Diet-based xanthophylls (zeaxanthin and lutein) are conditionally essential polar carotenoids preferentially accreted in high concentrations (1 mM) to the central retina, where they have the capacity to impart unique physiologically significant biophysical biochemical properties implicated in cell function, rescue, and survival. Macular xanthophylls interact with membrane-bound proteins and lipids to absorb/attenuate light energy, modulate oxidative stress and redox balance, and influence signal transduction cascades implicated in the pathophysiology of age-related macular degeneration. There is exclusive transport, sequestration, and appreciable bioamplification of macular xanthophylls from the circulating carotenoid pool to the retina and within the retina to regions required for high-resolution sensory processing. The distribution of diet-based macular xanthophylls and the lutein metabolite meso-zeaxanthin varies considerably by retinal eccentricity. Zeaxanthin concentrations are 2.5-fold higher than lutein in the cone-dense central fovea. This is an ~20-fold increase in the molar ratio relative to eccentric retinal regions with biochemically detectable macular xanthophylls. In this review, we discuss how the differences in the specific properties of lutein and zeaxanthin could help explain the preferential accumulation of zeaxanthin in the most vulnerable region of the macula. Humans cannot synthesize carotenoids de novo and must acquire them through their diet. The most abundant carotenoids in human serum are three nonpolar carotenoids  and three polar carotenoids  ,2. The lSince primates cannot biosynthesize lutein or zeaxanthin ,13, theyFor the purpose of this review, we highlight the fact that the distribution of specific macular xanthophylls varies with retinal eccentricity. Zeaxanthin and meso-zeaxanthin dominate in the fovea with concentrations declining more rapidly than those of lutein as distance from the fovea increases ,39. A 1°Not only is the orientation in the lipid membrane similar for lutein and zeaxanthin molecules  of its release into an aqueous environment is probably higher than that of β-carotene and lycopene. Zeaxanthin must be released from the food matrix, which is an easier process with regard to the location of this pigment in the chromoplast of fruits rather than in the chloroplast of the leaves of green vegetables. In addition to its intracellular location, other factors strongly affect the bioavailability of zeaxanthin ,87,88,89In nature, zeaxanthin exists in both free and esterified forms. Free zeaxanthin can be found in egg yolks , corn, aThese studies suggest that hydrolysis of the esterified form of zeaxanthin in the intestinal lumen is a highly efficient process.Similar to other carotenoids in plants, zeaxanthin exists predominantly in the all-trans configuration, which is more stable thermodynamically as compared with the cis configuration. However, light  and therAnother physical factor affecting the bioavailability of zeaxanthin is its aggregation. In aqueous systems, zeaxanthin may form two aggregate arrangements: J-zeaxanthin (head-to-tail aggregates with characteristic red-shifted absorption) and H-zeaxanthin (card-pack aggregates with characteristic blue-shifted absorption). Hempel et al. reported  that theThe next critical factor that should be considered as affecting the bioavailability of zeaxanthin is the food matrix in which the pigment molecules are incorporated. The release zeaxanthin from the food matrix is an easier process for simple food matrices, such as oil matrices, than it is for complex plant systems. Indeed, it has been shown that the xanthophylls were highly bioaccessible from fruits, ranging from 50 to 100%, compared with dark green vegetables, ranging from 19 to 38% .The last factor affecting the bioavailability of zeaxanthin is the co-presence of different compounds in the food matrix. Several studies reported that the co-presence of the other carotenoids may affect the bioavailability of zeaxanthin. A daily oral dose (10 mg) of lutein provided a fourfold increase in lutein serum concentration as well as an increase in the amount of zeaxanthin . In seveThe release of zeaxanthin from the food matrix starts in the stomach by the action of gastric acids and digestive enzymes. Next, molecules of zeaxanthin solubilized in lipid emulsion particles are transported from the stomach to the duodenum. Studies on the behavior of zeaxanthin in biological emulsion have shown that this dipolar molecule resides on the surface of oil droplets, together with proteins and phospholipids . ConversD ~ 0.6 μM) are most likely to drive the process of selective accumulation of xanthophylls into the macula [D ~ 1–2 μM). Macular xanthophylls were delivered in LDL and HDL complexes at physiologic concentrations to characterize distinct aspects of uptake for lutein, zeaxanthin and meso-zeaxanthin using a SRB receptor class over-expressing model cell system (HEK-293T) that does not endogenously express these proteins. LDL-bound lutein uptake was enhanced and mediated by SR-B1 and CD36 receptors. Zeaxanthin and meso-zeaxanthin delivered by HDL was taken up in appreciable amounts by cells overexpressing any of the three SRB proteins. SR-B2 over-expressing cells transported zeaxanthin at concentrations 10-fold to those for lutein. However, non-transfected (SRB-free) control cells took up higher amounts of zeaxanthin and meso-zeaxanthin than lutein, raising the possibility that selective accretion of zeaxanthins by these cells that may be SRB independent.The uptake and transport of macular pigment to the retina is considered selective because of the approximately 600 carotenoids identified in nature, 50 in the human diet, and 20 in human serum; only two forms of dietary xanthophylls, lutein and zeaxanthin, are present in the retina. Meso-zeaxanthin is the third major macular xanthophyll (reviewed in ). This se macula . These aIt is not clear whether macular xanthophylls are incorporated directly into the lipid-bilayer portion of retina membranes or are bound by membrane-associated xanthophyll-binding proteins. Three of the xanthophyll-binding proteins (xanthophyll transporters) have already been identified and characterized by Bernstein’s group. These are lutein-specific steroidogenic acute regulatory domain protein (StARD3) ,125, zeaThe zeaxanthin molecule is completely symmetrical compared with the asymmetrical lutein . StructuThe center of the fovea ,128 contWhy meso-zeaxanthin is produced in the retina from lutein and so efficiently replaces lutein in the central part of the fovea is still an unexplained phenomenon. To a certain degree, the high presence of meso-zeaxanthin in the foveal region of primates can be explained by the primates’ common diet, which is low in zeaxanthin and rich in lutein (precursor of meso-zeaxanthin). This points out the need for the presence of this particular macular xanthophyll in the central macula. The concentration peak of meso-zeaxanthin in the central fovea correlates with the peak of the cones; one can speculate that meso-zeaxanthin is associated with cones. When plotted as a function of eccentricity, the zeaxanthin (including meso-zeaxanthin)-to-lutein ratio follows the same pattern as the cone-to-rod ratio; as such, it has been proposed that these two xanthophylls are associated with different types of photoreceptors, i.e., rods versus cones . AnotherThe spatial distribution profile of macular pigment is measured by several physical techniques. Methods for macular pigment imaging include autofluorescence imaging, fundus reflection methods, resonance Raman spectroscopy, and fluorescence lifetime imaging ophthalmoscopy. Using the fundus reflectometry technique, MPOD can be determined by analysis of the reflectance of light from the foveal and perifoveal regions and the spectral contribution of the absorbance of xanthophyll molecules. The autofluorescence method measures the intensity of the autofluorescence of lipofuscin in the presence of excitation with two wavelengths, one fully and the other minimally absorbed by xanthophylls. The Raman spectroscopy method uses excitation of the carotenoids in their absorption band, which occur in the blue/green wavelength region, and detects signals from the stretch vibration of the carbon double bonds in part of the polyene chain of the carotenoid molecule. The above-motioned fluorescence lifetime imaging ophthalmoscopy method measures the lifetimes of retinal fluorophores, including the short lifetime of macular xanthophylls ,130. TheIn contrast with the spatial distribution of xanthophylls within the retina, information about the exact subcellular location of yellow pigments in different retinal layers is limited. An initial study of the distribution of xanthophylls in the human retina reported a similar relationship between the zeaxanthin-to-lutein molar ratio and cone-to-rod ratio with eccentricity , suggestZeaxanthin may quench singlet oxygen by a physical mechanism in which zeaxanthin can participate in multiple quenching cycles without degradation. During that physical process, the excess energy from singlet oxygen is transformed to carotenoid and into its excited triplet state. Next, the carotenoid-excited triplet state is deactivated through thermal decay. Retaining an intact structure in that physical process ensures that the zeaxanthin molecule can be reused, thus increasing the efficiency of the quenching process. The efficiency of physical quenching of singlet oxygen by carotenoids was reported to be greater than that of vitamin E  and is dIn plants, the excited triplet state of chlorophyll (photosensitizer) is efficiently quenched by the carotenoid molecule, leading to heat dissipation and preventing the formation of singlet oxygen. It should be mentioned that the quenching of the excited triplet state of photosensitizers by xanthophylls requires a close distance approach of these two molecules. Triplet chlorophylls in the light-harvesting complexes are promptly quenched by lutein  and zeaxBecause of the presence of potent photosensitizers in the retina, much oxidation damage can be caused by short-wavelength light. Photosensitizers that can be activated by blue light produce singlet oxygen, which may be a risk factor for harmful oxidation, leading to AMD . Both luThe chemical quenching of singlet oxygen by carotenoids involves a chemical reaction between oxygen and xanthophyll molecules and, in contrast with physical quenching, xanthophylls are consumed and destroyed in this chemical process. The chemical deactivation of singlet oxygen by carotenoids has been reported as a minor reaction as compared with physical quenching ,150,151.Another sacrificing mechanism that occurs during protection of the retina is radical scavenging by lipid-soluble molecules of zeaxanthin. However, this action also causes zeaxanthin to lose its intact structure. It has been shown that zeaxanthin scavenged the hydroxyl radical more effectively than lutein , and theAMD is a chronic, complex degenerative disease that affects the macular region and may result in a loss of central vision. Oxidative stress is implicated in the pathogenesis and pathophysiology of AMD. The Age-Related Eye Disease Study 2 (AREDS2)  