and there is no need for a template or internal  programmer to rule the relations. That is, our physiological systems, organs, tissues, and cells change spontaneously through their morphology and function, constrained by evolved genes and their expression, chemical species, natural and social environment, etc. . Then, eThe term “training”, understood as the process of learning/acquiring specific skills has been recently proposed to be replaced by the term of “synergizing”: combining or working together to be more effective . SynergiPhysical fitness is defined as the ability to carry out daily tasks with vigor and alertness, which is better achieved by developing fitness attributes and producing a substantial increase in caloric requirements over resting energy expenditure . In ExerFor instance, a gymnast has more chances to become dynamically stable  by specializing and diversifying the elements of their floor routine. This subsumes diverse functional synergies  coping with diverse and challenging environments (mainly represented by the opponents). In sports, this process of complexification is defined by the athlete’s functional diversity/unpredictability potential , being uThe WHO defines health as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity . This adOn the basis of current research evidence and simplified assumptions of Exercise Physiology, universal training programs are prescribed for healthy and clinical populations . These oThe application of the training principles of individualization, specificity, adaptivity, and periodization are a good example of excessively simplified assumptions of Exercise Physiology: (a) The exercise personalization is based on the objective evaluation of a patient’s baseline physiological status ; (b) theThe principle of training periodization is particularly controversial in pre-established training programs . The assMethodological criteria derived from NPE principles  and defined at multiple levels  can be uAs long as the training objective is focused on the diversification of complex physiological networks, and not on attaining pre-established fitness outcomes, the training process requires a redefinition of the role of the agents involved in it. Under the NPE perspective, exercise professionals and users/patients/athletes constitute a learning system, in which the exercise professional is not only the manager of the training environment but also a learning component . Since aCardiopulmonary exercise testing is the common assessment of choice for the accurate quantification not only of cardiorespiratory fitness but also for an integrative evaluation of the physiological response to exercise. Additional functional insights are also recommended through assessments of muscular strength, muscular endurance, and balance .2max, ventilatory thresholds, etc.) are unable to capture the changes in the network dynamics produced by exercise and training. New methodologies based on continuous and synchronous recordings of multiple physiological parameters are needed to assess the qualitative network reorganization and compensatory synergies accompanying the exercise perturbations.The extracted quantitative variables from cardiopulmonary exercise testing  or toward rigid order (in which case correlations tend to increase). From this point of view, complexity is conceived as an optimal compromise between order and disorder. This dynamic is characterized by long-range correlated series  include: (i) cross-correlations of instantaneous phase increments – cerebral autoregulation and stroke , and migTogether with the aforementioned data science methodologies, other methods such as bivariate methods may be useful for analysis of stochastic processes with two macroscopically defined variables. More methods such as multivariate transfer entropy may be applied to interacting components at microscopic level and used for inferring more complex directed network structures e.g., . For sysFurther research is required to develop new tests based on interorganic  and multilevel  interactions, to complement the current assessment protocols used to evaluate fitness and the effectiveness of different exercise interventions. A better understanding of the physiological responses to exercise may assist exercise professionals with the selection of the most appropriate and safe exercise interventions. With the aim of uncovering the effects of exercise on the interactions among different physiological systems, future research programs within the framework of NPE should collect data simultaneously recorded from key organs including the brain, heart, or muscle during exercise. High spatio-temporal resolution instruments such as electroencephalography, electrocardiography, electromyography, accelerometry, or 3D MRI are promising tools to reveal important insights and successfully apply the aforementioned data analysis methods.2, expired fraction of CO2, ventilation, systolic blood pressure, diastolic blood pressure, and heart rate) and through the information entropy measures , or hysteresis behavior  but also on top-down influences , including the effects of environmental constraints on physiological states, physiological systems, organs, or genes . There mConcretely, current main research directions of NPE aim to: (1) investigate how each organ system coordinate and couple its own