Plant-sourced proteins offer environmental and health benefits, and research increasingly includes them in study formulas. However, plant-based proteins have less of an anabolic effect than animal proteins due to their lower digestibility, lower essential amino acid content , and deficiency in other essential amino acids, such as sulfur amino acids or lysine. Thus, plant amino acids are directed toward oxidation rather than used for muscle protein synthesis. In this review, we evaluate the ability of plant- versus animal-based proteins to help maintain skeletal muscle mass in healthy and especially older people and examine different nutritional strategies for improving the anabolic properties of plant-based proteins. Among these strategies, increasing protein intake has led to a positive acute postprandial muscle protein synthesis response and even positive long-term improvement in lean mass. Increasing the quality of protein intake by improving amino acid composition could also compensate for the lower anabolic potential of plant-based proteins. We evaluated and discussed four nutritional strategies for improving the amino acid composition of plant-based proteins: fortifying plant-based proteins with specific essential amino acids, selective breeding, blending several plant protein sources, and blending plant with animal-based protein sources. These nutritional approaches need to be profoundly examined in older individuals in order to optimize protein intake for this population who require a high-quality food protein intake to mitigate age-related muscle loss. It is important to preserve skeletal muscle mass to maintain or improve metabolic homeostasis and physical function. In this context, the rates of protein synthesis and degradation in skeletal muscle constantly adapt in order to maintain muscle mass. Muscle protein synthesis and muscle protein breakdown rates are highly influenced by physical activity and food intake ,2. In heSeveral studies have shown that the ability of muscle to respond to meal-associated anabolic stimuli, i.e., amino acids and insulin, is impaired during aging ,13,14,15The aim of this review is to evaluate the quality of plant- versus animal-based proteins and to assess the ability of plant-based proteins to stimulate muscle protein synthesis rates and help sustain skeletal muscle mass in healthy adults. Given the importance of maintaining skeletal muscle mass during aging, we focus on evaluating anabolic muscular response to intakes of plant-based proteins in older people, especially in physiopathological situations like sarcopenia.Dietary protein quality is assessed based on the essential amino acid composition of a protein as it relates to human needs and the ability of the protein to be digested, absorbed, and retained by the body . The nutFood protein quality as assessed by digestibility, net protein utilization, and biological value has so far been better for animal-based protein sources like meat, eggs, milk and its constituents than for plant-based protein sources like raw cereals and legumes . The ProIn addition to the PDCAAS, the FAO Expert Consultation on Dietary Protein Quality Evaluation in Human Nutrition suggested that proteins should be described based on their digestible amino acid content. Each amino acid should be considered as an individual nutrient, since digestibility may differ among amino acids . Thus, iPlant-based proteins are less digestible than animal proteins . This coIn addition to the extent of protein digestion, a protein’s nutritional value also depends on its rate of digestion in the gastrointestinal tract . StudiesThere is a long history of studies evaluating acute muscle protein synthesis response or long-term changes in lean and skeletal muscle mass in response to the ingestion of plant-based protein sources. The bulk of these studies have investigated young-adult animal models or human subjects  protein intake ,93,95. TAs discussed above, consuming larger quantities of plant-based proteins per meal is expected to efficiently overcome their lower anabolic capacity and close the gap to the anabolic response observed with animal-based proteins. In this regard, Norton et al.  reportedSeveral studies have shown that leucine is able to stimulate specific intracellular signaling pathways related to mRNA translation and thereby acts as a signal nutrient in the stimulation of protein synthesis ,76. An aA few rare studies have examined, in human populations, the effect of cereal fortification with lysine on the growth of children in developing countries. Zhao et al.  showed aCereal proteins (which are deficient in lysine) and legumes (which are deficient in sulfur amino acids) have complementary amino acid profiles . In theoVery few studies have evaluated the effect of combining cereals with legumes on protein digestibility ,111,112 Taken together, these studies highlight the importance of fortifying cereal foods with legumes to improve their essential amino acid compositions and thus promote better body protein retention. Nevertheless, a further increase in the legume enrichment level in these products, to meet essential amino acid requirements according to body needs, could potentially achieve comparable protein retention to that induced by animal proteins like casein. However, to our knowledge, the nutritional benefits of this kind of combination have never been investigated in older subjects. Further research is warranted to test whether the strategy of blending legumes and cereals in the same foodstuff can efficiently limit muscle loss during aging.Several studies have evaluated the effect of using a blend of 50% casein, 25% whey protein, and 25% soy protein on muscle protein synthesis in both young and older subjects ,118,119.Using conventional plant breeding or genetic engineering to improve the nutritional quality of food crops  may be an effective strategy to improve muscle protein synthesis response to the intake of plant-based proteins . QualityHigh-quality protein consumption optimizes protein metabolism at both the whole-body and skeletal-muscle level, especially in older people. Plant-based protein sources that are rich in fiber and micronutrients may be valuable , but the


The current therapeutic scenario for inflammatory bowel diseases (IBD) involves aminosalicylates, corticosteroids, and immunomodulators, but concerns regarding their safety profiles and high costs heavily impact their widespread use. In recent years, the beneficial effects thatbiophenols—from fruit and vegetables—have on human health have been investigated. The antioxidant and anti-inflammatory properties of phenolic fraction, from olive leaves and fruits, have been suggested, and a potential application in gut inflammation has been supported by in vitro and IBD-animal models studies. In the present review, we first introduced the potential therapeutic role of olive tree biophenolsin chronic inflammatory disease. Then, we aimed to describe their most interesting application for gut inflammation, as the results of basic science studies and animal experimental models. Finally, the potential role of olive tree biophenols in the setting of human IBD is discussed. Inflammatory bowel disease (IBD) is a group of long-lasting idiopathic disorders characterized by a chronic inflammatory process involving the gastrointestinal (GI) tract. Both immunological dysregulation and environmental factors are key players in the pathogenesis of the disease. The main types of IBD are represented by ulcerative colitis (UC), affecting the large intestine (colon), and Crohn’s disease (CD), which can affect any section of the GI tract, while atypical forms are recognized as collagenous colitis and indeterminate colitis . The sigOlea europaea L.) represent the basis for their recognized beneficial effects on human health ,9,108,9,n health . Antioxin health . After iThe main product obtained from the olive tree is olive oil, which comes from the fruit and accounts for the majority of the antioxidant activity attributed to the Mediterranean diet . Olive lCentral obesity and insulin resistance are recognized as common underlying factors of diabetes and metabolic syndrome, while also being associated with a chronic inflammatory state . At a mo2+ concentration, which leads to mitochondrial dysfunction [A growing body of evidence is expanding the concept that chronic inflammation exerts a critical role in tumor development and progression . Severalfunction . The potfunction . In tumofunction . Similarfunction . The antfunction .Consumption of high-polyphenol-content olive oil decreased both plasma low density lipoprotein (LDL) concentration and atherogenicity in healthy volunteers, while promoting the high density lipoprotein (HDL) cholesterol efflux capacity which represents the main antiatherogenic function ,43. OlivA positive association between EVOO phenolic fraction consumption and an improvement in rheumatoid arthritis (RA) has been largely observed in mice. In experimental models of RA, animals showed a reduction in joint edema, cartilage destruction, and bone erosion, along with diminished levels of proinflammatory cytokines, prostaglandin E2, and COX-2 expression in the joint after dietary treatment with EVOO-polyphenol extract . SimilarAt a molecular level, it has been indicated that EVOO biophenols are capable of modulating the oxidative, inflammatory, and immune status in the intestinal epithelial layer . Recent Recently, oleuropein has been studied in human colon biopsies, taken from UC patients and grown according to an ex vivo organ culture model. In both protein extracts and supernatants from colonic biopsies, which were challenged with oleuropein, a significant reduction in IL-17 levels—which has been found to be increased in the colonic mucosa and serum of UC patients—has been documented. Furthermore, the treatment of biopsy samples with oleuropein led to a restoration of the typical microscopic damage of UC, with a strong decrease in the inflammatory infiltrate, disappearance of focal cryptitis/crypt abscesses, and recovery of mucin-forming goblet cells. These results were likely obtained through the modulation of the CD3+ and CD4+ subsets of T lymphocyte cells, whose number dramatically decreased at the immunohistochemistry assessment in samples challenged with oleuropein .Another interesting study evaluated the immunomodulatory properties of an olive leaf extract, containing more than 80% oleuropein, in ex vivo organ cultures of mucosal explants from CD patients . AuthorsIn vivo studies using animals with experimentally induced colitis indicate that EVOO-derived phenolic compounds can be effective in preventing and treating intestinal inflammation and related injury . In an eGiner et al. investigated the anti-inflammatory effect of oleuropein in a dextran sodium sulfate (DSS)-induced colitis mouse model . After tEffects of olive tree-derived biophenols from basic science and animal models studies are summarized in Olive oil is one of the cornerstones of the Mediterranean diet, whose benefits for human health are well recognized . DietaryAnother randomized controlled double blind crossover human trial evaluated fecal quantitative changes in microbial population after three weeks ingestion of 25 mL/day of phenolic-enriched olive oil, showing both the fecal increase in bifidobacteria and the fecal hydroxytyrosol and dihydroxyphenylacetic acids, which are microbial metabolites of the phenolic compounds responsible for antioxidant activity . As can The therapeutic potential of biophenols derived from the olive tree in human IBD is an intriguing topic, but their actual contribution to inducing and maintaining remission needs to be elucidated by well-designed randomized clinical trials. At the same time, further research is needed to clarify the mechanisms underlying the beneficial effects from the phenolic fraction of olive trees, in order to design appropriate therapeutic strategies and recommendations.