was a phIn the AREDS2 formulation, the dominant carotenoid is lutein. Similarly, most of the vision supplements commercially available primarily contain high amounts of lutein and low amounts of or no zeaxanthin. This decision was made based on the distribution of zeaxanthin and lutein in foods. For supplement production, zeaxanthin can be obtained from microbial sources ,171,172 The content of macular xanthophylls in the retina cannot be measured directly. However, the amount of retina carotenoids is related to MPOD. MPOD is the highest in the central fovea and decreases rapidly with increasing eccentricity . It has In MacTel type 2, macular xanthophylls have characteristic distribution with the depletion of xanthophylls from the central part of the fovea and their accumulation in the fovea surrounding ring. Unfortunately, in patients diagnosed with MacTel type 2, the lutein/zeaxanthin supplementation did not increase the xanthophyll content in the central fovea, the area where the macular xanthophylls were previously absent ,189.The biophysical and biochemical properties of macular xanthophylls support inferences on their physiologic significance. Membranes of photoreceptors containing polyunsaturated fatty acids susceptible to photo-oxidation exist in the retina at high oxygen tension and under chronic light exposure. Several vitamins with antioxidant properties and other antioxidants are implicated as protective agents in the retina, and these include vitamin E ,191,192,Several factors explain how zeaxanthin (and meso-zeaxanthin) can be concentrated to a greater extent than lutein within the fovea. First, the presence of two functional ionone hydroxyl groups at the ends of this molecule determines its transmembrane orientation, which enhances the stability of zeaxanthin in the lipid bilayer membranes ,70,203. As mentioned in Based upon our review of the evidence, it is our opinion that, although some physical and chemical properties of lutein and zeaxanthin are similar, the distinct properties of zeaxanthin offer an advantage for modulating processes implicit in the pathogenesis of AMD. These differences are not vast, but they are significant. Major differences include greater chemical stability , more ef


Cells can communicate through special “messages in the bottle”, which are recorded in the bloodstream inside vesicles, namely exosomes. The exosomes are nanovesicles of 30–100 nm in diameter that carry functionally active biological material, such as proteins, messanger RNA (mRNAs), and micro RNA (miRNAs). Therefore, they are able to transfer specific signals from a parental cell of origin to the surrounding cells in the microenvironment and to distant organs through the circulatory and lymphatic stream. More and more interest is rising for the pathological role of exosomes produced by cancer cells and for their potential use in tumor monitoring and patient follow up. In particular, the exosomes could be an appropriate index of proliferation and cancer cell communication for monitoring the minimal residual disease, which cannot be easily detectable by common diagnostic and monitoring techniques. The lack of unequivocal markers for tumor-derived exosomes calls for new strategies for exosomes profile characterization aimed at the adoption of exosomes as an official tumor biomarker for tumor progression monitoring. In the common scenario, the cell is seen as a closed entity protected by its plasma membrane. Instead, the physiological and pathological functions in an organism depend on strong cellular connections. Cell-cell communication occurs among close and distant cells, involving different chemical signals, such as hormones, cytokines, signal molecules and proteins, and miRNAs, which are secreted by specific cell types. These signals exploit the circulatory stream and the extracellular spaces reaching their final destination by binding to specific receptors on the target cell surface or being internalized, activating a signaling cascade and producing several downstream effects.The ensemble of circulating components responsible for cell-cell communication is included in the concept of “circulome”. In pathological conditions, the circulome components reflect the course of a certain disease. The “tumor circulome” is constituted of circulating components derived from tumor tissues that includes circulating tumor cells, tumor derived nucleic acids, tumor-educated platelets, and a large subset of extracellular vesicles . In cancTumors are biological entities that are constantly changing. The tumor dynamism is associated with the evolution of a delicate “tumor ecosystem”, which is composed by several interacting players that move from the primary cancer site up to long distances, where they trigger the formation of tumor niches, thus sustaining the progression of cancer metastasis and the relative tumor microenvironment (TME). The diagnostic techniques that are commonly used in oncology allow tumor diagnosis  and assessment of disease progression and therapy response; however, they are inevitably invasive and risky for the patient . Thus, oDespite the standard techniques, such as Positron Emission Tomography - Computed Tomography (PET-TC) imaging and tissue biopsy, represent the gold standard in cancer diagnosis, the analysis of tumor circulome by liquid biopsy is a promising tool for early detection and follow up of cancer patients. However, there are some limitations in the choice of the circulome components as markers of tumor diagnosis, monitoring, and prognosis, as summarized in As far as the best candidate for diagnosis, it is not easy to demonstrate the reliable diagnostic utility of each circulome component. For example, Germano et al. assessed the difference in the use of Circulating Tumor Cells (CTCs) and circulating tumor DNA (ctDNA) in Liquid Biopsy of Colorectal cancer (CRC) patients . CTCs weWith regard to the use of all circulome components in the liquid biopsy approach, it must be considered that the presence of circulome components does not represent an unequivocal sign of tumor presence, and tissue biopsy and radio-imaging techniques are still required for the final diagnosis .After the outstanding discovery of micro-vesicles as exfoliation of the ectoenzyme membrane by Eberhard G. Trams and colleagues in 1981 [2+ increase are commonly recognized to be required for the exosomes release [Classified as small E.V. of endosomal origin, the exosomes are 30–100 nm diameter vesicles, which are physiologically produced by all cell types and secreted through an exocytosis process in blood, urine, cerebrospinal fluid, other body fluids, and the medium of in vitro cell cultures. Even though the mechanisms of synthesis and secretion of exosomes have not been completely clarified, the crucial roles of the Endosomal Sorting Complex Required for Transport (ESCRT) and the intracellular Ca release ,12, whil release . Further release .The main question is how the exosomes recognize the target cells. To date, this issue has not yet been clarified, and several studies are focusing on the preferential internalization of exosomes in some cell types instead of others. Some reports identified specific molecules on the exosomal membrane and the membrane of target cells that guide the membrane-membrane interaction, resulting in the fusion of the membranes followed by the pouring of the exosomal cargo inside the target cell . In partA large variety of protocols and a number of commercial kits are currently available for isolating exosomes and analyzing the exosome cargo . ExosomeSeveral reports support the pivotal role of exosomes in tumorigenesis, mediating the immune response, antigen presentation, cell migration, cell differentiation, tumor survival, tumor invasion, and angiogenesis . It was In this context, the components of innate immunity play a particular role, such as polarized M2 macrophages, capable of releasing pro-angiogenetic factors contributing to the self-renewal of the tumor and its relapse . Under hExosomes are capable of transferring metastatic potential to surrounding cells through the transfer of genetic information and/or pro-metastatic proteins . ExosomeInterestingly, exosomes also induce drug-resistance in tumor cells due to their cargo in terms of multi-drug resistant protein release, tumor immune escape mechanisms, changes in apoptotic homeostasis, and tumor stroma interaction .It has been shown that the treatment of a weak melanoma cell line (F1) with exosomes derived from the highly aggressive melanoma B16 cell line and with strong metastatic power, resulted in the expression of the metastatic marker met 72 in the F1 cell line, differently from untreated cells, showing that exosome treatment increased aggression of the weaker cell line . In patiProteomic analysis of metastatic melanoma derived exosomes identified proteins involved in cell motility, angiogenesis, and immune response. In particular, proteins involved in angiogenesis, such as EGFR, PTK2/FAK1, EPHB2, and SRC, have been found in metastatic melanoma cells derived exosomes, while proteins involved in the regulation of apoptosis and cell motility are represented in exosomes derived other melanoma weaker cell line, characterized by minor invasion capacity. Constantly, exosomes secreted by metastatic cell lines are able to increase the migratory capacity of less aggressive cells .Treatment of some cancers requires therapies with immune checkpoint inhibitors, such as PD-L1, targeting antibodies . ExosomeThe Avβ3 integrin is part of the protein cargo of exosomes derived from prostate cancer (PoC) cell lines and has also been found in the blood exosomes of prostate cancer (PCa) patients. Its levels are higher in patients’ tumor-derived exosomes than in healthy donors . Plasma CD151, CD171, and tetraspanin 8 were highly expressed in Non-Small Cells Lung Cancer (NSCLC) patients exosomes with respect to healthy donors, representing a powerful biomarker of tumor burden . CD63 anReflecting genetic and nongenetic cancer cell components, exosomes could contain miRNA with several regulation functions . miRNAs Due to their ability to reach target cells located in far districts, the exosomes play an important role in the context of the hematopoietic system as they promote the crosstalk of different cell populations of bone marrow with the peripheral tissue. In order to support tumor survival and progression, hematological malignancies are characterized by the production and secretion of exosomes. Leukemia- or multiple myeloma-derived exosomes are involved in different processes and mechanisms, which promote drug-resistance, stimulation of tumor microenvironment, inhibition of the immune system, and re-modeling of the bone marrow ,59.In the last few decades, exosomes have generated great interest as a new powerful tool for the rapid and early prognosis of lymphoproliferative diseases. In 2014, Hong and colleagues revealed high plasma levels of exosomes  in acute myeloid leukemia (AML) patients compared to healthy controls . DespiteCaivano et al.  also desWell known is the role of monocytes, macrophages, and innate immunity components in the progression of neoplasms, mediated by the action of cytokines and interleukins . The CLLShifting the focus