Nanostructured polymers (NSPs) are polymeric materials in the size of nanoscale, normally consisting of nanoparticles, nanofibers, nanowires, nanospheres and other morphologies. Polymer nanoparticles (PNPs) can be fabricated either by physical methods  or by direct nanosynthesis, using micro- or nanoemulsions with nanoreactor compartments to perform polymerization. Polymer nanofibers (PNFs) can be produced via various techniques and the most commonly used approach is electrospinning, whereby a charged solution of a polymer when exposed to an opposite high electric field is pulled into long thin nanofibers. NSPs in general exhibit enhanced properties such as excellent structural and mechanical properties, making them promising candidates for some particular building applications. A variety of PNFs have been developed and used for noise and air pollution filtration. Moreover, PNFs can also be fabricated with phase change materials which are usually employed for thermal energy storage in construction industry. In this review, we will summarize the morphologies and nanosynthesis methods of NSPs, in particular, PNPs and PNFs. In addition, representative NSPs mainly used in construction are introduced for building applications. Polymers are one of the most important engineering materials ,2. Over Several key properties are to be considered if a polymer is suitable for construction applications. First of all, its mechanical properties are of the highest importance for all applications in construction. Polymer’s mechanical properties can be determined by testing its deformation and flow characteristics under stress, and such a polymer can subsequently be classified to use as an elastomer (rubber-like products), rigid or flexible plastics, or as a fiber depending on its measured mechanical behavior obtained. Secondly, thermal properties of a polymer usually refer to its thermal stability defined by the temperature range over which it can maintain its useful properties. Commonly, polymers have low thermal conductivity and thus the materials have found application as insulators. Thirdly, polymer flammability is another important factor to be considered in construction. Usually, the response of construction polymeric materials to a combustion process is very complicated and depends on the specific type and detailed additives used in the polymers. For example, the engineering thermoplastics tend to soften and flow before ignition takes place whereas the thermosetting plastics rather undergo surface charring and sometimes the charred residue even forms an insulating layer of the flaming place. Other properties such as weathering, permeability, chemical stability, etc., are important as well and they can greatly affect the polymer performances. Comprehensive consideration and evaluation must be made before applying a polymer for real building applications. Several polymers and their common applications in construction are listed in The rapid development in the field of nanotechnology allows for new opportunities in the application of nanostructured polymers (NSPs) as construction materials. Polymer nanotechnologies not only enhance material properties and other unique functions but also facilitate energy conservation ,7,8. NSPNanoparticles (NPs) are defined as solid, colloidal particles in at least one dimension of 1–1000 nm. Thus, polymer nanoparticles (PNPs) are referred to polymeric particles which are in nanosize, typically for nanospheres and nanocapsules. Nanospheres are solid particles that have entire solid mass spherical shape. Nanocapsules are core-shell structure particles. Generally, a liquid core (either oil or water) is surrounded by a solid polymeric shell which is a kind of protection strategy for core materials to surroundings ,14,15.The methods for synthesis of PNPs can be generally divided into physical and chemical approaches, for example, dispersion and polymerization respectively. Dispersion strategy includes solvent evaporation/extraction ,17, nanoSolvent evaporation/extraction was the first method to prepare PNPs from a preformed polymer . A typicThe nanoprecipitation method of preparing PNPs is also called as solvent displacement method . It is bSalting-out method is a modified emulsification process which is achieved by adding a high concentration of salt, avoiding the usage of surfactant and chlorinated solvents . CommonlThe PNPs prepared using techniques mentioned above are from preformed polymers and do not involve any polymerization processes. Therefore, these techniques limit the preparation of PNPs in a wide variety. Direct synthesis is a possible way to make objects in nanosize, so preparation of PNPs can be done via the polymerization of monomers by careful design. Although suspension, interfacial and living radical polymerization can be employed in the preparation of PNPs, emulsion polymerization is the most common method used for the production of PNPs. The benefits of such a polymerization include (1) the use of water as the dispersion medium which is environmentally friendly; (2) excellent heat dissipation during the course of the polymerization; (3) rapid polymerization to yield high molecular weight polymers with low polydispersity; (4) easy separation of final product; and (5) mild and cost-efficient reacting conditions . In a tyPolymer nanofbers (PNFs) are defined as polymer based fibers that are at least one dimension in the size of 100 nm or less. Compared with common bulk, PNFs demonstrate comparable size-dependent behaviors similarly to other nano-objects. Experimental studies have demonstrated that PNFs will have a set of favorable properties such as increased surface-to-volume ratio, controlled release of drugs, high anisotropic electrical conductivity, enhanced light scattering and photoluminescence as well as outstanding mechanical and thermodynamic properties . As a neThere are a number of methods that are used for synthesis of PNFs in recent years such as drawing, template synthesis, phase separation, self-assembly and electrospinning. Among these techniques, electrospinning process seems to be the only approach that is for massive production and can be used for production of one-by-one continuous PNFs whereas other techniques are used to fabricate PNFs in small scales.Drawing process of PNF preparation involves a micropipette or a glass rod in contact with polymer solution droplet which is then withdrawn slowly subsequently . Single Template synthesis of PNFs uses membranes or templates to make NFs of solid or hollow shape structure . NanoporPhase separation synthesis of PNFs is usually used to prepare three-dimensionalobjects . The proSelf-assembly synthesis of PNFs is a process in which individual units organize themselves into defined patterns to form nanostructured geometries . UsuallyElectrospinning synthesis of PNFs is a simple and versatile process and most widely used for the production of PNFs ,42,43. AAlthough many of the published work have reviewed the synthesis and morphology of PNPs and PNFs, review on the polymers commonly used in construction for their nanostructures remains scarce. In this review, we focus on two areas closely related to these NSPs, (1) synthesis and morphology (2) building applications. Our intention is to fill in missing gaps and give readers a general understanding of NSPs from their synthesis, morphology and building applications.There are numerous types of polymers that have successfully been utilized on construction applications including pipes and fittings, foundations, roofing, flooring, paneling, roads and insulation, etc. These polymers often have excellent resistance to environmental