Limited resources in these areas and poor access to healthcare by persons with epilepsy (PWE) result in a wide anti-epileptic treatment gap, poor seizure control and a high burden of seizure-related complications. Recent community-based surveys highlight the need for epilepsy management strategies suitable for remote onchocerciasis-endemic villages to ensure better health outcomes for PWE. In this paper, we propose a feasible approach to manage PWE in such settings.OnchocerciasisImproved management of PWE in onchocerciasis-endemic areas may be achieved by decentralizing epilepsy care. Simplified approaches for the diagnosis and treatment of epilepsy may be used by non-physicians, under the supervision of physicians or specialists. To reduce the treatment gap, a regular supply of subsidized anti-epileptic drugs (AED) appropriate for different types of onchocerciasis-associated epilepsy should be instituted. Setting up a community-based epilepsy surveillance system will enable early diagnosis and treatment of PWE thereby preventing complications. Community awareness programs on epilepsy must be implemented to reduce stigma and facilitate the social rehabilitation of PWE. Finally, strengthening onchocerciasis elimination programs by optimizing community-directed treatment with ivermectin (CDTI) and considering alternative treatment strategies might reduce the incidence of epilepsy.A community-based approach with task-shifting of epilepsy care from specialists to non-physician health workers will reduce epilepsy-associated morbidity. Increased advocacy and collaboration with various stakeholders is needed to establish a sustainable, cost-effective chronic care model for epilepsy that will significantly improve the quality of life of PWE in onchocerciasis-endemic regions.The online version of this article (10.1186/s40249-019-0523-y) contains supplementary material, which is available to authorized users. Please see Additional file -endemic regions, particularly in areas where the intensity of infection is high [Onchocerca volvulus (the parasite that causes onchocerciasis), may directly or indirectly, be causing a wide spectrum of seizure disorders now described as onchocerciasis-associated epilepsy (OAE) [O. volvulus was shown to augment the risk of epilepsy in a microfilaria load-dependent manner [. In addition to generalized tonic-clonic seizures, absences and focal seizures, OAE also includes two clinical entities namely the nodding syndrome  and the Nakalanga syndrome  [Epilepsy is highly prevalent in onchocerciasis is high –3. The r is high , 5 as we is high –9. Althosy (OAE) , 11  –14. An epilepsy) ; howeverNearly 80% of persons with epilepsy (PWE) live in low- and middle-income countries  includinWe performed a selective search on PubMed for relevant articles focusing on epilepsy management in resource-limited settings, including onchocerciasis-endemic areas. We also took into account recommendations from the World Health Organization (WHO)  and concIn remote onchocerciasis-endemic villages in Africa, access to healthcare and anti-epileptic drugs (AED) is generally difficult . PWE hav-endemic villages, poor accessibility, general poverty, inadequate healthcare services , high epilepsy prevalence, poor health seeking behaviour leading to late diagnosis and frequent complications , low literacy rate with frequent school drop outs at the primary level, frequent sexual abuse, misconceptions and stigma [During our recent surveys in onchocerciasis-endemic villages –9, we nod stigma , 19, 30.It is expedient that PWE in onchocerciasis-endemic areas receive appropriate treatment and that new cases of OAE be prevented by strengthening onchocerciasis elimination in endemic areas , 14. EpiWe propose to use the following definition of epilepsy: “the occurrence of at least two unprovoked seizures separated by at least 24 hours” . The ter-endemic region; (iii) A high prevalence of epilepsy in the village and families having more than one child with epilepsy; (iv) No other obvious cause for the epilepsy ; (v) Onset of epilepsy between the ages of 3 and 18 years; (vi) Normal psycho-motor development before the onset of epilepsy. Local health personnel working in onchocerciasis-endemic settings are encouraged to check for exposure to O. volvulus in PWE either clinically  and/or biologically .In case of a positive response to any of the 5 screening questions, the second step should be to refer the person to a trained nurse or clinical officer to confirm or reject the diagnosis of epilepsy using another questionnaire  , temporaEpileptic seizures are treated using anti-epileptic drugs (AED) but only a limited number of AED are available and/or affordable in low resource settings . AED thaFor PWE taking antiretroviral drugs (ARV), valproate is preferred as it presents less interactions with ARV . There iO. volvulus or macrofilaria after repeated consecutive doses [O. volvulus microfilaria in the absence of treatment increases the risk for OAE [For public health reasons and also as a specific treatment measure, PWE residing in onchocerciasis-endemic areas should receive ivermectin at least once a year  at the rve doses . The oncve doses . Althougve doses  because  for OAE . In pers for OAE .PWE are at risk of seizure-related injuries and have more frequent accidents even without a seizure . Common Burn injuries should urgently be cooled with clean running water for about 20 min, and then the victim should be rushed to a health facility. The health personnel should perform thorough debridement and adequately dress the wound. Local antiseptics could be applied. Tetanus immunization associated with serotherapy, and empirical antibiotic treatment should be given. As for submerged (drowning) PWE, they should rapidly be rescued from water and given cardiopulmonary resuscitation as required: repeated cycles of 30 chest compressions and two rounds of mouth-to-mouth ventilation . Upon trTreatment for PWE should be dispensed through epilepsy clinics established at primary health care facilities, which should serve as the focal points to ensure epilepsy care and AED delivery. A senior nurse/clinical officer at the health facility should be trained to head the clinic; his/her duties will be to consult suspected cases of epilepsy, confirm the diagnosis, prescribe AED, evaluate for adverse effects and treatment outcomes and notify doctors/specialists in case of treatment failure, side-effects or complications. Nurses from target zones can be collectively trained during periodic seminars supervised by competent specialists and should be given practical manuals to ease implementation. Physicians trained in epilepsy care and/or specialized doctors working in nearby health structures are encouraged to regularly visit the clinics to personally consult some PWE and offer field supervision to the clinic heads.Another task for the head of the clinic is to ensure the continuous supply of AED by ordering them every month based on the needs. Given the low purchasing power of the affected population, we propose a participatory approach for AED purchase whereby the affected families pay a yearly token (USD 2–USD 3 per PWE per year) which will be complemented by the government, local authority, or a partner organization to ensure an uninterrupted supply of AED all year round. This will have the double advantage of ensuring sustainability and increasing treatment adherence by PWE as they seek to fully utilize their invested funds. Epilepsy clinics should negotiate directly with accredited AED suppliers to deliver the drugs on site. These AED suppliers could benefit from certain privileges (such as tax reduction or exemption) to ensure continuous availability of routinely used AED at affordable costs. Valproate is much more expensive than the other AED, and should be subsidized to encourage treatment adherence. Indeed, we have observed that certain PWE switch from one AED to another or may stop treatment because the drugs are too expensive.Clinical features: anthropometric parameters, physical examination, seizure characteristics, complications, co-morbidities, deathsTreatment outcomes: adherence to AED, seizure frequency, side effectsQuality of life: degree of autonomy, socialization, school/work, anxiety/depressionEpilepsy-related expenses: cost of AED and care, transport cost to health centre, number of days of work lostManagement: AED and dosage, other measures, date for next appointmentAn important aspect of the clinic is proper documentation of all patient-related data and activities of the clinic. This will be done primarily using reporting forms adapted from the WHO training modules on mental health gap action program  for thisEpilepsy clinics should equally provide psycho-social support to PWE and their families. This can be achieved via support group sessions with patient-carer associations, during which advice and tips are given to PWE to equip them for healthier and more autonomous lives. Practical issues to be discussed include: treatment adherence, balanced diet, sufficient sleep (≥ 7 h per day), avoiding substance/alcohol abuse, physical exercise such as jogging, and school/work resumption. PWE should be encouraged to share their success stories so as to encourage others.CHW constitute the support staff and community arm of the epilepsy clinic. The clinic head should train them to suspect epilepsy using the 5-question approach and refer suspected PWE to the clinic for confirmation. As such, they will be instrumental in community-based surveillance of epilepsy by tracking suspected cases within their communities and referring them to the clinic for early diagnosis. Early diagnosis allows for epilepsy care to be initiated before the onset of complications. Also, a community-based surveillance system provides more realistic estimates of the burden of