distinct physiological rhythms, at a range of different frequency domains and over several magnitudes of timescales in response to exercise-induced fatigue and training load (intra-organ interactions), for instance, how different muscle fibers in a given muscle interact with each other and adjust their activation to create an optimal contraction; (2) explore how different muscles synchronize their activation to optimally perform a certain task (inter-muscular interactions); and (3) uncover the mechanisms underlying the synchronized activation among different brain areas and cortical rhythms and distinct key organ systems  during exercise (inter-organ interactions).According to the basic assumptions and current theoretical framework of Exercise Physiology, the physiological assessment of patients and athletes is traditionally focused on the evaluation of quantitative markers extracted from isolated variables and functions. Such markers provide little information about the coordinated activity and synergies of the physiological systems that are essential to generate behavior at the organism level and appear to not be sensitive and sufficiently responsive to training effects , fatigueAccording to the interaction-dominant dynamics of neurobiological systems, an NPE approach may prove to have larger potential to evaluate the fitness and training states on a coordinative basis and inform more accurately about the risks of dysfunctions. In this line, the NPE-based assessment has two main objectives: (a) evaluation of physiological networks structure and dynamics, and their evolution in time during and after acute and chronic exercise, and (b) evaluation of the responsiveness of the physiological network interactions to exercise perturbations. The first objective may use connectivity, modularity, causality, and synergy measures , while tThe development of adequate technology of wearable devices, which are able to provide continuous and synchronous recordings (time series) of selected coordinative variables (order parameters) extracted from different physiological levels, is needed to study physiologic network dynamics. Computational intelligence methods, comprising algorithms inspired by nature  and robuPrinciples of training derived from Exercise Physiology have remained largely impervious to the transdisciplinary and holistic insights emanating from complex systems approaches . In thisPhysical activity is taking on an increasingly key role in the prevention and treatment of multiple chronic diseases, health conditions, and their associated risk factors. Despite its well-known health benefits, physical inactivity is considered a global pandemic and has been identified as one of the four leading contributors to premature mortality . GovernmAlmost all studies testing the benefits of exercise for healthy persons and clinical patients closely adhered to the exercise guidelines of Aerobic activity and strength training, prescribed as basic medication, are the core of programs addressed to healthy persons and clinical patients. Other type of activities related to flexibility such as Yoga or Pilates, which allow the improvement of range of motion and balance, are considered complementary. The recommendations are similar for Alzheimer’s disease, aneurysm, asthma, atrial fibrillation, bleeding disorder, blood lipid disorders, cancer, chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disorder (COPD) depression or anxiety, heart failure, heart valve disease, HIV/AIDS, hypertension, fibromyalgia, inflammatory bowel disease (IBD), low back pain, mobility limitations, osteoarthritis, osteoporosis, overweight/obesity, pacemaker, Parkinson’s disease, peripheral arterial disease, prediabetes, pregnancy, rheumatoid arthritis, and Type 2 diabetes. Small load adjustments, in combination with some complementary practices, are recommended according to the specific disease.Aerobic exercise, either alone or in combination with resistance training, at a moderate intensity , performed in two to five sessions per week with bouts equal or higher than 10 min is the general recipe. Ten to sixty minutes per session, with the ultimate objective of achieving at least 150 min/week is the minimum exercising time. Because of the assumed dose-response relationship, for more intense outcomes, the exercising time can be extended to 300 min/week or reduced to at least 75 min/week if the exercise has a more vigorous intensity. Strengthening activities performed at moderate or high intensity and involving all major muscle groups and practiced 2 days a week provide additional health benefits.Despite the adoption of a relatively homogeneous prescription approach, aerobic and strength training have been, for the most part, associated with benefits across a diverse range of populations e.g., . On thisEven though most studies present favorable results, systematic reviews and metaanalysis on exercise prescription point to the lack of high-quality studies showing the sustainability of standardized programs  and the Individuals respond and evolve in distinctive ways to standardized training programs , showing2 max, used in the evaluation of aerobic programs, have been widely discussed , caution is recommended when interpreting these data: (1) the effects of exercise therapy are usually compared against a non-intervention control group