elements—they neither rot nor rust, and require very little maintenance. With development of nanotechnology, researchers have been keen on exploring the polymers commonly used in construction industry for their new applications. In the following section, selected nanostructured—Polyurethane (PU), Polystyrene (PS), Polyacrylonitrile (PAN) and Polyvinyl Chloride (PVC) will be discussed. Their nanosynthesis and morphologies are summarized in Polyurethane (PU) is a synthetic polymer composed of organic units linked by carbamate bonds. They are traditionally and most commonly formed by reacting a di- or poly-isocyanate with a polyol. Both the isocyanates and polyols used to make polyurethanes contain, on average, two or more functional groups per molecule. There are numerous applications for PUs in everyday life. In construction industry, PUs are mainly used for coatings and building insulation. During the last decades, the application of nanostructured polyurethane (NS-PU) such as polyurethane nanoparticles (PU-NPs) has increased rapidly, as they can be used for various applications, including adhesives and coatings, etc., due to their good adhesion to metallic surfaces, high mechanical performance, and good resistance against chemicals.PUs are generally synthesized via direct polycondensation of diisocyanate and polyols monomers. In recent years, water-soluble or biocompatible/biodegradable monomers have been more frequently utilized for PU synthesis. Serkis-Rodzen, M. et al., prepared waterborne PU based NPs by polycondensation of polycarbonatediols (PCD), 2,2-bis(hydroxymethyl)propionic acid (DMPA) and 1,6-diisocyanatohexane (HDI) . The forl-lysine ethyl ester diisocyanate (LDI) or hexamethylenediisocyanate (HDI) and poly(ethylene glycol) (PEG) . B. B50]. BLev, J. et al. also reported using electrospinning technique to prepare PU-NFs . The as-Another promising approach to PU-NFs was reported by Guan, K. et al., using solution blowing technique . TypicalPolystyrene (PS) is a synthetic aromatic polymer made from monomer styrene by single bonds. They are typically formed by undergoing self-polymerization initiated by free radicals and the final PS can be in the state of solid or foam. They are usually used as building insulation materials and various packing materials in construction industry. In recent years, nanostructured PS (NS-PS) has been investigated extensively and applied in many fields due to its promising physical properties and excellent chemical stability.Generally, PS nanoparticles (PS-NPs) are prepared by direct synthesis using various polymerization techniques. Among these methods, emulsion polymerization is widely used because of its rapid polymerization rate, high conversion, environmentally-friendly and readily scalable characteristics . A typicCompared to conventional preparation of PS-NPs, Ernawati, L. et al. reported the synthesis of highly dispersed cationic PS-NPs with small diameters . The comPS nanofibers (PS-NFs) have been explored as well as one of the important NS-PS materials. Asran, A. Sh. et al. prepared PS-NFs with a diameter range from 150~800 nm b,c usingw/v % PS solution under the voltage of 20 kV [Hashemifard, N. et al. made the electrospun PS-NFs as well with 15 of 20 kV . The preof 20 kV . Investiof 20 kV . InteresLi, H. et al. prepared the ultrafine 19 nm-diameter PS-NFs by a facile approach based on the fast freeze technique . A PS diPolyacrylonitrile (PAN) is a synthetic, semicrystalline organic polymer plastics made from the monomer acrylonitrile. Acrylonitrile is also a co-monomer unit in several important copolymers, such as the known polymers of styrene-acrylonitrile (SAN) and acrylonitrile butadiene styrene (ABS) plastic. PAN is a versatile polymer and is used for various applications in construction industry, i.e., ultra filtration membranes, outdoor awnings and fiber-reinforced concrete, etc. Nanostructured PANs (NS-PANs), especially PAN nanofibers (PAN-NFs) have been widely explored and applied in many fields.N-vinyl pyrrolidone) (PVP) complex as both a macroinitiator and a colloidal stabilizer [The preparation of PAN nanoparticles (PAN-NPs) is usually achieved via different polymerization techniques. Landfester, K. et al. reported the preparation of PAN-NFs via miniemulsion polymerization . As showabilizer . The aveabilizer . Their s3O4 nanoparticles) were added in oil phase during the synthesis  belong to another important class of NS-PAN materials and their preparation and modification have been widely investigated. Youm, J. S. et al. prepared PAN-NFs by typical electrospinning synthesis . In orde3, AgNO3 were then mixed in DMF solvent and stirred at 120 °C for 4.5 h. The resulting solution was processed by electrospinning technique to make modified PAN-NFs with a diameter of 50–100 nm. Silver ion was incorporated into PAN matrix via Click chemistry, resulting in the dramatic enhancement of antibacterial property of the prepared PAN-NFs. Almasian, A. et al. also made surface modification of electrospun PAN-NFs using amine and it was found that the modified PAN-NFs were promising candidates for anionic dye adsorption from colored wastewater with high adsorption capacity [2 doped PAN-NF based membrane using electrospinning synthesis, followed by further treatment with UV-ozone [Wang, W. et al. reported an efficient and convenient method for the synthesis of modified PAN-NFs with antibacterial property . PAN polcapacity . SimilarUV-ozone . ElectroUV-ozone . The modUV-ozone . It was In addition to widely employed electrospinning technique, other approaches to preparation of PAN-NFs have also been explored by researchers. Jang, J. et al. reported the facile preparation of PAN-NFs using microemulsion polymerization , and thePolyvinyl chloride (PVC) is one of the world’s most widely produced synthetic plastics which are made from monomer vinyl chloride by single bonds linkage. Pure PVC is a white, brittle solid and exists commonly in two basic forms: rigid and flexible. The rigid PVC is usually used for pipe and floor coatings in construction industry. The flexible PVC can used for plumbing, electrical cable insulation, inflatable products, etc. Similarly, nanostructured PVCs (NS-PVCs) have been investigated, reported and employed in applications.Vatani, Z. et al. reported the fabrication of 40 nm PVC-NP with polyaniline at the presentence of various surfactant to form nanocomposites . The proPVC nanofibers (PVC-NFs) have also been prepared and studied. Phatcharasit, K. et al. reported the preparation of PVC-NFs and its corresponding nanofaborous membrane . The synN,N-dimethylacetamide (DMAC) were uniform and had an average diameter of ~45 nm. Additionally, the SEM images  removal, has been of great importance to the living quality and health of people. Wu, H. et al. developed a fast, efficient and free-of-high-voltages technique via blow-spinning for the large-scale direct coating of PAN-NFs onto window screen for indoor PM pollution protection . TypicalJing, L. et al. reported the preparation of ionic liquid modified PAN-NFs by electrospinning . Highly 2 doped PAN-NFs for air filtration. The prepared nanofiber membrane was shown to exhibit high filtration efficiency and high photocatalytic activities at the same time [In addition, PNF based nanocomposites have also been reported in the development of air filtration systems. Zhang, S. et al. reported the preparation of polyacrylonitrile/polysulfone (PAN/PSU) composite based membranes for air filtration . The preame time .n-octadecane mixture contained PS micro/nanoparticles for low-temperature latent heat thermal energy storage applications [−1, showing good performance