from CLL to MM disease, MM-derived exosomes showed a strong component in miRNAs. It is well known that circulating miRNAs, whether present or absent in exosomes, have a pivotal role in tumorigenesis. In particular, let-7b and miR-18a were found in exosomes derived from MM patients and acted as independent predictors of survival and progression-free survival . In 2019The role of exosomes was also analyzed in mantle cell lymphoma (MCL), which requires new methods for monitoring due to the rarity and poor prognosis of this disease. A study by Hazan-Halevy et al. demonstrated the major presence of MCL exosomes in patients with high white bloos cells (WBC) count . MoreoveThe invasive nature of traditional biopsy is an unfriendly procedure and can lead to a misleading cancer profiling and poor monitoring of tumor progression due to the genetic and phenotypic intra-tumor heterogeneity ,82,83. RA clear evidence is that the presence of a larger quantity of exosomes detected in cancer patients compared to healthy individuals represents a clear sign of tumor presence and progression. However, this is not enough to clinically validate the exosomes as excellent biomarkers for tumor monitoring since we need to identify specific markers of exosomal subtypes and to characterize their peculiar function and/or group of functions relatives to the tumor progression.Efforts in this direction have been made by researchers worldwide applying different approaches and opening up new avenues in devising liquid biopsy options for effective early detection of TDEs shed into the body fluids by tumor cells. A basic approach to unravel the correlation between cancer progression and exosomes is represented by the evaluation of differential expression of common exosomal surface proteins in pathological conditions. In this context, Yuh-Ying Yeh and co-workers have identified the tetraspanin, CD9, CD63, and CD37 as abundantly expressed markers in tumor exosomes of CLL patients by flow analysis and immunoblotting, in contrast to the modest expression of CD41, CD56, and CD3 .By reflecting the proteomic and lipidomic profile of their parental cells, exosomes can be validated by mass spectrometry for the presence of tumor markers overexpressed by their tumor of origin. In 2017, Alicia Llorente and colleagues performed a high-throughput mass spectrometry quantitative analysis of urinary exosomes of prostate cancer patients and healthy controls and compared them with those produced by prostate cancer cell lines . They prAn additional approach for personalized medicine is the development of antibodies and peptides, recognizing biomarkers that are unequivocally expressed by tumor-derived exosomes. In the context of B-cells malignancies, a key role is played by the immunoglobulin B-cell receptor (IgBCR). The IgBCR is expressed on the surface of the B-cell membrane surface during the B-cell development, and it is responsible for antigen-binding and specific immune response. Several reports demonstrated the role of IgBCR in the pathogenesis and progression of B-cells malignancies, such as CLL  and MM , throughThe exosomes biology and function strongly indicate their potential applications for non-invasive tumor diagnosis and monitoring. Based on the experimental results on TDE-associated with cancer research, we need further insight into the molecular nature of exosomes and the distribution of some categories of exosomes containing supportive tumor molecules. The final goal is to detect exosomes by using biomarkers matching the most representative signatures of the parental tumor cells. Recent progress in exosomes isolation by nanotechnology techniques represent the cornerstones in the device of cost-effective exosome-based diagnostics that will hopefully allow a full exploration of the potential application of TDEs in the clinical practice for cancer diagnosis and beyond.


This paper establishes a non-equilibrium thermodynamic constitutive model that can predict the undrained shear behavior of saturated sand. Starting from the basic laws of thermodynamics, the model does not require the classical concepts in elasto-plastic models, such as the yield function, the flow rule, and the hardening rule. It is also different from the existing thermodynamic constitutive models in soil mechanics literatures. The model does not use a complex nonlinear elastic potential as usually and introduces a coupling energy dissipative mechanism between the viscosity and elasticity relaxation, which is essential in granular materials. Then this model was used to simulate the undrained shear test of Toyoura sand. The model can predict the critical state, dilatancy-contraction and hardening-softening characteristics of sand during undrained triaxial shearing. In the deformation process, granular materials show not only the characteristics of elastic solids, such as a certain degree of shear stiffness or the ability to propagating shear waves, but also the rheological properties of viscous fluids, such as the liquefaction and steady shear flow . PhysicaResearchers have carried out several experimental studies under various stress conditions of sands, which shows the granular material exhibits two unusual physical properties near the phase transition point. One is the so called significantly increased apparent friction angle problem. Sture et al. (1998)  performeThe solid-liquid-like nature of the granular material near the “zero effective stress” state is similar to the elusive nature of liquefaction and large post-liquefaction deformation called the “flowing sand” in soil mechanics and geotechnical engineering. When saturated sand is under earthquake or other undrained shear process, the effective stress decreases with the pore water pressure rises, the sand will show more liquid-like mechanical properties. “Flowing sand” can cause serious damage to lifeline infrastructures embedded in it, such as power and water transmission lines, tunnels, and bridge piles. Therefore, in the study of geotechnical earthquake engineering, the research about liquefaction of saturated sand and post-liquefaction deformation has been conducted for more than half a century. It has long been the core research content of soil mechanics and geotechnical earthquake engineering. In Japan, even based on the above studies, the Japanese Seismic Design Specifications for Highway Bridges (1966) regulates in simple rule of thumb the horizontal thrust of the pile foundation caused by the “flowing sand” after liquefaction. To establish a continuous constitutive model with better prediction for sand liquefaction is the consistent voice of the scientific and engineering community for many years.This paper abandons the classical solid mechanics or soil mechanics approach, and does not follow the thermodynamic method proposed by Houlsby and Puzrin (2000) in geo-mechanics ,7, but tIn the previous research, the Tsinghua research group has established a thermo-hydro-mechanical coupling thermodynamic constitutive model  for clays ,10,11, wThe non-equilibrium thermodynamics takes the local equilibrium as the core assumption, and regards the thermodynamic state of an isolated system as the statistical sum of the micro-elements in thermal equilibrium. The thermodynamic state of elements can be completely and uniquely described by a set of independent state variables, and the entropy is introduced to describe the thermal motion intensity of the system. The system always evolves in the direction of “entropy increasing”, and the dynamic evolution of the system can be treated by extreme value analysis of entropy.As a kind of complex material, granular material has a unique mesoscale compared with conventional materials . Macroscopic continuous theory such as classical fluid dynamics is no longer applicable at this scale. Starting from the framework of non-equilibrium thermodynamics, Jiang and Liu  introducThis paper first introduces the non-equilibrium thermodynamic dissipation mechanisms and constitutive equations derived for sands accounting for the coupling mitigation coefficient between the viscosity and the elastic relaxation in the thermodynamic dissipation mechanism. Based on this modified TTS model, the critical state , and the dilatancy-contraction and hardening-softening properties before the critical state were qualitatively analyzed. Then, the undrained triaxial experiments of saturated Toyoura sand under medium and high consolidation pressure with different void ratios are simulated ,13. ThisNon-equilibrium thermodynamic theory describes the mechanical characteristics of granular materials compared to general solid and liquid materials by selecting suitable independent state variables and specifying the dissipative mechanisms. These new theoretical features are summarized as so-called transient hyper-elasticity and granular fluctuation in granular materials.The transient elasticity of the sand indicates that once the particle is deflected by the external disturbance, it deviates from the thermodynamic equilibrium state, generates inelastic deformation and is accompanied by an energy dissipating process. The particles will reach a new equilibrium state after the disturbance is over. That is, the granular material does not have a pure elastic stage as described in the classical elasto-plastic theory, but elastic energy is continuously dissipated during the disturbance process. This process is called elastic relaxation process resulting from the transient elastic properties of granular materials.The theory of gas molecular dynamics uses the concept of entropy to quantitatively describe the energy dissipation in the system caused by the molecular irregular movement under the macroscopic incentives. Granular materials also have similar irregular motion mechanisms at the mesoscopic level (particle level). Under the macroscopic incentives, in addition to the macroscopic average kinetic energy, there will be a velocity shift between the particles inside the material, and this will cause interactions, such as collision, friction, vibration, and rolling between the particles, resulting in an additional dissipation mechanism. This phenomenon is called granular fluctuation. Jiang and Liu (2009) introduced the concept of granular entropy in the GSH theory, analogous to the entropy theory in the classical thermodynamic theory. The granular entropy increasing equation is used to quantitatively describe the dissipative process produced by granular fluctuation, as follows:The granular entropy increasing equation indicates that the increase in granular entropy will be determined by the granular entropy production rate According to Onsager relation, a linear relationship between dissipative force and flux is satisfied near the equilibrium of thermodynamics, and then the relationship between them can be described by the mitigation coefficient matrix as follows:In this coefficient matrix, the meaning of the four diagonal terms is: The mitigation coefficient matrix also contains an off-diagonal element. Mathematically, the Onsager dissipative relations represent a Taylor series expansion of the dissipation function near the equilibrium state, and the off-diagonal elements of the matrix represent the coupling between two dissipative