epilepsy, which is usually underestimated in hospital settings. It has been suggested that instead of CHW, community-directed distributors of ivermectin (CDD) could be trained for epilepsy screening, follow-up and surveillance in onchocerciasis-endemic areas .CHW equally have to ensure community follow-up of PWE via home visits, ensuring good treatment adherence, monitoring treatment outcomes and reminding families of the monthly follow-up visits. They should monitor seizure frequencies of PWE and report in monthly forms  to prevent aspiration; check airway, breathing and pulse. A person with a prolonged seizure or short recurrent seizures within the same day should urgently be taken to the health centre.Outreach programs need to be organized in the community, schools, churches, markets and other public gatherings to sensitize the population about epilepsy. In onchocerciasis-endemic villages, clustering of PWE within some households fosters the wrong belief that epilepsy is transmissible by touch . PrimaryEpilepsy may affect education and other lifetime opportunities, income, social and professional fulfilment especially in low-income countries . YoungerThere is strong epidemiological evidence suggesting an association between epilepsy and onchocerciasis, with increasing onchocerciasis transmission resulting in increased epilepsy prevalence , 4, 10. To develop a sustainable comprehensive management program for PWE, a participative approach including integration into the national health system, must be established from the very start. A clear vision needs to be communicated to community leaders, elites, authorities, existing patient and advocacy associations to make them buy into the project early enough so as to participate in its implementation. Regular and concise reporting will improve credibility and build enough impact for the program to ensure sustainability. The local population should be convinced to consider epilepsy care as a priority community intervention in which they will voluntarily participate. Various parties in the epilepsy program and their roles are shown in Fig. -endemic regions. Performing research in these regions however is difficult because of their remoteness, the lack of medical and research infrastructure, lack of trained healthcare workers and local researchers. A few research priorities that should be addressed to ameliorate epilepsy care in these regions are outlined in Table Knowledge gaps still exist in the domain of prevention and management of epilepsy in onchocerciasis-endemic regions with sub-optimal control measures. Compared with HIV, another chronic stigmatizing condition, there is a large gap in treatment and care services available for PWE. In these regions, epilepsy stigma is further compounded by onchocerciasis stigma, thus limiting treatment-seeking behaviour. Establishing a comprehensive, decentralized community-based epilepsy treatment and care program that will equip non-physicians in the remote villages may be the way forward to improving epilepsy care. This requires proper advocacy and collaboration among many stakeholders – including pharmaceutical companies to provide cheap/free AED – and a strong political commitment for its implementation. Finally, onchocerciasis elimination programs should be reinforced to prevent future cases of OAE.Epilepsy remains a major neglected public health problem in many onchocerciasisAdditional file 1:Multilingual abstract in the five official working languages of the United Nations. (PDF 487 kb)Additional file 2:Main components of a community-based epilepsy program. (DOCX 14 kb)Additional file 3:Forms for epilepsy diagnosis and follow-up. (DOCX 80 kb)


Over the past decades, a large number of drugs as well as drug candidates with poor dissolution characteristics have been witnessed, which invokes great interest in enabling formulation of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be broken through. Minimizing a drug’s size is an effective means to increase its dissolution and hence the bioavailability, which can be achieved by specialized dispersion techniques. This article reviews the most commonly used dispersion techniques for pharmaceutical processing that can practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion (drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or capsulizing), covering the formulation development, preparative technique and potential applications for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed. Various dispersion techniques provide a productive platform for addressing the formulation challenge of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged to develop for formulation of poorly water-soluble drugs. Drugs with poor aqueous solubility are still an ongoing challenge in the successful formulation of therapeutic products due to their low oral bioavailability. It is a hard nut to crack that has discouraged pharmaceutical practitioners for many years. In the 1990s; the biopharmaceutical classification system (BCS) was introduced to characterize various drugs according to their solubility and permeability . These aA variety of formulation strategies have been explored to overcome the poor aqueous solubility of drugs, including micronization , nanocryPharmaceutical engineering involves all sorts of dispersion systems, including suspension system, colloidal system and solution system, in which a drug can be dispersed by itself or in a solid matter, a semisolid matter, a solvent or nanoparticles. Among these, solid dispersion (SDs), lipid-based dispersion and liquisolid dispersion are well-developed and more commonly used pharmaceutical dispersion techniques. These dispersion systems have been widely applied to formulation of poorly water-soluble drugs to address the issues related to solubility and permeability. Solid dispersion technology is a method of dispersing a drug in an inert carrier excipient  in the solid form. This technique allows complete removal of drug crystallinity and molecular dispersion of a poorly soluble drug in a hydrophilic polymeric carrier . In soliLiquisolid system as a viable alternative to the conventionally used dispersion techniques for dissolution and bioavailability improvement has received considerable attention in recent years . LiquisoIn this article, a comprehensive survey on the use of solid dispersion, lipid-based solubilization and liquisolid technique for dissolution and bioavailability enhancement of poor water-soluble drugs are carried out. Specific aspects focus on the formulation development, excipient application, preparative techniques and oral delivery efficiency of these dispersion-based formulations. In addition, other dispersion techniques that can improve the dissolution as well as bioavailability are also briefly outlined. It is strongly recommended that these promising pharmaceutical dispersion techniques can well serve for the development of oral dosage forms of poorly water-soluble drugs.Dispersion is a technique resulting in a substance dispersed or embedded in another molecule or continuous phase. A dispersion can be classified in a number of ways according to the size and the state of dispersed matter. Generally, there are three main types of dispersions as depicted in Drug dissolution refers to a process that the interaction between drug molecules is displaced by the one between the drug and dissolution medium . If the Solid dispersions are a dispersion mixture of one or more active ingredients in an inert carrier at the solid state prepared by melting, solvent, solvent-melting or other methods. The approaches used for preparing SDs are referred as solid dispersion techniques. According to Noyes–Whitney equation, the dissolution rate of a drug in a given medium depends on the concentration difference between the dissolving interface and the bulk solution. For poorly water-soluble drugs, the dissolving rate on the interface is positively associated with the particle size of drug, especially above 100 nm . SDs canco-vinyl acetate) (PVP/VA), and poly(vinyl acetate-co-vinyl caprolactame-co-ethylene glycol) (Soluplus®). Carrier excipients play an essential role in formation of SDs, drug dissolution and absorption, and stability of SDs. Pharmaceutical excipients that have been used for production of SDs are exhaustively collected in ®, a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, has been extensively investigated for preparation of SDs , in, in67], Melting method is the earliest technique used for SDs preparation proposed by Sekiguchi and Obi in 1961. They prepared sulfathiazole SDs by melting the drug with urea and investigated the drug absorption in the form of eutectic mixture . In thisSolvent evaporation method circumvents the suffering of high temperature, thus suitable for heat-labile APIs. In this process, both drug and carrier are dissolved in organic solvent. After dissolving, the solvent is evaporated using a special apparatus, rotatory evaporator. The solid mass is ground, sieved and dried. It requires that the drug and selected carrier excipient can completely dissolve in the solvent so as to form amorphous dispersions or solid solution. Of course, this approach likewise confronts challenges from two aspects: to remove the residual solvent and to harvest the SDs. Ethanol is the proposed solvent to use in the production of SDs. But, in some cases, other harmful solvents have to be adopted in order to dissolve some water-insoluble drugs. If the issues of solvent residue and product harvesting in the evaporator can be overcome, solvent evaporation method may after all be accepted as workable technology for manufacturing SDs. With this technique, Dos Santos et al. developed SDs of β-lapachone using PEG 6000 and PVP k30 as hydrophilic polymers and evaluated the dissolution rate in aqueous medium .Solvent-melting