for latent heat thermal energy storage at low temperature. Similarly, Fang, Y. et al. also prepared octane contained PS-NPs via ultrasonic-assisted microemulsion polymerization [Storing heat from renewable thermal energy sources for consumption at a later time and a different location has been of great interests on energy storage. Phase change materials (PCMs) can effectively store thermal energy during phase changes and have been used in buildings to enhance the thermal comfort of lightweight buildings for energy savings. Therefore, the storing and releasing of latent heat energy through the melting and solidifying of phase change materials (PCMs) has become the most efficient and cost-effective way for a variety of thermal energy storage applications. PS-NPs, especially PS encapsulated PCM nanocapsules, have been developed rapidly for the purpose of thermal energy storage. Sari, A. et al. reported the preparation of n-tetracosane and ications . The PCMrization . The diarization .co-acrylonitrile) (PSAN) and LA PCM to make nanofibers via electrospinning [In addition to the widely used PNPs, PNFs have also been used in thermal energy storage materials. Lu, P. et al. reported a simple and reliable approach to the fabrication of lauric acid (LA)-containing PS-NFs . The fibspinning . Their ispinning . It was spinning . ThermalIt is well known that noise commonly have serious adverse effects on both human beings and machines, so noise is often referred to as a form of pollution and is the object of environmental regulations. Rabbi, A. et al. reported the use of PAN-NFs or PU-NFs incorporated in PET nonwovens as highly effective sound absorbers . First, In addition to the application discussed above, there are other building applications achieved by NSPs as well, some of them are summarized below:Corrosion is a natural process. The gradual destruction of materials  by chemical and/or electrochemical reaction with their environment, causes huge economic losses. Gaballah, S. et al. developed new, cost effective and high performance creia PVC-NF nanocomposites for corrosion resistance of aluminium . The PVCDue to their good adhesion to metallic surfaces and excellent mechanical properties, PU-NPs have been developed as metal adhesives or coatings. Müller, K. et al. prepared PU-NPs with high molecular weight via nonaqueous emulsion polyaddition . The aveRazavi, S. M. J. et al. prepared smooth, continuous PAN-NFs with a diameter of 362 ± 87 nm using electrospinning . The fibIn construction industry, flame retardants are a key component in reducing the devastating impact of fires on people, property and the environment. They are commonly added to potentially flammable materials, including textiles and plastics. Xiao, L. et al. reported the preparation polyamide 66 nanofibers (PA66-NFs) incorporated with nanoscale grapheme hybridized with red phosphorus (NG-RP) . The novPolymers are essential materials in construction industry given their many inherent structural and mechanical properties. The incorporation of nanotechnology into polymeric materials allows for greater improvement in these vital properties. In this review, nanostructured polymers, especially polymer nanoparticles and polymer nanofibers have been introduced for their general fabrication techniques. In addition, nanosynthesis and morphologies of widely used polymers in construction, including PU, PS, PAN and PVC, have been highlighted for their nanostructured materials. Polymer nanoparticles are generally prepared by direct synthesis via various polymerization techniques whereas polymer nanofibers are mostly fabricated by electrospinning synthesis. Finally, building applications of a wide variety of nanostructured polymers, such as air filtration, thermal energy storage, sound absorption as well as some of other applications are reviewed. It can be predicted that the field of nanostructured polymers in construction industry will be gradually transformed from a budding stage to a blossoming stage and more fundamental research is required to develop new polymeric nanomaterials in a large scale. These efforts will eventually speed up the commercial utilization of nanostructured polymers in construction.


Indoxyl sulfate (IS) is one of the most potent uremic toxins involved in chronic kidney disease (CKD) progression, induction of inflammation, oxidative stress, and cardiovascular diseases occurrence. It is proved that hypertension is a common CVD complication and a major death risk factor as well as contributes for decline in a renal function. The aim of our study was to investigate how implementing of antihypertensive therapy impact IS concentrations and the associations between IS and markers of renal function, inflammation and oxidative stress.Study was conducted on 50 patients diagnosed with CKD and hypertension, divided into three groups: without hypotensive therapy (CKD-NONE), hypotensive monotherapy (CKD-MONO), and hypotensive polypharmacotherapy (CKD-POLI), and 18 healthy volunteers. The markers of inflammation , oxidative status , and selectins were determinate using immunoenzymatic methods. IS levels were assayed using high-performance liquid chromatography and other parameters were analysed using routine laboratory techniques. Then cross-sectional analysis was performed.Elevated levels of IS, indicators of kidney function, markers of inflammation and blood pressure values were observed in each CKD subgroups. There was no effect of antihypertensive therapy on IS levels between studied groups, as well as there was no clear relationship between IS and blood pressure values in each studied group. The positive associations between IS and Cu/Zn SOD, neopterin, hs-CRP, creatinine and neutrophils/lymphocytes ratio were observed in CKD-NONE and CKD-POLI subgroups. Additionally, in CKD-POLI group IS positively correlated with TNF-α, ferritin and neutrophils. In CKD-MONO group, IS was positively related to oxLDL-abs, neopterin, E-selectin and creatinine, whereas it was inversely associated with hs-CRP.Our study showed for the first time that the antihypertensive therapy has no impact on IS levels in CKD patients with hypertension. However, the introduction of the antihypertensive therapy modified the dependencies between IS and the studied markers of kidney function, inflammation, oxidative stress and hematological parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension.The online version of this article (10.1007/s11255-018-02064-3) contains supplementary material, which is available to authorized users. Inflammation as an essential part of chronic kidney disease (CKD) has been recognized in the late 1990s, when it was linked to nearly 20 times higher mortality in CKD resulting from cardiovascular disease and an exceptionally high mortality rate overall . Among tUremic toxins are endogenous products of metabolism and are accumulated in the body fluids during the progression of CKD due to inadequate renal clearance. One of the most potent, protein-bound uremic toxin is indoxyl sulfate (IS)—dietary tryptophan (Trp) derivative . There iNot only the concentrations of uremic toxins increasing along with the progression of CKD. Another factors strongly correlated with the stage of renal failure are values of blood pressure (BP). Generally, BP increases linearly with the progression of a loss of the renal function. Simultaneously, elevated BP accelerates severity of the kidney disease leading to the occurrence of hypertension (HTN), which is the risk factor for heart disease, stroke, and death. This detrimental feedback interaction between kidney function and BP was observed in early experiments with animal