mechanisms. In this paper, the coupling coefficient In the above expression, the coefficients Based on the theory of non-equilibrium thermodynamics of saturated soil, Zhang and Cheng (2015) proved that the total stress of the soil is:In the formula, the elastic stress In the formula, Under undrained triaxial conditions, there is no volumetric strain, the axial strain is controlled by the loading conditions, (1) Equation of granular entropy increasingIn the formula, (2) Equation of elastic relaxationAmong the undrained triaxial shearing process, (3) Elastic potential energy density functionThe elastic potential energy density function can be defined by the four functional forms of Internal energy, Helmholtz free energy, enthalpy, and Gibbs free energy. These definitions can be transformed by Legendre transformation. This paper uses the Helmholtz free energy function to define the elastic potential energy function. In the original TTS model, the nonlinear elastic potential function proposed was selected. However, in this paper, the simplest linear elastic model is adopted:(4) Equation of effective stressBased on the elastic relaxation equation and elastic potential energy density function, the effective stress equation under undrained triaxial shear conditions can be obtained as follows:From the effective stress equations, influence of the coupling mitigation coefficient is manifested by the compression-shear coupling effect, and both the elastic shear strain The critical state is the quasi-static steady state that the soil material reaches after large deformation ,15,16,17Since the effective stress of the material remains unchanged in the critical state, the elastic strain rate In the above formula, In the undrained triaxial shear test of sand, there are two issues as concerned as the dilatancy-contraction, hardening-softening characteristics. As shown in the above formula, the coupling mitigation coefficient introduced in this paper will produce a compression-shear coupling effect in the elastic relaxation equation and effective stress equations. In the elastic relaxation equation, the development of the shear strain will have a coupling effect on the volumetric elastic strain, and since the critical state and the volumetric elastic strain level of the initial state are directly determined by the material density and the initial consolidation conditions, the compression-shear coupling effects may make the elastic volumetric strain show a non-monotonic process during the development from the initial state to the critical state.That is, at the beginning of shearing, the volumetric elastic strain rate Based on the modified TTS model, this paper simulates the undrained triaxial test of Toyoura sand. Sand samples were undrained sheared under strain control conditions . The sample reaches a quasi-static rheological state with constant volume, constant effective stress, and constant shear stress. As shown in As described in For over-consolidated medium dense sand sample with void ratio e = 0.833 and initial consolidation pressure Then the elastic volumetric strain continues to decrease, the elastic shear strain gradually enters a steady value, and the material will appear to be in a softening state and eventually stabilize in a critical state. Compression-shear coupling effect generalized by The constitutive model of geo-materials based on classical elastoplastic mechanics cannot form a unified theoretical framework. In order to solve different problems, different concepts and amendments need to be introduced. In addition, the elastoplastic model lacks rigorous theoretical basis and may be contrary to the second law of thermodynamics.The classical constitutive model based on thermodynamic theory framework uses the thermodynamic principle to obtain the yield function and flow function of geo-materials, which can fully satisfy the first and second laws of thermodynamics, and avoid the theoretical defects of plastic potential function in classical elastoplastic model. Thermodynamic models usually define corresponding independent state variables for all dissipative mechanisms, which are used to construct the corresponding dissipative potential functions. This descriptive method of energy dissipation is actually an imitation of the elastic potential function, and has not strictly proved the selection of the dissipative mechanism.The theoretical framework of hydrodynamics used in TTS model, is based on the laws of conservation and non-equilibrium thermodynamics. In this theoretical framework, there is a well-established quantitative theory for determining dissipative forces and dissipative flows, namely the Onsager migration coefficient model. In addition, the TTS model following GSH introduces particle entropy to describe the fluctuation motion of granular particles and the dissipation caused by it. This model considers the connection and difference between the macroscopic behavior and the mesoscopic behavior of the material in a unified constitutive functions. In this model, elastic strain and inelastic strain are always accompanied, without the concept of yielding surface. This is closer to the true mechanical characteristics of geo-materials.The modified TTS model is a constitutive model that does not require yield surface, flow rule, loading/unloading criteria, and hardening-softening criteria. The quantitative description of energy dissipation is attributed to the determination of a series of Onsager mitigation coefficients.(1)The model can predict the critical state characteristics of sand, including the rate-independence of critical state, the void ratio–mean effective stress relationship, and the frictional angle at critical state. When (2)Without the definition of complex non-associate flow rule, the modified TTS model has the ability to simulating the dilatancy-contraction and hardening-softening phenomenon during undrained shearing of sand. This ability is mainly derived from the compression-shear coupling provided by the coupling mitigation coefficient The coupling mitigation coefficient


The maintenance of systemic energy homeostasis is vital for organismal fitness and viability. This Research Topic is aimed at furthering our understanding of how systemic metabolic homeostasis can be achieved, by providing an overall view of how endocrine factors act, the receptors through which the endocrine factors elicit their effects, the complications arising from deranged energy metabolism, and finally the new evolutionary aspects of metabolic factors.Ieka et al. reported for the first time the presence of enzymatic activities associated with steroidogenesis in the rat salivary glands, thereby indicating that steroid hormones are generated throughout the body and could work with other metabolic factors to mediate cross-talks between tissues or as metabolic regulators within specific tissues. Another important hormone of energy metabolism, ghrelin, is produced and released by the stomach and conveys information to the hypothalamus to enhance the use of carbohydrates and reduce fat utilization. Ghrelin also directly stimulates adipogenesis in mature rat adipocytes; however, its role in the preadipocytes is not clear. In an original research article, Miao et al. elucidated that ghrelin enhanced the proliferation of mouse 3T3 preadipocytes and human primary preadipocytes and suppressed their differentiation. These findings provide further understanding of the previously-unrecognized roles of ghrelin on adipocyte lipid metabolism. Cytokines are critical endocrine factors in systemic energy homeostasis regulation. In a review article, Shi et al. revealed deeper insights into the negative roles of various cytokines in the induction of metabolic dysfunction, which to this far are still not well-understood beyond their associations with lipid accumulation and inflammation in tissues. The notion of utilizing these cytokines as biomarkers for the early detection of metabolic disorders was also discussed in the review. Khan, in a review article, discussed the regulation of metabolic factors, emphasizing the mechanisms by which insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), a pleiotropic polypeptide, controls the bioavailability and localization of IGF-I and IGF-II in the central nervous system, and their functions on neuronal growth and development.Numerous factors, including the cytokines and hormones, are known to play important roles in mediating tissue-tissue communications essential for achieving overall metabolic equilibrium. Steroid hormones, produced and secreted primarily by the adrenal cortex, play an important role in regulating energy metabolism and stress responses. An original research article by Zhao et al. focuses on the receptor tyrosine kinase (RTK) family of cell surface receptors, which respond to hormones, cytokines, and growth factors to trigger a diverse set of cellular and metabolic signaling pathways. The article describes the emerging molecular mechanisms of RTK signaling and highlights the unexpected roles for receptor families in regulating glucose and lipid metabolism. In another review article by Hardy and Fernandez-Patron, readers are introduced to the theme of bone remodeling by the extracellular matrix metalloproteinases (MMPs). Understanding bone remodeling, a process whereby bones renew themselves, is germane to our theme of systemic metabolic control and balance as the skeleton exerts an important endocrine regulation of glucose homeostasis and also bone cells regulated by certain hormones may send signals to influence the hormone-producing cells under a feedback loop. Building on the topic of glucose homeostasis, Yang et al. in a review article focuses on diabetic peripheral neuropathy (DPN), a common chronic complication of diabetes mellitus that arises from glucose metabolism dysregulation. With diabetes mellitus now reaching epidemic proportion, it is expected that the incidence of DPN will increase dramatically. This review describes recent advances in the diagnosis of DPN and the precision medicine techniques that may be used to improve treatment of this debilitating disease. Last but not least, an original research article by Segev-Hadar et al. reported the identification of a second myostatin gene (mstn2) in the aquaculture fish species, Nile tilapia. Myostatin is a growth and differentiation factor that regulates skeletal muscle development which in turn impinges on the production of myokines essential for systemic energy metabolism. Results from this article showed that mstn2 is not expressed in muscle cells but in the brain, and that centrally- and muscle-expressed mstn genes differ in their responsiveness to diverse challenges, suggesting a differential gene- and tissue-specific regulation of their expression.Through receptors, metabolic factors effectively elicit their effects in target organs to direct metabolic homeostasis. A review article by In summary, this Research Topic provides an integrated overview of the endocrine regulation of systemic metabolic homeostasis and brings forward our understanding of this complex but important field.H-YL wrote the editorial. WW, YN, and KP-K critically reviewed the editorial. 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.