method is an improvement to melting method and solvent evaporation method. In this process, API is first dissolved in a small quantity of solvent and then added into the molten carrier excipient. The solvent used can be removed through instant evaporation upon contacting with the hot carrier or through an evaporator. This technique overcomes the disadvantages of high temperature and the use of larger volume of solvent, which is suitable for moderately thermostable and practically insoluble APIs. However, it also requires the therapeutic dose of API to be low. For instance, Chen et al. prepared emulsified SDs containing docetaxel by three approaches, i.e., melting method, solvent-melting method and solvent method . It was Milling method, also known as co-grinding method, refers to a preparative process of SDs by exploiting external mechanical power to knead the drug and carrier together. The drug and carrier are physically mixed for some time in a blender and then charged into the chamber of a colloid mill or fluid-energy mill to grind strongly with or without a small amount of solvent. The resulting dispersions are collected, dried and pulverized ready for use. As an example, chlordiazepoxide and mannitol SDs were produced by this method . Of noteSpray-drying method refers to the preparation of SDs by dissolving or suspending the drug and carrier in a common solvent or solvent mixture and then drying it in a hot air stream to remove the solvent, which can be deemed as an improvement on the solvent method. Upon atomization, the solvent promptly evaporates and SDs are formed simultaneously. Spray-drying method can directly obtain SDs powders with good flowability or pellets by co-precipitating on the surface of blank beads using fluid-bed coating. It can completely yield drugs in the amorphous or molecular state , though 2). Apart from lower critical temperature (Tc = 31.1 °C) and pressure (Pc = 73.8 bar), CO2 is nontoxic, nonflammable and inexpensive for use. In general, two basic SCF techniques can be utilized to prepare SDs [Supercritical fluid (SCF) technology shows tremendous advantages and favorable operating conditions (low temperature and high dissolving power), making the method more attractive for SDs production. The most commonly used SCF for a variety of pharmaceutical applications is supercritical carbon dioxide  that largely facilitates the drug dissolution. In addition, some carrier excipients such as Poloxamer and Gelucire have the abilities of promoting drug absorption and inhibiting drug efflux. These advantages impart SDs excellent performances for oral delivery of various therapeutic agents .Cmax) and area under plasma concentration-time curve (AUC) were achieved through SDs after oral administration compared to the levels resulting from a marketed product (Sporanox®). Efonidipine hydrochloride ethanolate (NZ-105) is a novel API with calcium antagonist activity, but has a very low solubility in water. Otsuka et al. employed the microwave technology, a modified melting method, to prepare NZ-105 SDs using hydroxypropyl methylcellulose acetate succinate as a carrier and urea as an auxiliary component [Piperine, an alkaloid with poor water solubility, has been prepared into SDs with sorbitol, PEG and PVP by solvent evaporation method . Piperinomponent . It was Lipid dispersion refers to formation of nanoparticles using lipid excipients. Distinct from solid dispersion, the products resulting from lipid excipients are generally in the form of liquid dispersion. Even though solidified by spray-drying or lyophilization, they possess poor powder property, low storage stability, and great difficulty to pulverize. Nonetheless, formulating drug into lipid carriers represents an effective dispersion technique that can enhance the dispersibility of drug and create a supersaturated concentration in the gastrointestinal lumen for drug absorption. Herein, it is obviously inappropriate using the terms of solubility and dissolution to describe the dissolution characteristics of lipid-formulated drugs. Solubilization and release turn into the descriptors to characterize the drug lipid dispersions. Lipid dispersion technique is more applicable for formulation of highly lipophilic, low-melting-point, and poorly permeable drugs. These drugs are easily prepared into lipid nanoparticles with satisfactory physiochemical stability.Dispersion of drug can either be accomplished through excipient-free top-down (milling) and bottom-up  methods that forms drug nanocrystals , or throSolid lipid nanoparticles (SLNs) represent the first generation of lipid nanoparticles composed of a high-melting-point solid lipid and a small number of surfactant, which are developed on the base of from O/W emulsions . SLNs prSLNs exclusively involve solid lipids that have a high crystallinity in the lipid core, thus existing potential drug expulsion upon storage . The solw/w) [Pharmaceutical nanoemulsions are generally O/W emulsions in the nanometer scale made up of oil phase, water phase, emulsifier, and a selected co-emulsifier. By virtue of facile preparation and smaller particle size, nanoemulsions have been getting considerable attention in recent years as smart drug delivery system . The oilw/w) . The excw/w) . Drug diLiposomes are spherical vesicles consisting of one or more bilayers formed by phospholipid and cholesterol. Due to flexible controllability and good biocompatibility, liposomes have become a talented drug delivery system, and several liposomal products are clinically available at present . LiposomUnlike liposomes, phytosomes are not vesicle-based drug carrier. They are phospholipid dispersions containing a natural active ingredient . PhytosoLipids are substances consisting of fatty acids and their derivatives, including oils, fats, waxes, sterols, monoglycerides, diglycerides, triglycerides, and phospholipids. Lipid-based drug delivery systems are mostly constructed upon lipid vesicles or matrixes. The lipid excipients have abilities to solubilize, disperse, encapsulate and stabilize lipophilic drugs that are poorly water-soluble in nature, thus enhancing their bioavailability. The unique characteristics of lipid excipients have been motivating the pharmaceutical practitioners to develop various lipid-based formulations for coping with challenges from compounds with inadequate solubility and permeability . Apart fThe merits of lipid-based formulations for oral drug delivery have been profoundly reviewed ,107,170.To ameliorate the oral bioavailability, various lipid nanocarriers have been explored for oral delivery of poorly water-soluble drugs. For instance, Wang et al. utilized SLNs to orally delivery sorafenib, an anticancer agent for hepatocarcinoma, in order to achieve a desirable liver targeting . The desAlthough lipid carriers have been proven to be potential as oral delivery vehicles, it should be noted that the lipolysis of lipid carriers substantially takes place in the gastrointestinal transport process. As a matter of fact, the in vivo degradation of lipid nanoparticles is not contradictory with their absorption-promoting effect, since lipids can facilitate drug absorption by co-transport and cytosis in the form of intact nanoparticles or reconstituted micelles . The in Lipid-based formulations are generally liquid preparations that have low physiochemical stability, which will cause inconveniences for storage and quality control. Although lipid nanocarriers belong to colloidal dispersion system, they are just stable on a short-term basis. When storing for a long time, the phenomena of nanoparticle aggregation and precipitation would inevitably occur due to particle collision and gravitational settling . The staFreeze drying is a practicable technique to settle the long-term storage of colloidal nanoparticles. By removing the water from the aqueous dispersions, a dried form of lipid dispersions is harvested whereby to improve the physiochemical stability of colloidal nanoparticles. Freeze drying of nanosuspensions not only requires consideration for the formulation factors, but also the lyophilization process. The process conditions have a crucial effect on the stability of nanoparticles during and after freeze drying. During lyophilization, the nanoparticles will be subjected to various stresses, such as particles agglomeration and desiccation, which may be detrimental to the stability of nanoparticles. Therefore, a proper cryoprotectant and optimized lyophilization process must be adopted so as to minimize damage to the nanostructures. For example, Howard et al. tested nine kinds of cryoprotectants and different freeze drying conditions to optimize lyophilization process of solid lipid nanoparticles loading dexamethasone palmitate for improving the long-term stability . The resSpray drying is proposed for use as a promising alternative to stabilize and preserve the colloidal nanoparticles in a dried form. In spraying drying, the liquid is promptly evaporated when the liquid lipid dispersions are sprayed into the hot air stream, in which solid micropowders such as starch and aerosil or blank pellets are pre-charged. The nanoparticles immediately precipitate on the surface of carriers upon water evaporation. This dehydration-solidification technique intended for lipid nanoparticles is normally termed as nano spray drying ,186. It in situ self-emulsification. SEDDS are physically stable formulations and can be manufactured into the semisolid soft capsules  [Self-emulsifying drug delivery systems (SEDDS) are emulsifiable water-free formulations made up of oil and emulsifier with or without hydrophilic co-solvent. SEDDS are utilized to solve low bioavailability issues of poorly soluble and highly permeable drugs . Self-emdimmun®)  or liquidimmun®) . Water-fThis approach converts liquid lipid nanoparticles into powdered form