models of kidney injury and later in clinical data . The welCurrently, there is no data regarding the influence of pharmacotherapy for hypertension and its form on the levels of IS and its associations with the markers of the inflammatory state, oxidative status as well as parameters describing the renal function. Taking all together, the aims of our work were: (I) to evaluate the concentrations of IS, the markers of inflammation and oxidative status, and indicators of renal function in patients with CKD treated with diversified antihypertensive therapy and compared obtained results with control group and patents with CKD without implemented pharmacotherapy; (II) to assess the influence of used antihypertensive agents on dependencies between the levels of IS and above-mentioned parameters.n = 50) were categorized into three different CKD groups: CKD-NO , CKD-MONO , and CKD-POLI . Patients were treated with angiotensin-converting enzyme inhibitors, calcium channel blockers, and beta-adrenergic blocking agents. As a control group served healthy volunteers (n = 18) matched for age and gender. They were not taking any medications, dietary supplementation, and were on a standard diet. In the past, hypertension, renal failures, diabetes mellitus, chronic inflammatory status, and vascular diseases were not reported.Fifty consecutive patients diagnosed with CKD and HTN who had been hospitalized in Nephrology and Clinical Transplantation Department of Medical University of Bialystok  were enrolled in the study. The diagnosis was made clinically, based on actual KDIGO classification’s guidelines . All of The study was approved by the Ethical Committee of the Medical University of Bialystok (No. R-I-002/233/2017) and complied with the provisions of the Good Clinical Practice Guidelines and the Declaration of Helsinki.Venous blood samples (10 mL) were taken in vacutainer tubes under sterile conditions from patients and controls in the morning. Plasma was obtained from freshly drawn blood, rapidly centrifuged after collection. Plasma was quickly frozen at − 80 °C and stored until assayed.The concentrations of IS in the plasma were measured by high-performance liquid chromatography (HPLC), accordingly to Al Za’abi  with ourPlasma Cu/Zn superoxide dismutase (Cu/Zn SOD) levels were measured by ELISA-kit . The levels of autoantibodies against oxidized LDL (ox-LDL-abs) were determined by an oLAB ELISA-kit (Biomedica). TNF-α levels were measured in the plasma with HS human TNF-α ELISA-kit . To determinate concentrations of IL-6 we used IL-6 ELISA-Kit . Plasma hs-CRP levels were determinate using ELISA-kit . Neopterin concentrations were also measured using ELISA-kit . Levels of E-selectin and P-selectin were measured using ELISA-kits provided by American Diagnostica . All tests were performed according to manufacturers’ instructions by the same person.Biochemical and the complete blood count tests were performed by routine laboratory techniques using an automated analyzer.t test or nonparametric Mann–Whitney test were used to compare differences between CKD group and control group, whereas for gender diversity and CVD occurrence Chi square test was performed. The analysis of variance (ANOVA) was used to check differences between the CKD subgroups. The correlations between studied variables were determined by Spearman’s rank correlation analysis. A two-tailed p value < 0.05 was considered to be statistically significant. Computations were performed using GraphPad 6 Prism Software . The power of the analysis was estimated using StataIC 13 Software .The normality of distribution was tested using the Shapiro–Wilk test and quantitative data were expressed as mean ± SD. The non-Gaussian data were presented as median (full range). The Student's p > 0.05). Overall CKD population and each of the CKD subgroups reflected significantly increased values of SBP, DBP, and MBP compared to the control group , however, there were no statistically significant changes of these parameters amidst the CKD subgroups. The overall history of CVD events and CKD stages assignments are presented in Table p < 0.001), however, there were no statistically significant changes inside all of the CKD subgroups. Mean albumin values were statistically decreased in each of uremic groups compared to controls, whereas only CKD-TOTAL and CKD-POLI group presented lowered concentrations of total protein compared to controls, achieving p < 0.05. There were no changes in the levels of glucose, however, CKD-POLI group presented lower alanine aminotransferase test (ALT) values than controls (p < 0.05) and there was only a difference in ALT values inside the CKD-subgroups (p < 0.05). Regarding the complete blood count analysis, we observed changes with statistical significance in the levels of red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT)—for both, CKD-TOTAL and each of the CKD-group p < 0.001. All the values were decreased in each CKD subgroups and CKD-TOTAL compared to controls. In addition, CKD-TOTAL, CKD-MONO and CKD-POLI subgroups were characterized by reduced percent of lymphocytes (LIM) . There were no changes in white blood cells (WBC), neutrophils (NEU), and platelets (PLT) count between the CKD patients and the control group. None of the complete blood count test parameters was significantly changed amongst the CKD subgroups, however, result of multiple comparison test in case of PLT count was on the edge of significance (p = 0.066). The values of neutrophils to lymphocytes ratio (NLR) were statistically elevated in CKD-TOTAL and in all of the CKD subgroups, however, similarly to other morphological the complete blood count parameters there were no differences between in the subgroups.A total of 50 patients  and 18 age and sex-matched healthy controls were enrolled in the study as shown in Table p < 0.001 for CKD-TOTAL, CKD-MONO, and CKD-POLI compared to the controls), a slight increase was observed in CKD-NO (p < 0.01) subgroup. Among the CKD subgroups, there were no significant changes in the levels of IS. As shown in Table p < 0.05), there were no changes in its concentrations between controls and each of CKD-subgroups. In terms of concentrations of Cu/Zn SOD and E/P-selectins, there were no differences found between CKD subgroups and the controls as well as amongst the drug-treated subgroups.Measured plasma levels of IS were about two to fourfold higher (p < 0.01), whereas, in CKD-MONO subgroup there was no correlation observed. Other varied results have been observed in the dependencies between IS levels and oxLDL-abs concentrations—in CKD-POLI group IS correlates inversely with oxLDL-abs, whereas in the CKD-MONO subgroup the statistically significant (p < 0.05) correlation was positive. Similarly, in the case of TNF-alpha, hs-CRP, and ferritin-obtained results were varied and achieved statistically significant values. All of the CKD subgroups show a strong correlation  between IS levels and the measured concentrations of neopterin. In the case of ferritin, there is inverse correlation between this parameter and IS in CKD-NO, whereas the positive relationship existed between above parameters in CKD-POLI subgroup. As shown in Table Table p < 0.05 for CKD-NO and p < 0.01 for CKD-MONO and CKD-POLI). The levels of IS were inversely associated with the albumin concentration in CKD-NO and CKD-POLI groups (p < 0.05), however, there was no dependence in CKD-MONO group. Interestingly, IS levels correlated with MBP values in CKD-NO and CKD-MONO group, not in CKD-POLI subgroup. There were no associations between IS levels and SBP nor DBP values regardless of subgroup. Regarding correlations between plasma concentrations