In acute ischemic stroke, early recanalization of the occluded artery is crucial for best outcome to be achieved. Recanalization aims at restoring blood flow to the ischemic tissue (reperfusion) and is achieved with pharmacological thrombolytic drugs, endovascular thrombectomy (EVT) devices, or both. The introduction of modern endovascular devices has led to tremendous anatomical and clinical success with rates of substantial reperfusion exceeding 80% and proven clinical benefit in patients with anterior circulation large vessel occlusions (LVOs). However, not every successful reperfusion procedure leads to the desired clinical outcome. In fact, the rate of non-disabled outcome at 3 months with current EVT treatment is ~1 out of 4. A constraint upon better outcomes is that reperfusion, though resolving ischemic stress, may not restore the anatomic structures and metabolic functions of ischemic tissue to their baseline states. In fact, ischemia triggers a complex cascade of destructive mechanisms that can sometimes be exacerbated rather than alleviated by reperfusion therapy. Such reperfusion injury may cause infarct progression, intracranial hemorrhage, and unfavorable outcome. Therapeutic hypothermia has been shown to have a favorable impact on the molecular elaboration of ischemic injury, but systemic hypothermia is limited by slow speed of attaining target temperatures and clinical complications. A novel approach is endovascular delivery of hypothermia to cool the affected brain tissue selectively and rapidly with tight local temperature control, features not available with systemic hypothermia devices. In this perspective article, we discuss the possible benefits of adjunctive selective endovascular brain hypothermia during interventional stroke treatment. Several randomized controlled clinical trials have demonstrated the clinical benefit of endovascular thrombectomy (EVT) in selected patients with acute ischemic stroke due to large vessel occlusions (LVO-AIS) –7. The iBrain ischemia triggers a cascade of molecular and cellular mechanisms many of which have been identified . FollowiAs a result of these molecular pathways, functional and structural changes follow, such as impaired vasomotor regulation , 32, cytParadoxically, reperfusion of the ischemic brain tissue can exacerbate these destructive processes that have been triggered by stroke. This is called reperfusion injury and is thought to be the result of multiple pathways of tissue insult, oxidative stress, leukocyte infiltration, complement activation, mitochondrial dysfunction, platelet activation and aggregation, and blood-brain-barrier disruption, culminating in neuron death, brain edema or hemorrhagic transformation , 40–42. EVT devices are well-suited to remove the target thrombus and anatomically clear the artery to restore blood flow, but do not offer direct therapy of metabolic consequences of ischema. For ameliorating metabolic disruptions, therapeutic hypothermia has been one of the most promising concepts based on its pleiotropic mechanisms of action , 49. In Although there are numerous endovascular devices available to remove a clot from the neurovasculature, in principle, they are of two main types –7. One hThe clinical benefit of the combined treatment approach, i.e., systemic pharmacological therapy and endovascular clot extraction, over pharmacological therapy alone, is due to its high effectiveness to anatomically revascularize the occluded artery. In addition, endovascular catheters may be used to locally infuse fluids and various drugs. However, drugs that are considered neuroprotective and for intra-arterial use are rather limited , and curThe rate for symptomatic ICH, often seen with parenchymal hemorrhage, following the combined treatment of acute ischemic stroke varies and may be as high as 10% –39. ClinTherapeutic hypothermia has been identified as one of the most promising neuroprotective methods. Systemic cooling experiments in stroke models involving animals across various species have shown that hypothermia is neuroprotective in terms of reduction in infarct size and improvement in neuro-behavioral testing scores  without increasing the risk for ICH . The cliThe neuroprotective effect of cooling is the result of hypothermia's pleiotropic mechanisms of action. Among a plethora of demonstrated effects that help to produce a physiological state of ischemic tolerance, cooling causes metabolic depression reducing the cellular demand for oxygen and energy, has anti-excitotoxic, anti-inflammatory, anti-edematous, and anti-apoptotic properties, and suppresses the breakdown of the blood-brain-barrier , 57, 58.What appears to be simply natural and is repeated year after year in hibernating mammals, in humans the process of inducing and maintaining systemic hypothermia are extremely difficult, complicated, prolonged, and painful due to the strong physiological counter mechanisms and frequent adverse events , 61 Fig. As suchSelective brain hypothermia is an attractive alternative to systemic hypothermia, providing focused cooling of the injured organ and avoiding the complications of systemic hypothermia, including intubation, shivering, pneumonia, altered coagulability, and cold-induced stress reactions . A varieExperiments in animal stroke models, commonly with transient occlusion of the middle cerebral artery, have found a significant improvement in outcome  with brief endovascular selective brain cooling [average effect size 51% ] , 74. HerSpeed of brain cooling is one of the unique features of SEBC that distinguishes itself from any form of systemic hypothermia. This is because only a selected vascular territory of the brain is cooled, rather than the whole body, and a direct modification of the arterial input temperature is performed . The cooSEBC has also been studied in humans . The feaThe advantages of endovascular selective brain cooling for the treatment of LVO stroke are mani-fold. One, with significantly reduced time to target temperature of the organ of interest, the brain, hypothermic neuroprotection can be achieved quickly. Hereby, the physical concept of SEBC is ideally suited to achieve brain cooling quickly  and with minimal invasiveness because it directly modifies the cerebral arterial input temperature and would be administered via the routine endovascular route. Two, selective brain cooling allows to reduce the impact of cooling on the body, thus minimizing or avoiding systemic hypothermia and its adverse consequences. Three, due to the endovascular route, SEBC is ideally suited to be applied as an adjunct treatment to endovascular recanalization procedures in LVO stroke. Four, due to its selective and immediate cooling features and endovascular route, SEBC would be capable to attenuate the destructive forces of reperfusion injury, locally and directly, following endovascular clot-extraction.In practice, and taking the direct infusion method as an example, the SEBC catheter would be placed in the ipsilateral (ischemic hemisphere) internal carotid artery through the same intra-arterial access as used for clot extraction . The catThe key to reducing the impact of ischemia and reperfusion injury is the suppression of their pathophysiological mechanisms. While it is clear that SEBC-induced hypothermic neuroprotection would be delayed in LVO patients when they finally undergo endovascular clot-extraction, regardless of how quickly brain cooling can be achieved, the results from animal stroke models and our understanding of the molecular and cellular evolution of stroke suggest that brain cooling is neuroprotective, even when delayed for several hours. This is a plausible assumption. If the early stage excitotoxicity cannot be prevented, brain hypothermia may still suppress the later-stage inflammatory processes, reduce edema, and prevent vessels from becoming too “leaky.” Disturbance of the structural integrity and leaky vessels are considered the basic preconditions for developing post stroke ICH.The beneficial impact of SEBC on the potential harms of sudden reperfusion is more evident when considering SEBC is applied as an adjunct to endovascular clot-extraction. Furthermore, SEBC induced via the direct mixing method with IACI could offer additional benefit as the incoming blood would be diluted, therefore reducing the impact of inflammatory promoters and immune cells on the ischemic and reperfused brain tissue. Another important advantage of the infusion method is that the dimensions of the infusion-type cooling catheter would be small enough to fit through the guiding sheath that has already been placed to navigate the EVT catheter to remove the clot, requiring only an exchange of catheters or even allowing concomitant use of both catheter systems .There are limitations of SEBC. First, although hypothermia induction would be rapid, the duration of cooling would be limited by the routine times allowed for indwelling endovascular catheters to remain in the arterial system. Second, the direct mixing method with IACI, albeit the fastest cooling method in physical terms, would be limited by the volume that could be infused within a certain period. In contrast, the extracorporeal blood cooling concept would theoretically address the issue of hypervolemia as practically the same amount of blood is re-introduced into the cerebral circulation as it was removed from the system before exposing the blood to the external heat-exchanger. With this isovolemic cooling concept, long-term brain hypothermia would become feasible. However, this isovolemic method adds layers of invasiveness and complexity to the hyperacute workflow, such as a second arterial puncture (blood outflow), vascular reconstruction , necessity of a perfusion specialist, and heparinization of blood in the external circulation. Third, potential adverse effects may occur from local exposure to cold, additional fluid volume  and mechanical stress from the endovascular cooling catheter. Thus, careful monitoring of vitals, dilution, local temperature, and potential vascular injury and spasm would be necessary. Lasty, there are yet no devices on the market for SEBC. Only routine catheters have been used to explore and investigate the safety and feasibility of brief SEBC (10–15 min) in elective and acute cerebrovascular patients. While the results have been promising and larger trials are underway, it is questionable whether brief and uncontrolled IACI will deliver the answers to the ideal depth, duration, and timing of brain hypothermia the determination of which should be based on physiological parameters and cerebral metabolic demand, such as changes in brain metabolism, cerebral blood flow, and infarct evolution. This could become more critical when infusing fluids distally to a cerebral artery occlusion (intra-ischemic brain cooling) without any information about the metabolic and hemodynamic condition of the ischemic tissue bed. As such, we believe that to provide a safe and most efficient SEBC, specialized catheter systems are necessary that offer excellent heat-exchange, mixing, and embedded safety and control mechanisms.Given the growing and widespread utilization of endovascular clot-extraction in LVO stroke and lack of additional means to counter the deleterious mechanisms of ischemia and reperfusion injury , 85, SEBThe original contributions presented in the study are included in the article/JC and JP-S contributed conception of the article. JC wrote the first draft of the article. All authors have approved the final version of the manuscript, contributed critical review and revision of the manuscript.JC and JS are co-founders of Hybernia Medical, LLC. SP and JS are consultants to Hybernia Medical, LLC. 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.