and then formulates them into tablets or capsules, which differs from the following liquisolid system directly developed from a drug solution. The liquid lipid dispersions must be concentrated to a relatively small volume that can be fully adsorbed by additional adjuvants, such as microcrystalline cellulose (MCC) and aerosil. Liquisolid compact tablets or capsules can be obtained after lipid dispersions are loaded into adsorptive excipients and form dry-looking, freely flowing and compressible powders. For example, Nnamani et al. developed low-dose liquisolid tablets of artemether-lumefantrine (AL) from NLCs and estimated their potential for oral delivery of AL in malariogenic Wistar mice . The resMolecular solution represents the highest dispersion of drug in a variety of formulations. In SDs, a poorly water soluble drug can form solid solution with a suitable carrier excipient. Solid pharmaceutical intermediates are readily processed into a final dosage form, such as tablets and capsules. Accordingly, there should be a possibility by which liquid substances can be changed into the solid form. Liquisolid dispersion technique is the right means to materialize solidification of liquefied drug. A liquisolid system refers to formulation implemented by conversion of lipophilic drug in a nonvolatile solvent into dry-looking, freely flowing and compressible powders by blending a drug solution with adsorptive excipients followed by processing into suitable dosage forms  is generalized in ® EL. Of course, other hydrophilic or amphipathic solvents such as Transcutol®, Solutol® and Labrasol® are also oftentimes involved in the liquisolid systems. Non-volatile solvent used in liquisolid systems should be inert, lowly viscous, preferably water-miscible and meanwhile have a strong solvent power as liquid vehicle. Various solvents with high boiling point are explored for the formulation of liquisolid systems, including PEG, propylene glycol, glycerin, and polysorbate. The non-volatile solvent simultaneously acts as a solvent and a binding agent in the liquisolid formulation. It has been shown that the solvent had a significant effect on drug release from the liquisolid system . For rap® and Ceolus®), lactose, sorbitol, anhydrous dibasic calcium phosphate , amorphous magnesium aluminometasilicate (Neusilin®), etc. Among these, Fujicalin® and Neusilin® represent the newly-developed carrier materials, which exhibit especially large SSA, up to 40 m2/g and 300 m2/g, respectively [® not only can be used as a carrier material, but also function as a coating material by virtue of excellent adsorption and flowability properties [In the liquisolid system, carrier materials play the key role in gaining the dry form of powders from the solubilized liquid drug. Carrier materials mainly contribute to liquid adsorption. It requires that the carrier should be porous and possess large enough specific surface area (SSA) . Carrierectively . Neusilioperties .® and Cab-O-Sil® M5. Amorphous silica gel , Neusilin®, calcium silicate (Florite®) and ordered mesoporous silicates that have suitable flowability and compressibility can also be used to prepare liquisolid formulation [Coating material plays a key role in covering the wet carrier particles to form dry-looking and freely flowing powders. It should be a material possessing fine and highly adsorptive micropowders that can adsorb excess liquid to ensure good flowability of the admixture. In the liquisolid system, coating material and carrier material must be used in conjunction in order to enhance the flowing and compressing properties of powders as illustrated in mulation .Apart from non-volatile solvent, carrier and coating materials, the liquisolid system usually use some other additives to develop solid dosage forms. Tablets or capsules normally experience the disintegration process before dissolution. Therefore, disintegrants such as sodium starch glycolate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose (L-HPC) are generally included in liquisolid formulation to allow a fast disintegration. In addition, release modifier  and crystal growth inhibitor  are frequently contained in the liquisolid compact tablets ,213. TheA given powder can only retain limited amount of liquid medication while maintaining acceptable flowability and compressibility. Before preparation, it generally performs the pre-formulation studies, including solubility study, determining the flowable liquid retention potential , calculating the liquid load factor (Lf), and measuring the repose angle of admixture. Theory on liquisolid system was developed in 1992 by Spireas and his colleagues based on the concept of powdered solution .According to the pre-formulation’s information, the candidate drug is dissolved in the required quantity of nonvolatile solvent, and then the resulting drug solution is incorporated into the calculated amounts of carrier and coating materials. Generally, the mixing process is carried out in three steps as proposed by Spireas and Bolton . During Liquisolid dispersion technique has been widely used to improve the dissolution and bioavailability of poorly water-soluble drugs with a low dose . A liqui® PH102 as carrier material and Aerosil® as coating material [® EL, Avicel® PH102 and Aerosil® 200 as functional excipients [®). Sharma et al. developed a liquisolid system to improve the dissolution rate and bioavailability of curcumin using PEG as liquid vehicle, Avicelmaterial . The syscipients . It was AUC). The examples above indicate that liquisolid technique was a potential tool in increasing dissolution and bioavailability of poorly water-soluble drugs. In another work, Khames et al. developed risperidone liquisolid formulation using versatile solvents  mixture) as liquid vehicles and evaluated its dissolution and bioavailability . The resCo-precipitation technique refers to a process by dissolving a drug in a solvent containing an insoluble adsorbing material and then evaporating them to result in drug precipitation onto the surface or the internal pore of the absorbing material, thus forming solid dispersions . It is dIn recent years, pharmaceutical cocrystals have gained increasing attention to developing drug in solid-state formulations , which cIn most cases, inclusion complexes are not regarded as a pharmaceutical dispersion. However, it is unreasonable to exclude inclusion complexes from pharmaceutical dispersions, since the guest molecule (drug) is fully incorporated into the cavity of host molecule that results in a complete dispersion of drug. It is merely that, in solid dispersions, the drug is embedded between carrier molecules, but in inclusion complexes, the drug is embedded within the molecule. In addition, solid dispersions and cyclodextrin inclusion complexes shared some common preparative techniques, such as kneading method and solvent evaporation method. From these points of view, drug inclusion into another molecule can be deemed as a practicable dispersion technique. Cyclodextrin complexation, but not limited to cyclodextrins, has shown the potential to precisely improve the aqueous solubility, dissolution rate, and bioavailability of poorly water-soluble drugs . For insTo date, oral administration remains the most preferred route that patients take the medicine, and solid dosage forms are the prevalent modality of pharmaceutical preparations. Pharmaceutical processing always results in a dispersion of a drug in the solid, semisolid or liquid excipient in particulate, colloidal, amorphous or molecular state. Super-advanced dispersion can engender additional benefits for dissolution and bioavailability of poorly soluble drugs, which, of course, greatly depends on effective dispersion techniques. It has been shown that solid dispersion, lipid-based dispersion and liquisolid dispersion are becoming useful tools to solve the formulation challenges of poorly soluble drugs.


In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities. Cancer therapy has advanced greatly over the past several decades, and recent advances in immunotherapy have led to marked improvement in outcomes and quality of life in patients with cancers previously thought to be incurable , 2. HoweThe stromal microenvironment of a tumor presents an underlying challenge to the efficacy of cancer immunotherapy. In their seminal review, Hanahan and Weinberg named evading immune destruction as an emerging hallmark of cancer among other related activities, such as metabolic reprogramming and induction of angiogenesis within the TME . For cytLeveraging the components of the stromal microenvironment, tumors employ a variety of strategies for immune evasion. These strategies can be broadly grouped thematically into the following categories: immune cell regulation, metabolic reprogramming, and hypoxia. These immune evasion strategies collectively synergize to blunt the efficacy of tumor-infiltrating lymphocytes (TILs) with regard to both activation and infiltration. Clinically, this may significantly limit significant limitation of cancer immunotherapy. Indeed, evidence suggests that baseline infiltration of both T cells and natural killer cells as well as expression of various chemokines involved in immune cell recruitment to the TME are strongly associated with prognosis for a variety of histological types of cancer . TherefoRadiation therapy is a gold standard of cancer treatment, with more than 50% of cancer patients needing local therapy with XRT . With in+ T-cell recruitment and demonstrated that chemokine blockade inhibited migration of CD8+ effector T cells in vivo , and MDSCs and form an immune-suppressive TME . TME conact TILs . In addiact TILs . Overall2, that inhibit DC activation and maturation and suppress the activity of CTLs and natural killer-mediated immunity , interleukin (IL)-10, transforming growth factor (TGF)-β, adenosine, and prostaglandin Eimmunity . For exaimmunity . Likewisnd IL-12 . M2 TAMsmotility . Upon phmotility . Clinicaw ratios .