of IS and the complete blood count parameters, in CKD-MONO subgroup no statistically significant associations have been found. But then, both CKD-NO, as well as CKD-POLI subgroup, were correlated with the number of neutrophils and NLR ratio, and inversely correlated with measured lymphocytes. Moreover, IS was inversely correlated with hemoglobin values in CKD-POLI subgroup.As presented in Table None of the measured parameters correlated with the levels of IS in the control group.uremic milieu—the term introduced in the 2010s’ describing existence and accumulation of many factors contributing to cardio-renal syndrome and vicious circle of renal disease [Decline in renal function, chronic inflammation, oxidative stress, as well as hypertension (HTN) create  disease . Recentl disease  and risk disease . In cont disease .Emerging evidence indicates that IS can be one of the uremic toxins associated with renal insufficiency progression and increased cardiovascular mortality . DespiteAs mentioned above, there is a strong evidence that along with the progression of CKD the values of blood pressure increase, resulting in the occurrence of hypertension. Meanwhile, due to insufficient renal clearance, toxic metabolic products are being accumulated in the body. The important observation resulting from our study is the lack of effect of antihypertensive therapy on IS levels between the studied subgroups. The recent studies correlated increasing values of BP with rising concentrations of uremic toxins—as a marker of progressive renal insufficiency . Our resMany studies highlighted proven track record of contiguous associations between IS levels and inflammatory markers at every stage of CKD . One of Another pro-inflammatory molecule, which has been proposed as a prognostic marker for CVD and risk for occurrence of hypertension during CKD is TNF-α. The molecule is produced mainly in the acute phase of inflammation by activated macrophages, however, in chronic inflammation may be released also by CD4+, eosinophils, neutrophils, and natural killer cells and its levels increase even 100-fold . TNF-α pIL-6 is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells making this molecule as a promising therapeutic target during CKD . RecentlRecent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes and macrophages, are elevated in patients with CKD and seem to be a prognostic marker for major CVD events . AvanzasPreviously, Chu et al. defined IS as a strong factor leading to misbalance in redox status and correlated with progression of CKD due to oxidative damage of endothelial cells, vascular smooth muscle cells as well as other functional structures of nephrons leading to the occurrence of viscous circle . To checAnother marker linking inflammation, oxidative stress and CVD risk during CKD is oxidative modified LDL (ox-LDL), which contributes to the CVD via induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation . Nearly Anemia associated with CKD has substantial importance for the occurrence of CVD in nephrological patients. Results of Barany et al. shows that while anemia is closely associated with a reduction in eGFR levels, much of this association appears to be the result of confounding by associated factors, especially the presence of chronic inflammation . Due to Serum albumin is a significant risk factor for cardiovascular disease in CKD patients . AvailabShen et al. suggested that IS may play an important role in the development of CVD in kidney diseases during inflammation by increasing endothelial expression of E-selectin . At the To make our research possible wide, we also checked if the form of the treatment influenced the correlations between IS and crucial hematological parameters related to inflammation and CVD death risk obtained using the complete blood count test. The evaluated WBC count, LIM and NEU percent were in the line with previous papers discussing the occurrence of changes in morphological parameters along with the CKD progression . In the The main limitation of the study is a sample size—total number of patients and their allocation in three independent group increased the risk for bias occurrence and significantly reduced statistical power of performed analyses. The current study has some other possible limitations that should be noted. We are aware that our results have to be considered as a preliminary report—number of analysed parameters and many potential confounding factors are the main weak points of the conducted study. Besides, we did not introduce differentiation in terms of specific groups of antihypertensive therapy and used agents, and we are not able to explain some of the mechanisms underlying observed phenomena. Particularly, the conclusions drawing from the results demonstrated in CKD-MONO group should be interpreted with care.In conclusion, our study is the first to show that the introduction of the antihypertensive therapy influences the dependencies between the indoxyl sulfate and studied parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension. The resultant of the changes are to a large extent unpredictable, however, seem to affect many parameters related to oxidative stress, inflammatory status as well as immunological response. At this moment, the results of our preliminary study have to be treated as potential signposts leading to better understanding discussed issues.Below is the link to the electronic supplementary material.Supplementary material 1. This figure presents relationships between IS and markers of inflammation, oxidative status, and selectins in studied CKD subgroups. Cu/Zn SOD - superoxide dismutase 1, oxLDL-abs – oxidized low-density lipoprotein antibodies, TNF-alpha – tumor necrosis factor alpha, hs-CRP – high sensitivity C-reactive protein. (JPG 236 KB)Supplementary material 2. This figure shows the correlations between IS and blood pressure values, morphological the complete blood count parameters, and renal function markers in studied CKD subgroups. MBP – mean blood pressure, eGFR – estimated glomerular filtration rate, WBC – white blood cells, LIM – lymphocytes, NEU – neutrophils, NLR – neutrophils to lymphocytes ratio. (JPG 215 KB)


Immune checkpoint inhibitors propelled the field of oncology with clinical responses in many different tumor types. Superior overall survival over chemotherapy has been reported in various metastatic cancers. Furthermore, prolonged disease-free and overall survival have been reported in the adjuvant treatment of stage III melanoma. Unfortunately, a substantial portion of patients do not obtain a durable response. Therefore, additional strategies for the treatment of cancer are still warranted. One of the numerous options is dendritic cell vaccination, which employs the central role of dendritic cells in activating the innate and adaptive immune system. Over the years, dendritic cell vaccination was shown to be able to induce an immunologic response, to increase the number of tumor infiltrating lymphocytes and to provide overall survival benefit for at least a selection of patients in phase II studies. However, with the success of immune checkpoint inhibition in several malignancies and considering the plethora of other treatment modalities being developed, it is of utmost importance to delineate the position of dendritic cell therapy in the treatment landscape of cancer. In this review, we address some key questions regarding the integration of dendritic cell vaccination in future cancer treatment paradigms. Since William Coley made his early contributions to the study of cancer immunotherapy in the 1890s, harnessing the capabilities of the immune system