Leishmania infantum, is the most frequent clinical manifestation of the zoonotic infectious disease. A 4-month-old female Shih Tzu-terrier dog with significant weight loss and depression and chronic erosive skin lesions around eyes and the area above the nose was presented to the Semnan University Veterinary Hospital teaching, Semnan, Iran. The main clinicopathological findings included marked leukocytosis, neutrophilia, left shift, monocytosis, mild hypoproteinemia, and hypoalbuminemia. The diagnosis of leishmaniasis was performed based on the presence of a large number of Leishmania amastigotes in skin Fine Needle Aspiration (FNA). The dog was euthanized and sent to the autopsy department for further investigation.Cutaneous involvement in canine leishmaniasis, caused by  Phlebotomus and Lutzomiya from the Old World and the New World, respectively  and humid (suburban) wound. It is estimated that 12–14 million types of this illness exist in the world , 70%–75%L. Tropica, its vector is Ph. sergenti. The urban-type of this disease is reported from almost 14 centers in eight cities all around Iran; these reports are mostly from metropolises, like Tehran, Mashhad, Neyshabour, Shiraz, Kerman, and Bam  and cutaneous (suburban); in urban leishmaniasis or anthroponotic cutaneous leishmaniasis (ACL), the cause of the illness is  and Bam .L. gerbil and L. turanica are diagnosed in rodents . The owner of the studied dog stated their written consent.The dog has received treatment with antibiotics for 3 weeks in other veterinary clinics and had not responded to antibiotic therapy at all, the condition of her wounds got worst by the pass of time.Lymphadenopathy and chronic erosive skin lesions around eyes and the area above the nose were found on physical examination papule. FNA was taken from cutaneous lesions and impression smear was prepared for direct microscopy diagnosis. Blood samples were collected from the jugular vein for Complete Blood Count (CBC) and Plasma was obtained for determination of biochemical parameters.Leishmania amastigotes inside and outside of macrophages , neutrophilia , left shift (bands 867/μL) and monocytosis  were detected from hematological examination. Mild microcytic hypochromic anemia was also reported by the laboratory . The mosLeishmania amastigotes inside and outside of macrophages in light microscopy of the stained smears prepared from FNA samples collected from cutaneous lesions, which is referred to as the gold standard for the diagnosis of leishmaniasis . In cases where cytology is not a determinant, the diagnosis should be made by histology/immunohistochemistry or PCR on surgical biopsies .One of the common hematological findings of canine leishmaniasis is anemia which in the present study is documented the presence of anemia in this case with severe cutaneous leishmaniasis. This anemia manifests as a normocytic normochromic form. Several factors have been suggested for the onset anemia in canine leishmaniasis, including extravascular hemolytic anemia due to phagocytosis of RBC by the enlarged spleen and liver caused by inflammatory response  or impaiIt seems neutrophilia, that is mostly caused leukocytosis, has been related to the cutaneous lesions resulted by the secondary infection . The impLeishmania-infected dog had low concentrations of serum Tp and albumin. The manifestation of Tp reduction in canine cutaneous leishmaniasis is completely contradictory with canine visceral leishmaniasis and requires more attention (In this study, the ttention , 30. It The severe form of cutaneous leishmaniasis in the presented case could cause marked clinicopathological manifestations. These changes include anemia, leukocytosis, neutrophilia with left shift, monocytosis and hypoproteinemia, and hypoalbuminemia.


Whilst effective treatments exist for substance use and alcohol use disorders, they are not commonly practised. Studies have shown that only a small percentage of services provide evidence-based treatments such as addiction medications or psychosocial therapies. Although there is a growing body of literature on evidence-based treatment, no synthesis of research on the implementation of evidence-based addiction treatment exists. This proposed systematic review will synthesise and evaluate the effectiveness of implementation programmes in the treatment of patients with drug and alcohol problems using the Consolidated Framework for Implementation Research (CFIR) framework.We will search (from inception onwards) PubMed/MEDLINE, Cochrane Library, PsycINFO, Web of Science and CINAHL. Eligible studies will be clinical trials  and observational studies  evaluating strategies used to implement evidence-based psychosocial treatments for alcohol and substance use disorders. The primary outcomes will be related to the implementation, service system, or clinical practice . Two researchers will independently screen all citations, full-text articles and abstract data. Risk of bias of individual studies will be appraised using appropriate tools. A narrative synthesis will be provided.This project aims to provide evidence to help guide the design of translational research programmes to improve implementation of evidence-based care in drug and alcohol settings. Findings from the study will specify effective strategies for domains of influence including (1) intervention characteristics , (2) outer setting , (3) inner setting , (4) individuals involved  and (5) the implementation process . Identified gaps in knowledge will guide further study.PROSPERO CRD42019123812 The existence of a gap between clinical evidence and clinical practice is well established in the health services literature , 2. Studinterventions than there has been on developing evidence-based implementation strategies [A complex range of barriers operating at multiple levels of healthcare delivery must be addressed in order to bridge this gap, such as the patient level, the provider team or group level, the organisational level and the market or policy level . Historirategies . Interverategies , 14. Forrategies .The field of implementation science emerged accordingly as an organised and resourced approach to the study of implementation, allowing for the accumulation of knowledge about how to ensure that evidence-based practices are delivered to the necessary patients and thus bridging the gap between evidence and practice . WithoutVarious theories, models and frameworks have been proposed to synthesise the knowledge base derived from implementation research, to describe the process of translating research into practice, to understand the determinants of implementation outcomes and to evaluate implementation . The ConThe number of empirical evaluations testing implementation strategies in mental health settings is ‘dwarfed’ by the broader field of health care . This arThe objectives of this systematic review are to synthesise and evaluate the effectiveness of implementation programmes in the treatment of patients with drug and alcohol problems.We aim to evaluate implementation effectiveness with regards to the five domains of influence outlined by the CFIR framework. By providing this overview, we aim to provide evidence to help guide the design of translational research programmes to improve implementation of evidence-based care in drug and alcohol settings.The present review protocol is being reported in accordance with the reporting guidance the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement  see PRI. This reCriteria for considering studies for this review are classified by the following:In order to meet inclusion criteria, studies must involve an evaluation of implementation strategies used to transfer an evidence-based psychosocial treatment or treatment guideline into clinical practice in SUD settings. Psychosocial treatments include any attempt to affect change in patients’ substance use through behaviour, cognition, affect, interpersonal relationships or environment . Participants in these studies may include any clinician providing psychosocial interventions to SUD patients accessing outpatient or inpatient drug and alcohol services. ‘Clinician’ is defined as an individual employed to implement change in SUD patients’ substance use using psychosocial treatments exclusively. As such, studies will be excluded from the review if they focus on the development of psychometric instruments, drugs in sport, harm prevention or community awareness.The psychosocial intervention must be evidence-based and provide clear recommendations for practice. Studies will be excluded if they involve physiological, pharmacological or education-based interventions. Information including the nature of desired change, strategies employed, source of the intervention, mode of delivery , identification of who delivered the intervention and the timing, duration, and frequency of the intervention needs to be stated clearly. Only ethically approved studies will be considered.Only studies with a comparison group will be included. Comparisons may be made before and after the administration of the intervention, between two or more forms of intervention, or between different types of intervention(s) (or no intervention). We will include randomised controlled trials (RCTs), non-randomised controlled trials, observational studies including before-and-after studies, and time series analyses.Primary study outcomes will be related to the implementation, service system or clinical practice. Specifically, outcomes will include infidelity, attitudes toward or satisfaction with the intervention (acceptability), and adoption, appropriateness of the intervention to the target population, implementation costs, the feasibility of the intervention within the setting, and the sustainability of the intervention after implementation. The length of post-intervention follow-up period must be specified and any possible ceiling effects identified. Outcomes will be related to the effectiveness of the implementation process, as distinct from the efficacy of the intervention itself.Since SUD inpatient and outpatient treatment settings that provide counselling services to patients are the focus of the review, settings such as primary care, criminal justice or those investigating cross-cultural factors will be excluded from the review.The following electronic databases will be searched (from inception onwards): PubMed/MEDLINE, Cochrane Library, PsycINFO, Web of Science and CINAHL. Additionally, we will conduct reference searches of relevant reviews and articles. Similarly, a grey literature search will be done with help of Google and the Grey Matters tool which is a checklist of health-related sites organised by topic. The tool is produced by the Canadian Agency for Drugs and Technologies in Health (CADTH) .The search will include all relevant peer-reviewed studies. The search will be conducted across 4 relevant concepts  will be used to manage all records.intervention characteristics, outer setting, inner setting, characteristics of individuals and the implementation process). This method was used effectively in two previous reviews [Two researchers will extract data and organise it into variables based on the Cochrane Effective Practice and Organisation of Care Review Group (EPOC) Data Abstraction Form , the conceptual model of Proctor et al.   . The RoBWe do not anticipate having sufficient studies for a meta-analysis and therefore plan to perform a narrative synthesis. The main methods of synthesis will most likely involve tabulation, textual descriptions, qualitative synthesis of themes and vote-counting . We willMeta-biases such as outcome reporting bias will be evaluated by ensuring that a protocol was published prior to the recruitment of participants. Trial registries will also be checked to determine the integrity of reported outcome measures and statistical methods. The grey literature search may also assist with identifying publication bias.Strength of the evidence will be graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach . In the This manuscript provides a detailed account of this systematic review protocol used to advance effective components of implementation programmes in treating addiction. To our knowledge, this is the first systematic review of implementation studies for drug and alcohol settings for a range of evidence-based approaches. There has been one previous review of implementation of SUD treatment  that speGiven the complex, multi-level nature of implementing evidence-based practice, the results of this review will inform several stakeholders. For instance, those making decisions at the economic or policy level, organisational leadership, provider group management and clinicians being required to implement changes will be interested in the most effective means of translating evidence into practice. Researchers seeking to differentiate the efficacy of treatment outcomes from implementation outcomes will also benefit from the findings of this review, and several future research questions will be identified.Potential limitations at the study and review level include the diversity of implementation strategies, types of clinical interventions, study conditions and outcomes found in the included articles. This will create challenges for the reviewers with regard to accurately synthesising and comparing the information. This may become particularly evident as the authors are attempting to ascertain which components of a particular intervention are the most effective means of achieving certain desired outcomes, or in situations that call for an understanding of how a specific strategy might influence the effectiveness of the implementation. On the other hand, the use of the EPOC data form, the conceptual model of Proctor et al.  and the Despite the challenges that may be encountered, this review will make a valuable contribution to the growing body of literature on the implementation of evidence-based practice in SUD settings. Importantly, it will provide a summary of the most effective means of increasing the use of evidence-based treatments amongst drug and alcohol clinicians and subsequently assist with reducing the burden of disease associated with SUDs. This information will make a significant contribution to understanding how to improve the quality of treatment offered for SUD in specialised settings and in turn to improve the outcomes of people seeking treatment for these disorders.Additional file 1:. PRISMA-P 2015 Checklist.Additional file 2:. Draft search strategy.