+ infiltration and accumulation of Tregs, which were resistant to FasL due to higher c-FLIP expression. However, this blunting of CD8+ T cell infiltration was reversed by pharmacologic inhibition of prostaglandin E2 and VEGF, which were shown to cooperatively induce FasL expression on this tumor endothelial “death barrier”  has significantly altered our understanding of XRT's role in the immune system. This new paradigm demonstrates XRT to be an immunomodulatory tool that facilitates for recruitment and activation of the immune system to fight tumors. The main underpinning of XRT's effect on antitumoral immunity is increasing the release of tumor antigens and their availability for antigen-presenting cells (APCs) to take up and prime T cells. However, XRT also has direct effects on the surrounding stroma that enables the immune system to increase antitumoral responses.In addition, a potential strategy involves XRT to eradicate all gross disease followed by immunotherapy to eliminate remaining microscopic disease in cancer patients. Researchers demonstrated the benefit of this strategy in the recent PACIFIC trial (NCT02125461) examining sequential XRT and immunotherapy . AntonioWe can suggest that XRT and immunotherapy worked synergistically in the PACIFIC trial, in which XRT first ablated all gross disease, leaving behind only microscopic metastases, which immunotherapy controlled. The lack of recurrences in that study, resulting in extended PFS in patients receiving immunotherapy, stems from the enhanced ability of immune cells to infiltrate and eliminate microscopic metastases, which lack a stromal microenvironment but can still seed the growth of larger metastases. Indeed, a study by Zhang and colleagues demonstrated poor prognoses and increased rates of recurrence in non-small cell lung cancer patients with stroma-rich tumors, in whom the tumor: stroma ratio was quantified using hematoxylin-stained tissue specimens . TherefoThe landmark PACIFIC trial suggests significant improvements in patient outcome by utilizing XRT combined with immunotherapy. This will impact many future trial designs for multiple solid tumors with the goal of improving the patient outcomes. As described previously, XRT was initially used for its direct induction of DNA damage, leading to tumor cell death . Histori+ cell activation. This modality of cell death is termed immunogenic cell death (ICD). Traditionally, apoptosis is considered a tolerogenic process, which limits the ability of the immune system to develop a full response. However, with ICD, an external stress source facilitates the release of danger-associated molecular patterns (DAMPs), which elicit a signal to APCs and instigate cell death  expression, which leads to decreased recognition of tumor cells by effector T cells , 60. Clial doses –66. One al doses . Ultimatin vivo study using an anti-PD-1 therapy-resistant mouse lung cancer cell line, suppression of type I IFN expression was associated with anti-PD-1 therapy resistance due to reduced MHC-I expression, but tumors became responsive to anti PD-1 therapy after XRT  anti-glucocorticoid-induced tumor necrosis factor-related protein (GITR) antibody in an anti-PD-1–resistant murine lung adenocarcinoma model . They foMDSCs are also are also believed to be among the main drivers of TME immunosuppression, and their presence has been correlated with poor prognosis and response rates for many types of human tumors . Studiesin vivo , which is a member of the B7 superfamily , 108. Onin vivo . They foin vivo . Given tIn vivo studies of prostate cancer demonstrated that M2 TAMs which express arginase-1 and COX-2 are recruited to these hypoxic centers after irradiation and promote tumor growth (Hypoxia also poses a challenge for XRT and its ability to ablate tumors and recruit effector immune cells within the TME. MDSCs and TAMs are heavily recruited to these hypoxic environments through various mechanisms, including colony-stimulating factor 1, VEGF, endothelin, and several other proteins . Within r growth , 114. AtOverall, the evidence that XRT modulates the TME and the balance between pro-tumoral and antitumoral signaling is substantial. Investigators have placed an emphasis on how fractionation and dosing play a role in these changes , 116. HoAdditionally, the practicality of XRT in the setting of systemic disease is uncertain given increased time demands. For example, the time on the therapy table for each patient per isocenter would increase dramatically. Also, the precision required to target multiple isocenters is not yet possible even with the currently available SBRT technology. Given these practical and mechanistic limitations, our current understanding of XRT as monotherapy for systemic disease is limited. Further studies are warranted to evaluate the timing, dosing, and tolerance of multisite irradiation.Meanwhile, given the current landscape of multi-agent immunotherapy, such as the combination of anti-PD-1 and anti-CTLA-4 therapy, the body of literature on the synergy of XRT and immunotherapies is rapidly growing –119. TarThe rationale for combining XRT and immunotherapy is clearly apparent based on the aforementioned synergistic mechanisms. This is exemplified by the rapidly increasing number of ongoing prospective trials of combined-modality therapy for cancer , 121. AlThe construction of these prospective investigations has several implications for the design of future studies. Although many of the trials in a previous systematic review evaluated concurrent therapy, few specifically evaluated the risks and benefits of this approach with sequential therapy . MechaniFuture studies must also evaluate combinatorial therapy consisting of XRT and multi-agent immunotherapy as well as chemoimmunotherapy. Although a clear concern is that multi-agent immunotherapy may be more toxic than a single agent alone, multi-agent treatment yields better outcomes than do some single agents as noted in the CheckMate 067 metastatic melanoma trial . HoweverJust as candidate radiosensitizers have been and continue to be developed for XRT, another goal is to explore candidate immunosensitizers that are not immunotherapeutic compounds but rather promote and stimulate the immune system in ways that allow for enhanced immunotherapy effects while minimizing complication risks to normal tissues, thereby improving the therapeutic ratio. This is important because excessive immune system “drive” may result in potentially lethal toxic effects. Nevertheless, because the response rate for most immunotherapeutic compounds in seminal clinical trials is about 20%, novel biomolecules are needed to increase this rate , 132.Furthermore, the synergy between XRT and immunotherapy may be exemplified by using XRT as a “pseudo-systemic agent” in patients with oligometastatic disease or even widely metastatic disease with good initial responses to chemotherapy and/or immunotherapy . BecauseRecently, we have seen an increasing trend in the number of positive trials in which XRT is used to treat up to three metastatic sites. Patients with a greater number of metastases would also benefit, but such an approach would be logistically arduous due to the need for multiple isocenters. The development of technologies that make multi-site XRT easier, together with technologies that automate target delineation and treatment planning, such as deep and machine learning, may make XRT more pseudo-systemic in the future, especially when integrating it with other synergistic treatments, such as immunotherapy .The stroma is an important component of the TME to study because it has significant implications for limiting antitumor immunity. XRT has long been considered to damage cancer cell DNA, but its effects on the stroma have received little consideration. Given reported evidence, one of the greatest benefits of XRT is its ability to eradicate and reprogram the stroma, the same stroma that too often limits the delivery of systemic treatments such as chemotherapy, targeted therapy, immunotherapy, and even cellular therapy. Radiation's ability to eradicate areas of gross disease provides a strong rationale for its use with systemic agents, which would eradicate remaining circulating microscopic disease. Systemic agents are much more effective against the microscopic disease for many reasons, as they no longer face the hypoxic and metabolic changes associated with gross tumor deposits, providing much greater access to target tissues and improving T-cell functionality.Going forward, we must rationally combine radiation with other stroma-modifying agents, such as colony-stimulating factor 1 receptor, indoleamine 2, 3-dioxygenase 1, and TGF-β inhibitors, to further exploit these advantages. XRT already provides substantial benefits to patients with localized or oligometastatic disease. Combining XRT with immunotherapy will potentially benefits to patients with more advanced metastatic disease and continue to improve survival.All authors contributed to the writing of the manuscript. HM and RR compiled the first draft of the manuscript in preparation for submission. All authors contributed to revisions and subsequent edits.JW and JC have received research grants from Bristol-Myers Squibb. JW has also received grants from Varian Medical Systems and OncoResponse, and he is a co-founder of Healios, MolecularMatch, and OncoResponse. In addition, JW is on the scientific advisory boards for RefleXion Medical and Checkmate Pharmaceuticals and receives laboratory research support from Varian Medical Systems, Incyte, Calithera, and Checkmate Pharmaceuticals. JC is a shareholder of Global Oncology One. 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.