to eliminate cancer cells remained a long-sought dream –7. ImmunCurrently, the clinical application of immunotherapy is mainly defined by ICI. ICI target immune checkpoint molecules such as CTLA-4, PD-L1, and PD-1. These molecules have immune response inhibiting functions and are involved in the prevention of autoimmunity and the maintenance of peripheral tolerance. It is well known that tumor cells are able to upregulate the expression of checkpoint molecules, leading to anergy of cytotoxic T-cells in the tumor microenvironment. CTLA-4, PD-L1, and PD-1 have distinct functions; CTLA-4 exerts its inhibitory functions on the initial T-cell activation whereas PD-1 and PD-L1 have roles in the inhibition of the effector functions of T-cells , 9. ICI In 2010, ipilimumab  was the first immunotherapeutic agent providing clinical benefit in cancer patients, extending median overall survival (OS) to 10 months (compared to 6.4 months for the control group receiving a gp100 peptide vaccine) in metastatic melanoma . With anAfter these landmark studies, research into ICI accelerated. With the addition of PD-L1 targeting agents avelumab, atezolimumab, and durvalumab, the field of ICI now encompasses six FDA and EMA-approved monoclonal antibodies (mAb) , 15, 16.Besides PD-1, PD-L1 and CTLA-4, other checkpoint molecules (such as TIM-3 and LAG-3) have shown to inhibit the anti-cancer immune response . SeveralICI come with a different toxicity profile compared to other anti-cancer therapeutics, caused by specific immune-related side effects. Monotherapy with anti-PD-1 mAb and anti-CTLA-4 mAb are associated with 10–16% and 30–40% grade 3 or 4 adverse events, respectively , 22. In Since their discovery by Steinman in 1973, it became clear that DC are antigen-presenting cells crucial in activating the adaptive immune system . DC are ex vivo with danger signals and loaded with tumor-specific antigen(s) on their major histocompatibility complex molecules with the intent of activating antigen-specific T-cells which selectively eliminate antigen-bearing cancer cells  are subject of intense research. For example, several groups, including our own, use natural circulating DC instead of monocyte-derived DC. Natural circulating DC do not require extensive culturing which is believed to retain their functionality. Different maturation techniques are also being explored, such as the use of toll-like receptor ligands or electroporation with mRNA-encoding proteins that induce DC maturation , 32. AnoRegardless of the precise protocol employed, DC vaccination is associated with a very favorable toxicity profile. The majority of side effects reported in various clinical trials were short-lived grade 1 or 2 adverse events, consisting of self-limiting flu like symptoms, fever and local injection site reactions. Treatment-related grade 3 or 4 adverse events following DC vaccination as standalone therapy are uncommon , 24.The goal of DC vaccination is to kill tumor cells by the generation of functional antigen-specific T-cells . DespiteBesides the generation of T-cells, intense research is ongoing to find biomarkers, not only for DC vaccination but for immunotherapy in general. Considering ICI treatment, research into predictive biomarkers has revealed several biomarkers predictive for response on ICI  , 38. SimResponse rates to DC vaccination vary among cancer types with most studies showing response rates between 10 and 15% . Most clThe immunotherapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is very different from that of metastatic RCC and metastatic melanoma. Two phase III trials investigating ipilimumab showed, both in pre-docetaxel and post-docetaxel setting, no improvement in OS compared to their control groups , 43. PemNotably, sipuleucel-T gained approval for the treatment of asymptomatic or minimal symptomatic mCRPC. Sipuleucel-T is manufactured from autologous mononuclear cells obtained via apheresis. These cells are incubated with PA2024, a fusion protein of the tumor antigen prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). As DC are not specifically isolated from the apheresis product and the end product contains a variety of cells, sipuleucel-T should strictly speaking not be regarded as a pure DC vaccine. Despite this, sipuleucel-T is generally addressed as a DC based-vaccine and is considered to be the first DC-based therapy approved by the FDA. The approval of sipuleucel-T followed the results of a phase III trial including 512 mCRPC patients. The median survival was prolonged with 4 months compared to placebo . AnotherInitial enthusiasm about sipuleucel-T has somewhat subsided in recent years since labor intensive production resulted in a highly priced cellular product (around $125.000). At the moment, sipuleucel-T is only available in the USA as market authorization was not granted by the EMA. Recently, a Chinese conglomerate (Sanpower) acquired Dendreon (producer of sipuleucel-T) for over $800 million with the intention to extend the market to Asia. Sipuleucel-T enhanced immune responses toward its antigen (PAP/PA2024). A PAP/PA2024-specific immune response  was seen in 79% of patients. The immune responses correlated with OS and could be beneficial for the response on subsequent or concomitant immunotherapeutics, a paradigm which will be detailed in the final chapter of this review .In conclusion, in metastatic malignancies such as non-small-cell lung cancer, melanoma, urothelial cancer and RCC, where ICI are particularly effective, it is unlikely DC vaccination will gain a role as monotherapy in widespread metastatic disease due to its less established clinical benefit.Besides the application of anti-cancer therapeutics in the treatment of metastatic disease, the adjuvant treatment of patients after surgery of local disease is also common practice in oncology. Surgical resection with curative intent aims to excise all tumor burden. However, depending on the type of malignancy, occult residual disease remains in a variable portion of patients and can eventually lead to relapse . AdjuvanThere are some additional arguments to consider DC vaccination as an adjuvant treatment option. Besides efficacy, a low toxicity profile is an important hallmark of any adjuvant treatment as a substantial portion of cancer patients receiving adjuvant treatment would not endure a relapse even without this adjuvant therapy. As noted before, DC vaccination is associated with little toxicity, not only compared to chemotherapy but also compared to ICI. In addition, besides a direct clinical benefit for patients, adjuvant DC vaccination might also prove to be beneficial in improving response to subsequent treatment in case of relapse. In theory, tumor-specific T-cells induced by adjuvant DC vaccination might result in an increased tumor-specific immune response when ICI are given at a later moment in the metastatic setting. Indeed, this effect has been observed retrospectively with administration of ipilimumab in patients with relapse after adjuvant DC vaccination for stage III melanoma . In addiAdjuvant DC vaccination has been studied in GBM. In contrast to most malignancies, distant metastases seldom occur in GBM . NonetheHistorically, the central nervous system is considered an immune-privileged site, casting doubt whether GBM could be susceptible to immunotherapy. However, in recent years it has become increasingly clear the central nervous system is subject to active immunosurveillance even with an intact blood-brain barrier . Albeit Next to monotherapy with ICI, ICI combined with other standard treatment modalities is being investigated in phase III trials. For example, CheckMate 498 (comparing TMZ and radiotherapy to nivolumab and radiotherapy) and the CheckMate 548 , both involving nivolumab, are currently ongoing. Similar phase I and II trials combining pembrolizumab or ipilimumab with TMZ and radiotherapy are being performed. Results on such integration of ICI in standard treatment strategies are not yet reported.Considering DC vaccination studies concerning GBM, DC-based therapy is often integrated into the standard adjuvant treatment for GBM. As of now, the only available phase III trial data involving DC vaccines in GBM are the very recently published interim results of an ongoing clinical study involving a vaccine called DCVax®-L . Melanoma with lymph node metastasis has a 5-year survival rate ranging from 40% (stage IIIC) to 78% (stage IIIA) . In RCC,p = 0.002)  . Althoug= 0.002) , 84. In = 0.002) , 20. Adjp = 0.03). However, utility is limited due to high toxicity and lack of OS gain . The primary endpoint however, 3-year PFS rate, was not significantly improved probably due to the small number of patients   . Markowi= 0.108) . No phasIn RCC, research on DC vaccination is mainly focused on metastatic disease and little data regarding adjuvant DC vaccination is available. However, a phase III trial was performed with adjuvant DC vaccination in various stages of disease. Patients vaccinated with DC loaded with tumor lysate in combination with cytokine-induced killer cells were compared to patients treated with IFN-α. Mainly due to a very heterogeneous study population, no definitive conclusions could be drawn. However, the study showed significant PFS and OS benefit suggesting that further research on adjuvant DC vaccination in RCC is warranted .Currently, too little data is available to claim that DC vaccination is effective in the adjuvant setting. Yet, the above presented data, show favorable clinical results and consistently confirm the limited toxicity in a variety of cancers. More robust prove of efficacy may be under way as several phase III trials on adjuvant DC vaccination are currently being performed Table . WhetherAs noted before, the clinical benefit of monotherapy DC vaccination for patients with metastatic disease is probably limited. However, the ultimate role for vaccines may lie in the combination with other modalities. The generation of a cellular immune response upon DC vaccination is commonly reported and may potentiate the effect of other anti-cancer therapeutics . ConversBoth ICI and DC vaccination exert their effects primarily through the modulation of the immune system and do so on different steps in the cancer immunity cycle. For response on ICI, tumor-specific T-cells have to be present in the tumor microenvironment, the generation of which may be aided with DC vaccination . As intrin vitro  and DC vaccination in melanoma patients . DespiteConsidering its lower toxicity and better response rates compared to anti-CTLA-4 mAb, anti-PD-1 mAb might be more suitable combinational partners for DC vaccines. As of now, no data is published on the combined anti-PD-1 mAb and DC vaccination. However, several clinical trials investigating combinations of DC vaccination with clinically approved ICI are currently being performed Table .Besides currently approved ICI, DC vaccination can also be combined with ICI targeting alternative immune checkpoints . Currently, mAb targeting LAG-3 and TIM-3 are in various stages of clinical development as monotherapy and might be good candidates for combination. LAG-3 mAb for example, were shown to reduce expansion of Treg . TIM-3 wDespite several ongoing clinical trials, an important aspect of combinational strategies, the timing of administration, might be under-investigated. In theory, it would seem logical to first administer DC vaccines to generate tumor-specific T-cells and consequently release immune suppression with anti-PD-1 mAb. Conversely, the timing of administering DC vaccines and ipilimumab may be more complex as both ipilimumab and these vaccines exert their functions in the priming phase of T-cells. Indeed, in a pre-clinical prostate cancer model optimal response on ipilimumab was shown when given on the same day as vaccination . WhetherIn conclusion, combinational strategies for the treatment of cancer incorporating DC vaccination are a promising field of research. Considering the favorable results on the combination of DC vaccination and anti-CTLA-4 mAb, the results on the currently ongoing combinational clinical trials with anti-PD-1 and anti-PD-L1 mAb are eagerly awaited.Immunotherapy for the treatment of cancer is a fast-moving field. It is important to determine the relative position of DC vaccination to other treatments in this rapidly evolving landscape. Ideally, patients can be selected based on biomarkers predictive for response to therapy. Currently, no predictive biomarkers for DC vaccine response are applied in the clinic to guide treatment decisions but the immune landscape of the tumor might hold promise. Also, few clinically useful predictive biomarkers for ICI are known. With the success of ICI and the lesser clinical benefit of DC vaccination in metastatic disease, it becomes increasingly clear that the future of DC vaccination in extensive metastatic disease as standalone treatment is probably limited. However, the immune-inducing properties of DC vaccination makes it a prime candidate for combination with other anti-cancer modalities, especially ICI. The currently ongoing research on DC vaccination combined with ICI such as anti-PD-1 mAb has to determine whether this combination has a future perspective. The theoretical basis and the promising clinical data on anti-CTLA-4 mAb combined with DC vaccination does imply this perspective exists. With its highly favorable toxicity profile, another application of DC vaccination might lie in the adjuvant setting. Furthermore, DC vaccination as monotherapy may be more effective in adjuvant setting compared to its application in metastatic setting.Consequently, for DC vaccination to gain a definitive role in the therapeutic landscape of cancer, research should be focused on well-designed trials in the adjuvant setting, combinational strategies, and patient selection.ad hoc consultancy for Aglaia Biomedical Ventures; WG received research grants from Bayer; Astellas and Janssen-Cilag.WG received speaker's fees from Bayer and Bristol-Myers Squibb; WG participated in advisory boards of Amgen, Astellas, Bayer, Bristol-Myers, Dendreon, Squibb, and Sanofi. WG participated in WvW, KB, and IdV conception and design; WvW, KB, MB, GS, IdV, and WG writing, review, and/or revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The stress associated with caring for a loved one with Alzheimer’s disease or a related dementia can negatively affect mental and physical health. Mindfulness-based stress reduction (MBSR), teaching caregivers to focus on the present moment with non-judgmental awareness, has been shown to improve overall mental health, reduce perceived stress, and decrease depression. At HealthPartners, we implemented the Mindfulness Based Dementia-Care (MBDC) program, an 8-week program designed for family caregivers for those living with dementia. MBDC combines teaching of MBSR skills along with essential education for this chronic disease. Participants attend a 1-hour orientation session, 2-hour classes each week for 8 weeks, at-home practice between classes, and a 6-hour Saturday retreat. Secure electronic surveys are administered at baseline, program completion and follow-up for evaluation of the program. We will discuss barriers and learnings of implementation as well as preliminary results from the evaluation.