The rapid increase in online shopping and the extension of online food purchase and delivery services to federal nutrition program participants highlight the need for a conceptual framework capturing the influence of online food retail environments on consumer behaviors. This study aims to develop such a conceptual framework. To achieve this, mixed methods were used, including: (1) a literature review and development of an initial framework; (2) key informant interviews; (3) pilot testing and refinement of the draft framework; and (4) a group discussion with experts to establish content validity. The resulting framework captures both consumer- and retailer-level influences across the entire shopping journey, as well as the broader social, community, and policy context. It identifies important factors such as consumer demographic characteristics, preferences, past behaviors, and retailer policies and practices. The framework also emphasizes the dynamic nature of personalized marketing by retailers and customizable website content, and captures equity and transparency in retailer policies and practices. The framework draws from multiple disciplines, providing a foundation for understanding the impact of online food retail on dietary behaviors. It can be utilized to inform public health interventions, retailer practices, and governmental policies for creating healthy and equitable online food retail environments. Online food retail is an increasingly popular means of acquiring food and is expected to grow rapidly over the coming decade. In 2017, online food retail represented $13 billion in sales ,5. BasedOnline food retail has also emerged as an important avenue to improve food access. In 2018, the United States Department of Agriculture (USDA) selected 10 retailers in 9 states for a two-year Online Purchasing Pilot (“online Electronic Benefits Transfer (EBT)”) to test the use of Supplemental Nutrition Assistance Program (SNAP) benefits as payment for online food purchases . The affThese shifts in consumer food purchase behaviors, the increasing investment in online infrastructure, and the expansion of online food purchasing to participants in federal programs, highlight the need for an assessment of the online food retail environment. A substantial and growing body of evidence captures the influence of in-store food marketing on consumer purchases ,12. In cWhat is currently lacking is an integrated framework capturing both consumer- and retailer-level factors and their interaction that influence consumer behaviors within online environments. The few existing frameworks focus on specific consumer determinants like their attitudes, privacy concerns, social influences, facilitating conditions, hedonic motivations, and perceived risk or satisfaction with the online experience ,18,19. RIn the absence of a comprehensive conceptual framework that looks at consumer grocery purchase behaviors it becomes impossible to systematically study the effect of food retail environments on food choices. Such a framework is crucial for informing public health interventions, guidelines, retailer practices, and governmental policies to create healthy and equitable online food retail environments. To address this gap in the literature, the present study aims to develop and refine a conceptual framework capturing factors that influence consumer food purchase behaviors within online food retail environments. For the purposes of this study, online food retail environments were described as websites providing click-and-collect  or food delivery services. ‘Retailers’ include e-commerce platforms hosted by the retailer themselves or by a third-party vendor .A literature review and development of an initial frameworkKey informant interviewsPilot testing and refinement of the draft frameworkGroup discussion with experts to establish content validityThe development and refinement of the conceptual framework was guided by the approach suggested by Jabareen, 2009 , and invThe study methodology was reviewed and determined to be non-human subjects research by the Institutional Review Board at the Johns Hopkins Bloomberg School of Public Health.food, grocer*, supermarket*, retail*, shop*, store*, purchas*, buy*, online, ecommerce (or e-commerce), internet, and web. Search results were supplemented with health agency reports, trade publications, and industry reports from 2015 to 2019. Reference lists from peer-reviewed publications were also scanned. While peer-reviewed literature was not restricted by geographic location, only US-focused analyst reports and trade publications were included to ensure contextual relevance. Paper titles and abstracts were screened. A total of 136 industry reports and 97 peer-reviewed papers informed the development of the draft framework.A scoping review was undertaken between April and June of 2019 to identify peer-reviewed and grey literature, in English, on the attributes, preferences, and shopping behaviors of consumers that make purchases online, consumer interaction with and acceptance of technology, online and in-store food marketing and merchandising, and design of online retail environments. Databases were searched from January 2009 to May 2019  using combinations of the keywords We interviewed seven experts in grocery merchandizing and marketing, e-commerce and online retail, behavioral psychology, public policy, computer science and data privacy and digital marketing. Experts were identified through a combination of known contacts, through their published work, or were referred to by other experts during interviews. The interviews were conducted in person or via teleconference by a member of the research team and lasted 45–60 min.The interview began with an overview of the objectives of the study. Experts were presented with the draft framework and asked: (i) for their feedback on the extent to which it captured their understanding of factors influencing consumer food choices when shopping online; (ii) to identify constructs that could be improved or simplified; and (iii) for additional constructs that should be included. Follow-up questions were tailored to each key informant’s area of expertise. For example, an expert in computer science and engineering was asked an additional question about when and how personal data are collected from consumers along the path to purchase. Experts in food retail marketing were asked how personal data are used to adapt online marketing practices to specific consumers. Insights were requested on how the key domains influenced one another. Suggestions were incorporated, and the framework was refined after each interview.Study researchers  independently tested the internal consistency of the conceptual framework by using it to guide a mock shopping exercise. This was done to identify additional concepts that may have been missed during the literature review and the key informant interview, but not with the aim of formally testing the framework. An online shopping account was created at two U.S. online food retailers. Researchers navigated each store’s website, browsed through their departments, added three grocery items to the shopping cart, and proceeded to the checkout. The applicability of the conceptual framework to the experience of a consumer searching for and selecting food was discussed in detail. Revisions to the framework were incorporated as necessary.A teleconference discussion was convened with six members of the Healthy Food Retail Working Group to determine the content validity of the conceptual framework. This group is a collaborative effort of the Robert Wood Johnson Foundation’s Healthy Eating Research program and the Centers for Disease Control and Prevention’s Nutrition and Obesity Policy Research and Evaluation Network. Members include researchers and technical experts working on healthy food retail and related areas.To engage fully with the framework, members of the Working Group were asked to undertake a mock shopping exercise, similar to the one conducted by the study authors, two weeks prior to the call. A Qualtrics form was created to guide the sequence of product searching and selection activities and to record feedback. After selecting an online food retailer from a list of 21 options, members navigated to the grocery department homepage, the breakfast cereal department page, and the product pages of two specific brands of bread and canned fish. They documented marketing strategies, customizable features, tools, options, and multimedia content on each of these webpages. Members also recorded ease of navigation and site policies. Their feedback from this exercise was discussed in the teleconference, during which the purpose of the research was clarified, and a draft of the conceptual framework (including what the concepts represent and how they relate to each other) was presented. Members were asked whether the current framework captured their understanding of the range of factors influencing consumer behavior in the online store and for ideas for improvement. Notes from the discussion were recorded, and relevant revisions were incorporated into the framework.Insights from the literature review informed the development of a draft framework that captured the influence of consumer characteristics, online food marketing, and retailer and website characteristics on online grocery shopping intention. Feedback from the key informant interviews added further detail by delineating the different stages of the online shopping process, the sequence of online consumer behaviors, the key role of personalized marketing, relationships between online retailers and manufacturers, disclosure of sponsored content, factors influencing site design, and the use of personal information in customizing the platform.The pilot test provided additional insights into retailer characteristics related to membership and loyalty programs, privacy and data use, and order payment, fulfillment, and collection. This exercise also differentiated the static versus the dynamic elements of the online platform , differences in site functionality as viewed by an anonymous shopper versus a registered shopper, and marketing strategies employed at checkout.Healthy Food Retail Working Group members acknowledged the detail and clarity of the current version of the framework and agreed that it captured relevant constructs that influence consumer food choice in online environments. Their feedback focused on the applicability of the conceptual framework to specific subgroups of consumers , retailers , and online formats . These ideas were discussed, and relevant constructs in the framework were added or made more salient.The final framework combined elements of the Technology Acceptance Model, consumer behavior and decision-making frameworks, brick-and-mortar marketing categories  ,23, key Central to the conceptual framework is the sequence of consumer behaviors involved in online grocery shopping. This Path to Purchase consists of four stages—Pre-Shop, Online Shopping, Pick-Up or Delivery, and Post-Shop—encompassing six behaviors. Under Pre-Shop behaviors, the consumer selects an online retailer. He/she then searches for or discovers, selects, and purchases food (Online Shopping). The consumer receives the order (Pick-Up or Delivery) and prepares and consumes the food or/and discards it (Post-Shop). The quality of the consumer’s experience engaging in each of these behaviors determines their overall satisfaction with the retailer and likelihood of shopping again.Consumer behaviors are influenced by consumer- and retailer-level attributes, presented above and below the Path to Purchase in Consumer Characteristics, Preferences, and Past Behaviors: this domain encompasses consumers’ Technology Acceptance, Individual