Numerous individual differences, models, and measures have been associated with the ‘emotional intelligence’ (EI) label. This paper discusses one of the most pervasive problems regarding EI-related individual differences, namely, the lack of a meaningful theoretical framework. First, drawing upon existing theoretical frameworks, we argue that EI-related characteristics can be considered constituents of existing models of cognitive ability (ability EI), personality (trait EI), and emotion regulation (EI competencies). Second, having differentiated between these perspectives , we draw upon existing theory and research to build the Integrated Model of Affect-related Individual Differences (IMAID), which provides an initial mechanistic representation that explains how the different EI-related constructs are likely to interrelate and coalesce to influence affective outcomes. In essence, the IMAID is an integrated mediation model in which emotion regulation mediates the effects of ability EI and affect-related personality traits upon outcomes. Viewing EI-related constructs as interrelated extensions of well-established individual difference frameworks clarifies some pervasive misconceptions regarding EI-related characteristics and provides scholars and practitioners with a clear and useful theoretical framework ripe for exploration. We conclude by using the IMAID to suggest a theoretically driven agenda for future research. Despite this popularity, numerous concerns regarding the theoretical nature of EI-related constructs remain. Taken literally, EI should be a combination of emotion and intelligence. Emotions are considered affective episodes with a perceptual or intellectual component  that hold the property of intentionality , facilitation (using emotions to aid performance), understanding (comprehending how emotions arise and develop), and management (regulating one’s own or others’ emotions) of emotions  manage emotions appear to exist and fit within a broader cognitive ability framework . AbilityThe second perspective on EI was pioneered by Petrides and colleagues and is termed ‘trait EI.’ The definition of trait EI has evolved over time, from a construct that represents “behavioral dispositions and self-perceived abilities” , p. 426,Personality refers to the relatively stable traits that influence a person’s typical pattern of thinking, feeling, and behaving . Given tThe most popular measure of trait EI, the TEIQue , has a gHowever, later research demonstrated substantial overlap between existing personality measures and trait EI measures , suggesting that trait EI was not that new or that major . Indeed,Despite the substantial overlap between trait EI models and the Big Five, So, trait EI measures capture a number of affect-related or affect-laden personality traits that span the whole spectrum of personality . Having measures that provide a “comprehensive representation of the affective aspects of personality” , p. 336 In sum, whilst trait EI research is not as clear-cut as ability EI research, we can draw several important conclusions, namely that trait EI is distinct from ability EI and that trait EI is, in essence, a collection of affect-related personality traits. In order to make this overlap and theoretical perspective explicit, from this point, we refer to this perspective without using the term ‘intelligence.’ Instead, we refer to this perspective as ‘affect-related personality.’ Using a unique label was not a lightly taken decision because whenever novel terminologies are introduced the risk of confusing matters increases. We considered the term ‘personality trait EI’ or retaining ‘trait EI.’ However, on reflection, we considered that it would be more confusing to use term ‘intelligence’ when referring to a collection of personality traits.The third broad grouping of EI-related constructs commonly discussed pertains to Emotional and Social Competencies e.g., . EI compThe varied nature of these models has led numerous authors to refer to them as ‘mixed models’ e.g., , with miAlthough we see no meaningful future for current EI competency models, we do see that the general aim of assessing emotional competence and integrating it within a broad framework of emotion-related individual differences is of value. As noted above, the constructs included within competency models span three domains: personality, broad performance outcomes, and emotion regulation. Within the delineation of emotion-related constructs we present, the personality component is captured under the ‘affect-related personality’  banner, so any personality constructs here would represent construct proliferation, and the broad performance outcomes cannot reasonably be considered affect-related individual differences. However, we would argue that the elements related to emotion regulation do have a place within the broad domain of affect-related individual differences. Thus, we would prefer to see such work move away from EI competencies and focus instead on emotion regulation, which represents ‘the use of strategic cognitions or behaviors to improve or worsen [one’s] own feelings and those of other people, in the pursuit of hedonic, relational and instrumental goals’ , p. 71. Given that EI competencies and emotion regulation are both concerned with the same phenomena and the clear overlap in core constructs , emotion regulation models focus on the specific strategies utilized  have typically been based on sub-optimal definitions or measurement tools e.g., . For exaIn contrast, we have used the broader individual differences literature as the basis for our classification of EI-related constructs and were not bound by existing measurement tools or deficient definitions . As a result, our classification addresses calls to provide clear boundaries, aligned with traditional individual differences theory, for each of the major EI-related constructs . Importawhat is predicted by EI-related constructs but how these constructs influence outcomes. A greater understanding of how EI-related constructs interact and the nature of the mechanisms by which they influence outcomes stands to inform future theory, measurement, and intervention design.The key principles of the Integrated Model of Affect-related Individual Differences are as follows. We propose that ability EI (a sub-factor of cognitive ability) and affect-related personality traits  drive the identification, selection, and successful implementation of various emotion regulation strategies. In turn, emotion regulation influences important outcomes. A visual representation of the Integrated Model of Affect-related Individual Differences is presented in Figure A few previous papers have proposed and/or partially tested models that integrate some EI-related constructs e.g., . HoweverOverall, the Integrated Model of Affect-related Individual Differences makes several key contributions to the literature. First, by tying each EI-related construct to existing models of individual differences it provides a clear, theoretically coherent, and parsimonious description of the three key perspectives. Second, the model posits EI-related constructs not as competitors but as complementary constructs that are meaningfully entwined and which coalesce to produce emotion-relevant behavior. Third, through this integration, the model provides a framework that can explain how individual differences in ability EI and affect related personality traits influence patterns of emotion regulation and subsequently socially important outcomes. In the following sections, we discuss integration further and review extant empirical evidence in support of the key pathways hypothesized. The Integrated Model of Affect-related Individual Differences is inherently causal but most EI research is cross-sectional and correlational in design. Because such designs do not model data in a manner that is appropriate for determining causal relationships , where aAs discussed above, ability EI satisfies a number of important criteria to be considered a cognitive ability . More spTrait EI represents a compound construct containing affect-related personality traits . Given tEmotion regulation refers to the strategies used to adapt emotions  experienced by the self and others in order to facilitate goal-attainment . If you The recency with which the identification, selection, and implementation phases were espoused means that no specific theory, model, or empirical evidence describes relationships between the two. However, there is mounting evidence and increasing theoretical rationale to support a reliable link between ability EI and the use of emotion regulation strategies e.g., . For exaExperimental research in the field is mostly convergent, with ability EI linked to effective mood maintenance and repair following mood induction via film clips . Other traits  might predispose individuals to select certain classes of emotion regulation  and to implement them using specific strategies . It is also likely that intrapersonal affect-related personality traits  will predict the regulation of one’s own emotions, whilst the interpersonal traits  will predict the regulation of others’ emotions.Above, we hypothesized that there might be meaningful relationships between the three primary EI abilities  and the identification, selection, and implementation phases of emotion regulation. It is also likely that certain affect-related personality traits will predispose individuals to think and act in specific ways within these phases. For example, certain traits  might predispose individuals to invest more effort in monitoring one’s own and others’ emotions  processes . The IntFinally, we argue that emotion regulation influences meaningful intrapersonal  and interpersonal  outcomes. There is a wealth of empirical evidence to support this claim c.f., , with emThe first key contribution of this article was to present a simple theoretical framework that clearly states what each EI-related construct is and is not. Specifically, that ability EI represents an extension to existing cognitive ability models, affect-related personality  represents a collection of affective personality traits, and interest in emotional competence should focus on emotion regulation. To some researching at the cutting-edge of EI, this might seem a relatively modest extension of the extant literature. However, our reading of the EI literature suggests that it is a much-needed clarification, that explicitly demonstrates that the myriad of EI-related constructs can be accommodated within well-established individual difference frameworks, and in doing so, provides a clear theoretical base and boundaries for each. Our framework negates the need for atheoretical terms such as ‘mixed EI,’ is falsifiable, is more descriptive and explanatory in nature than previously published classifications , and is less adversarial because it does not set the different perspectives as competitors. The second notable contribution from this paper, the Integrated Model of Affect-related Individual Differences, comes from adopting these three perspectives and in drawing the different EI-related constructs together in a complementary manner. This model provides an initial mechanistic representation that explains how the different EI-related constructs are likely to interrelate and coalesce to influence important emotion-relevant outcomes through the identification, selection, and implementation of emotion regulation strategies. Accordingly, the model also provides a solid platform for empirical exploration, theoretical refinement, measure development, and possibly practical application.Despite its promise, the Integrated Model of Affect-related Individual Differences is clearly exploratory, and needs systematic, rigorous, and detailed empirical scrutiny. For example, some of the pathways proposed  could be argued to represent competing explanations for the same empirical effect. Hopefully, future research will examine these competing pathways and provide evidence regarding if/when each pathway is most pertinent. Nevertheless, the evidence discussed strongly supports the major premise of the model, namely, that both ability EI and affect-related personality traits influence the selection and implementation of emotion regulation strategies . AccordiFirst, calls to completely abandon all EI research e.g.,  seem misand personality, and consider the interactions between these variables. Equally, studies which estimate direct effects between outcomes and ability EI or affect-related personality traits are likely to underestimate the relations due to the omission of emotion regulation as a mediator.Second, our review of research surrounding the Integrated Model of Affect-related Individual Differences suggests that piecemeal assessment of EI related constructs will give misleading findings. Future research interested in explaining emotion regulation or broader outcomes needs to incorporate measures of ability Third, the research reviewed and the hypotheses made in this paper suggest that focussing upon global ability EI, broad factors containing multiple affect-related personality traits, and/or broad emotion regulation measures is likely to hide important nuanced relationships. Accordingly, we suggest that future researchers adopt a more specific approach measuring theoretically relevant abilities, personality traits (or facets), and regulation strategies. This call echoes similar calls in other applied domains  that need to be addressed through future measure development. We would urge interested readers to see the thoughtful critiques and guidance offered by Regarding affect-related personality traits, there is an important need for further measure refinements. Our review of item level content combined with a number of empirical studies shows clear overlap between existing personality measures and personality trait EI measures. What we now need is a systematic study from the facet level that can identify which trait EI facets are unique and which are redundant duplications. In addition, it would be of interest to know which affect-related facets, if any, currently included within broad measures of personality  have been missed by specific measures . These two lines of research would allow for the identification of much more comprehensive list of affect-related personality facets see also , which wFifth, the clear delineation of constructs raises the issue of nomenclature. We noted at the outset of this paper that logically speaking any construct labeled EI should consist of both emotion and intelligence. Currently, only the ability EI perspective meets this criterion and thus we would recommend that the label ‘EI’ is reserved exclusively for this perspective. We are far from the first authors to make such recommendations e.g., , yet, deIn this review, we have outlined three theoretical perspectives on EI and proposed the theoretically driven Integrated Model of Affect-related Individual Differences as a stepping-stone toward building a greater understanding of EI-related individual differences and subsequent affective phenomena. This model posits that despite often being pitted against each other, the different perspectives are actually meaningfully entwined and coalesce to produce emotion-relevant behavior. We hope that our review and model will serve to guide future research and theoretical development. Although we should continue to be skeptical of EI, and actively criticize overblown claims based on atheoretical models and measures, we hope that this review demonstrates that all is not lost with regards to EI-related constructs.Both authors contributed equally to the work and made a substantial, direct and intellectual contribution to the work. Both authors approved this manuscript 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.