with a sedentary lifestyle of recognized deleterious consequences, (2) metaanalyses and systematic reviews do not reduce but may enlarge the bias of studies that compound it .Finally, research methodologies may also need to be improved to contribute to the development of personalized recommendations. The use of statistical inference techniques without enough criteria in available fitness research has produced a false belief that a significant result reflects the reality . This beThe significant benefit of a generically dosed exercise on heterogeneous populations reflects the remarkable pleiotropic physiological impact of exercise. In this sense, it is warranted to investigate further the therapeutic properties of exercise medicine to reveal its whole potential role in healthcare. Although it is still not known whether alternative prescriptions adopting a more personalized approach will confer superior efficacy to exercise treatments, several efforts have pointed toward this direction . In factDue to safety reasons, the current standardized training programs addressed either to healthy individuals, clinical patients, and athletes require the controversial quantification of the relative exercise intensity . And, acIn fact, the growing number of fitness specialties  is a proof that many types of activities, not only those based on cyclic or repetitive movements, may contribute to fitness and health development. In particular, those activities chosen by users/patients/athletes and intrinsically motivating, if adequately adapted by an exercise professional , may favor the adherence to practice .Intelligence in CAS has been recently described as a tendency to evade and escape states of reduced fitness, that is, states of reduced functional diversity potential . This reThe growth of intelligence requires regular coupling to challenging and stimulating environments to evade the temporary stalemate, which may, on longer time scale, turn into decreasing functional diversity potential . On the As health and fitness have also subjective dimensions , they caSome long-lasting personal or environmental constraints may produce a cascade of long-lasting effects on physiological levels  and the It may become recommendable to reorient the main aim of prescribed exercise medicine toward gaining diversity through the development of multidimensional and multiscale synergies. Exercise dosage and formulation, as occuring in personalized medicine, may be adapted accordingly. The formula of an active life with varied stimulus, preferably at open air , would tAs synergy formation is better captured through the interactions among the involved components and processes, variables related to connectivity (number and strength of couplings) can be suitable to test the exercise program effects. Because components of the network cooperate to accomplish the common fitness goal, if the number and strength of couplings is reduced, other components of the network may become overwhelmed and the system may respond less effectively to perturbations, bringing about dysfunction and increased susceptibility to injuries .Exercise, in turn, having a profound impact on human metabolism , may proCurrent Exercise Physiology, deeply influenced by reductionism, is limiting the understanding of exercise-related phenomena and hampering practical applications to sports performance and exercise as medicine. Integrative Exercise Physiology approaches, methodologically based on statistical inference techniques and focused on timeless vertical, bottom-up mechanistic causation (from the sub-cellular and cellular levels to organ and systemic functions), are not sufficient to improve substantially the current state of physiological research.Inspired by the new field of Network Physiology and Complex Systems Science, NPE emerges to transform the theoretical assumptions, the research program and the current practical issues of current Exercise Physiology. It focuses the research efforts on improving the knowledge of the nested dynamics of the vertical network interactions and, particularly, the horizontal integration of key organ systems. Through the application of novel methods and approaches derived from recent advances in Network Theory, Nonlinear Dynamics, Computational and Statistical Physics, and Biomedical Informatics, it seeks to provide insights into Basic Physiology itself as well as for Exercise Physiology.The critical view on the current one-size-fits-all approach of exercise prescription in health and disease, in contrast with a new proposal based on complex systems and NEP principles, illustrates the potential practical impact of the approach, which aims to provide: (a) a theoretical framework to address problems and challenges in Network Physiology, and particularly, in NPE, (b) data-driven discoveries of the basic physiological laws and control mechanisms that underlay network interactions for various states under both healthy and pathological conditions with focus on Exercise Physiology and Sports Medicine, and (c) a forum for developing new methodologies, a vision and a programmatic approach on applications of NPE. In this fashion, more qualitative research directions in Exercise Physiology may be developed and an original and fertile research program can emerge in the near future.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.