and Household Demographics, Food-Related Preferences and Behaviors, and Attitudes and Beliefs , membership requirements prior to shopping, and delivery service areas . Privacy and Data Sharing policies include the terms and conditions that govern the collection, tracking, storage, use, and sharing of personal information by the retailer. Policies on Inventory Management guide the availability of products and brands, pricing strategy, and accuracy of inventory tracking, while policies on Collection and Payment determine the payment options accepted by the retailer , the integration of loyalty and reward programs, fees for delivery and restocking, and delivery options .The Pick-Up and Post-Shop behaviors are likely to be determined by Retailer Policies and Practices that govern Order Fulfillment, Order Delivery, and Returns and Order Cancellation. Policies on Order Fulfillment include the price and appropriateness of product substitutions during stock-outs and the quality of the food received. The availability of convenient time slots, delivery coordination , and the availability of secure delivery options are examples of policies associated with Order Delivery. Policies determining the ease of cancelling incomplete or incorrect orders of items purchased online  relate to Returns and Order Cancellation.Personalized Marketing by Retailers: a consumer’s search, selection and purchase of food are influenced by factors within the dynamic domain of Personalized Marketing. These marketing strategies are based on personal information provided by the consumer when registering with the online platform and from past purchases and browsing history. They may also be based on consumer data purchased by the retailer, shared by third parties, or automatically collected upon visiting the site . The consumer, either knowingly (by actively agreeing to) or unknowingly  or without full knowledge of the implications, allows retailers to use various sources of information to create a tailored experience.Personalized Marketing maps onto the marketing mix of Product, Price, Placement, and Promotion (“the 4Ps”), but manifests differently in the online food retail environment than in brick-and-mortar stores . ProductCustomization of the Website by the Consumer: this is the other dynamic domain that influences the search, selection, and purchase of food and includes Product Information Display, Site Navigation, and Shopping Tools. These attributes allow consumers to change what nutrition information they see (Product Information Display), filter products based on preferred attributes, save shopping lists, or request certain product comparisons (Shopping Tools). Combined with tools and tutorials to ease website navigation (Site Navigation), website customization features can increase the convenience of product searches, enhance consumer engagement with the product catalogue and improve the quality of the food purchase experience.Other Food Marketing: this dynamic domain includes Promotional Strategies, Social Media Strategies, and Immersive Strategies, recognizing that exposure to marketing in other settings (brick-and-mortar stores), through direct-to-consumer promotions, product endorsements, and sponsorships, and targeted marketing through social media platforms will affect food choices made online.Sophistication of Website and Frequency of Use: technological progress in interface design, communications, and data security is likely to improve consumer trust and increase the volume and frequency of purchases made online. Advancements in personal data collection, advertising technology, purchase data analytics, and consumers’ increased involvement in the co-creation of food retail platforms will allow retailers to better profile customers and more efficiently match them to products and promotions, increasing engagement. In this way, more sophisticated online platforms and frequent consumer visits will ensure greater personalization of retailer marketing strategies and a more customized website.Equity and Transparency are fundamental to retailer engagement with the consumer. Equity refers to the differential impact of retailer policies and practices on the food behaviors and privacy of underserved populations . For example, a consumer’s ability to utilize online services may be affected by the retail service area, availability of convenient delivery slots, or accepted payment methods. A retailer’s targeted and personalized marketing strategies may trigger impulse purchases or increase the basket size, differentially impacting low-income consumers, especially if the promoted products are of inferior nutritional quality. Transparency in policies and practices captures the retailer’s clear and upfront disclosure of data collection, storage and use of data, surveillance methods, marketing, sponsorships, etc., that may consciously or unconsciously influence the consumer’s choices along the Path to Purchase. For instance, disclosure of fees and hidden costs and collection of personal data prior to checkout may affect a consumer’s choice of retailer. Disclosure of product sponsorship at point of purchase may affect product selection.Social, Community, and Policy Context: this conceptual framework is nested in the socio-ecological model . ConsumeThis study presents a conceptual framework that captures factors influencing consumer behavior within online food retail environments. It also details the methodology for framework development and refinement—a process that identified and integrated evidence across multiple fields of study. The conceptual framework captures both consumer- and retailer-level influences across the entire Path to Purchase as well as the broader social, community, and policy context. Important static attributes of retailer policies and practices and consumer characteristics, preferences, and past behaviors are captured. The framework also emphasizes the dynamic attributes of the online platform, including those of personalized marketing by retailers, customization of the website content, navigation by the consumer, and the two-way interaction between these domains that enables a variety of online food retail interfaces uniquely tailored to consumer preferences.This conceptual framework makes an important contribution to our understanding of the burgeoning field of online food retail. It serves as a foundation for a deeper study into the influences on consumer food purchase behaviors within online platforms and the interactions between them. To our knowledge, this is the first time that the relatively under-studied domains of personalization and customization of the online food retail environment or the domains of equity and transparency or the social, community, and the policy context, have been considered in any framework. Further investigation is certainly warranted. Future studies could use the framework to compare brick-and-mortar retailers and their online platforms to identify the convergence and divergence of consumer behaviors and retailer responses within these settings. The conceptual framework itself could be empirically tested to support its validity and better establish a hierarchy between attributes. Previous work has used structural equation modelling techniques to examine the hypothesized relationships between constructs in a proposed model and identify possible causal relationships between them . While oThe conceptual framework provides a foundation for understanding how a lack of transparency within online retail platforms could impact health equity. Indeed, if an equity lens is not applied in the development and implementation of retailer policies, online platforms may unintentionally widen disparities in healthy food access, affordability, and diet quality for vulnerable groups . For insThe framework may help to study the effect of predatory marketing tactics, similar to those employed across other digital media where communities of color are targeted with the least nutritious products . Indeed,Finally, the conceptual framework could be used to inform and evaluate public health interventions aimed at improving consumer food choices in the online food environment. On the policy and practice front, the framework could inform: (i) recommendations and standards for best practices related to online food marketing; (ii) specific guidance for online retailers to ensure policy transparency, equitable access, and assurance of privacy; (iii) tailored educational content for consumers unfamiliar with online grocery retail; and (iv) personalized nutrition education and communication. For example, nutrition interventions delivered via the online retail platform could offer personalized healthy shopping lists that draw on information about consumer preferences and budget constraints, offer personalized healthy recipes or meal solutions, or develop a personalized labeling campaign that makes specific nutritional attributes of a product more salient at the point of purchase. SNAP-Ed—SNAP’s voluntary nutrition education program—could partner with online retailers to allow participants to interact with a registered dietitian in real time while food shopping. Local WIC agencies could work with online retailers to create a WIC-friendly web interface with WIC-eligible products, label products as being part of WIC food packages, and allow only WIC-approved substitutions in case of stock-outs.This study does have its limitations. Despite a comprehensive approach to development, the resulting conceptual framework may not have captured all the elements of the online food retail environment. The descriptions of the constructs in the framework serve as examples and are not exhaustive. The literature reviewed was almost entirely from the US and Europe. Pilot testing and content validity were established for the US context. Therefore, it is possible that the framework may not adequately capture the online environments in other contexts and would need further testing to gauge applicability in different settings, including its applicability to food purchases made via mobile applications. Advances in technology will result in new and innovative features that will need to be incorporated into the evolving conceptual framework.This study has several strengths. It leveraged multiple methods in the development and refinement of the framework, including key informant interviews, comprehensive systematic literature reviews, mock shopping exercises and group discussions, improving its validity. The framework development drew from multiple disciplines and benefited greatly from the insights of experts across different fields, allowing for an in-depth understanding of the factors influencing consumer purchases and underscoring the need for the public health community to collaborate with scientists and policymakers from non-traditional public health disciplines to map the influence of the online food environment. Finally, applying a public health perspective to the development of the framework expanded its utility in informing future interventions in this field.This paper integrated multiple perspectives across a wide range of fields to develop a framework capturing both consumer- and retailer-level factors influencing consumer purchases in the online food retail environment, as well as the broader social, community, and policy context. It identifies important static factors and emphasizes the dynamic nature of personalized marketing by retailers and customizable website content. Equity and transparency in retailer policies and practices are also captured. Researchers, retailers, advocates and policymakers are encouraged to utilize the framework to guide the development and evaluation of interventions, policies, and practices in the online food retail space.