Reliable estimates of the current and future disease burden of antimicrobial resistance (AMR) are essential to combat the global drug-resistant infection crisis , 2. Yet,Major, recent efforts to estimate AMR burden include the Global Burden of Disease (GBD) 2016 study , the RevMore accurately measuring AMR burden requires a fully described scientific measurement framework . The gloThe accuracy of AMR burden estimates depends on the quality and availability of input data . PresentThe development of GLASS is a step in the right direction, but it is at an early stage . GLASS lNecessarily stringent privacy concerns further limit data sharing. Linked data that matches clinical bacteria to patient mortality outcomes, patient information and comorbid conditions, are essential to measure the excess mortality risk of resistant infections – and they are virtually non-existent. In the absence of comprehensive and diverse datasets from various regions and income-bases, GBD estimates rely heavily on modeling, which increases uncertainty. This is particularly concerning in low-income regions, where surveillance data is almost non-existent, access to essential antimicrobials is limited, and substandard antibiotics are widely available , 3.High-income nations face their own challenges. An evaluation of Australia’s AMR response highlighted the need for a more robust animal surveillance system, and better One Health integration . AlthougDespite its shortcomings, Australia’s model of integrating AMR surveillance into system-wide risk-mitigation strategies may offer valuable lessons. The national Antimicrobial Use and Resistance in Australia network has identified alarming trends in resistance and antimicrobial use (AMU) . SurveilAMU surveillance initiatives in Australian tertiary and aged care facilities have facilitated the inclusion of antimicrobial stewardship standards within national medication safety and quality frameworks . OveruseBetter surveillance infrastructure requires ongoing funding and support from key donors and policymakers. The UK’s £265 million Fleming Fund for surveillance initiatives in low and middle-income countries is a welcome display of global leadership . LikewisRegional capacity-building must be part of a broad, coordinated international response. Governing bodies must assist countries to build AMR surveillance systems, while supporting the development and funding of national action plans in fragile states – currently, only one-fifth of national action plans are properly funded . To effeWithout a more concerted and collaborative global response, the disastrous forecast made in the Review on AMR of 10 million annual deaths from resistant infections by 2050 might eventuate. Initiatives that enhance monitoring capacity for resistant infections, and bolster the accuracy of AMR burden estimates, will provide essential information to guide policy and prevent a calamity of this scale.


From immunology to neuroscience, interactions between the microbiome and host are increasingly appreciated as potent drivers of health and disease. Epidemiological studies previously identified compelling correlations between perinatal microbiome insults and neurobehavioral outcomes, the mechanistic details of which are just beginning to take shape thanks to germ-free and antibiotics-based animal models. This review summarizes parallel developments from clinical and preclinical research that suggest neuroactive roles for gut bacteria and their metabolites. We also examine the nascent field of microbiome-microglia crosstalk research, which includes pharmacological and genetic strategies to inform functional capabilities of microglia in response to microbial programming. Finally, we address an emerging hypothesis behind neurodevelopmental disorders, which implicates microbiome dysbiosis in the atypical programming of neuroimmune cells, namely microglia. The various microbial ecosystems (“microbiota”) and their component genes (“microbiomes”) existing on and within the host body are increasingly recognized as significant contributors to a functional host immune system. Commensal microbiota consist of bacteria, fungi, viruses, and other microorganisms that make up distinct microbial ecologies of various host systems, such as the gastrointestinal tract, skin, mouth, and genitourinary tract . Within Given the wealth of evidence depicting microbiota as a driver of early peripheral immunity, an important follow-up question remains as to whether the microbiome may also drive immune development in the brain. The neuroimmune system, primarily comprised of glial cells, is distinct from the peripheral immune system in part due to anatomical barriers and developmental sequence. Microglia, the resident macrophage-like cells in the brain, play an especially critical role in neurodevelopment through their numerous functions in patterning and wiring of the maturing brain. Accordingly, recent studies on neurodevelopmental disorders, such as autism spectrum disorders (ASD), Rett syndrome, and schizophrenia, whose complex pathologies include neuronal and synaptic dysfunction, suggest improper microglial activity as a contributor to these disorders' neurobiological and behavioral outcomes –8. InterA growing number of studies pointing to distinct gut microbiome profiles among psychiatric patient populations allude to microbiota as an important corollary of disease pathology –14. The Disruptions to gut microbiota are also implicated in aberrant neurodevelopmental outcomes –20. HereWhile the gut microbiome is constantly evolving in response to dietary and environmental changes, longitudinal sampling of infant stool during the first 3 years of life demonstrated resiliency in its ability to return to original homeostatic conditions following short periods of antibiotic usage . AdditioNonetheless, large-scale epidemiological studies highlight compelling correlations between certain microbiome-modifying pregnancy events and subsequent diagnoses of neurodevelopmental disorders in children. Maternal infection and antibiotic use during pregnancy are often highlighted as potential risk factors for ASD –30. Of tPrevotella, Coprococcus, and Veillonellaceae compared to non-autistic children  resulted in an anti-inflammatory effect against LPS, but cultured murine N9 microglial cells elicited a pro-inflammatory response , which result from bacterial fermentation of complex carbohydrates and proteins in the colon. SCFAs refer to fatty acids consisting of one to six carbon atoms, but predominantly consist of acetic acid, butyric acid, and propionic acid in the mammalian gut . Of the response . Propionresponse .While SCFAs' best known functions are to serve as fuel for colonocytes and regulators of host metabolism, recent investigations revealed that SCFAs directly interact with the nervous system via G protein-coupled receptors, GPR41 and GPR43  , 66. PreMicroglia are primarily recognized as the resident macrophage-like cells in the brain that serve as first-responders to pathogens, apoptotic cells, and debris with the ability to secrete soluble factors that modulate inflammatory responses. Recent studies paint a more complex portrayal of these highly-motile glial cells, which have since been found ubiquitously throughout the central nervous system, including the spinal cord, with region-specific phenotypes –75. MicrCurrent hypotheses surrounding the underlying etiology of neurodevelopmental disorders focus on microglia's dual immune and trophic capacities. Neuroimaging studies of ASD patients showed hypermyelination in both left and right medial frontal cortex, hypomyelination of the left temporo-parietal junction, and decreased local and long-range functional connectivity , 80. TheIn the gastrointestinal tract, microbiota and associated metabolites have been shown to elicit both pro- and anti-inflammatory peripheral immune cell responses and to control cellular proliferation and epithelial barrier integrity , 87–89. The microbiome is also implicated in the neuroinflammation hypothesis underlying the ontogeny of neurodevelopmental disorders. With respect to ASD, anatomical evidence of unusual and sustained brain overgrowth in autistic children first alluded to improper cellular responses wherein the hyperproliferative stage of early neurodevelopment continues unchecked and unresolved , 92. ThuFfar2−/− mice that do not express the receptor gene for SCFA-binding also resembled a GF phenotype, which could be rescued by oral feeding of SCFAs in the former group but not the latter  mice, GF microglia had marked differences in mRNA expression profiles, including a reduction in genes associated with cell activation and immune signal transduction . While ne latter . Thus, bThe numerous microbiome-related studies across disparate scientific disciplines agree on a prevailing hypothesis that the microbiome is capable of communicating via immune, metabolic, and endocrine signals to modulate brain health and disease. The current evidence base from both human and animal studies to support this hypothesis, however, are largely correlational without definitive understanding of cause. The mechanisms by which the microbiome asserts microglial changes during neurodevelopment are also not yet known, although transgenic mice and single cell sequencing methods continue to inform molecular processes that are likely to be involved. At present, the majority of microbiome-related studies are conducted in adult mice and assume a linear direction of influence from microbiota to the host. In recognition of the microbiome's role in neurodevelopmental processes, future studies should include appropriate experimental models that address the maternal gut-fetal gut axis as well as the possibility of multidirectional signaling pathways.YL, VR-S, IA, and MT contributed to the manuscript preparation and writing. YL and VR-S generated figures. IA and MT conducted final editing and review of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.