This treatment is associated with acute and late toxicities, including myelosuppression, severe nausea/vomiting, irreversible renal failure, hearing loss, and neurotoxicity. Because of cisplatin's safety profile, treatment adherence to high-dose cisplatin can be suboptimal. Patients commonly receive less than the total cumulative target dose of 300 mg/m2 or the minimum recommended dose of 200 mg/m2, which can have a negative impact on locoregional control and survival. Alternatively, cetuximab plus radiotherapy may be most suitable for patients at high risk of non-adherence to high-dose cisplatin. We discuss the baseline characteristics dictating the unsuitability/borderline unsuitability of cisplatin and the available alternative evidence-based treatment regimens for patients with LA SCCHN. We non-systematically reviewed published phase II and III trials and retrospective analyses of high-dose cisplatin-based chemoradiation in LA SCCHN conducted between 1987 and 2018, focusing on recent key phase III studies. We defined the baseline characteristics and associated prescreening tests to determine unsuitability and borderline unsuitability for high-dose cisplatin in combination with radiotherapy in patients with LA SCCHN. Patients with any pre-existing comorbidities that may be exacerbated by high-dose cisplatin treatment can be redirected to a non-cisplatin-based option to minimize the risk of treatment non-adherence. High-dose cisplatin plus radiotherapy remains the preferred treatment for fit patients with unresected LA SCCHN; patients who are unsuitable or borderline unsuitable for high-dose cisplatin could be identified using available tests for potential comorbidities and should be offered alternative treatments, such as cetuximab plus radiotherapy.Concurrent chemoradiotherapy with high-dose cisplatin (100 mg/m Squamous cell carcinoma of the head and neck (SCCHN) is among the most frequent cancers worldwide . AlthougRadiotherapy plus concomitant chemotherapy for LA SCCHN (stage III-IV) has been shown to improve 5 year absolute survival by 6.5% compared with locoregional treatment alone, as reported in a meta-analysis . However2 every 3 weeks (high-dose cisplatin) with conventional fractionation radiotherapy or two cycles with altered fractionation radiotherapy  and the National Comprehensive Cancer Network, concurrent cisplatin-based chemoradiotherapy is the preferred treatment for fit patients with unresectable LA SCCHN and for those with resectable LA SCCHN but with a poor prognosis, functional loss, or high-risk features in the post-operative setting  , 5. The otherapy , 6.2 than in those who receive >200 mg/m2  is significantly lower in patients with HPV-negative LA SCCHN  who receive a cumulative cisplatin dose of ≤200 mg/m00 mg/m2 . However00 mg/m2 . Indeed,isplatin , 9, 10.  regimen , and a r regimen  showed tUnlike the population commonly enrolled into clinical trials, patients with LA SCCHN in the real-world clinical setting often present with more challenging baseline characteristics and risk factors . Unfortunately, no standardization of supportive care during chemoradiotherapy exists, and patient volume at treatment centers can affect the quality of treatment selection and supportive care . TherefoIn this review, we discuss risk factors associated with high-dose cisplatin that can enable physicians to identify which patients with LA SCCHN are eligible, ineligible, or eligible with a high risk of treatment non-compliance—the so-called “borderline unsuitable”—for concurrent high-dose cisplatin chemoradiotherapy with curative intent. Most of the data described here emerged before the distinct clinical entity of HPV-associated OPC was fully understood and when the proportion of patients with HPV-associated OPC enrolled in clinical trials was likely lower than that in contemporary cohorts. Therefore, the recent results of phase III studies of HPV-positive OPC exploring the clinical outcomes of cisplatin plus radiotherapy vs. alternative regimens are important.The addition of high-dose cisplatin to radiotherapy both exacerbates known radiotherapy-associated adverse events (AEs) and causes specific cisplatin-associated AEs , which aCisplatin-induced neurotoxicity, experienced at grade ≥3  by ≤10% of patients , affectsOtotoxicity is another highly distressing AE. Although its mechanism is not fully understood, ototoxicity arises predominantly from sensory hair cell death within the cochlea and is perpetuated by irradiation of and cisplatin-mediated damage to the cochlea (often neglected as an organ at risk) , 51, 52.Cisplatin-induced nephrotoxicity is the result of a combination of factors. The kidney absorbs cisplatin at higher concentrations than other tissues , 54. In Acute gastrointestinal symptoms associated with cisplatin-based chemoradiotherapy include nausea, vomiting, mucositis/stomatitis, xerostomia, taste alteration, constipation, and diarrhea and have a remarkably high incidence .2), cisplatin-induced vomiting occurs in 60–90% of patients , which, combined with radiation-induced loss of taste, can lead to marked dysgeusia and consequently poor food intake and nutritional problems , 62. AddSince cisplatin's introduction as a chemotherapy agent in the late 1970s, a strong need has emerged to clearly define the patient population that is able to tolerate this treatment. For this purpose, studies investigating the correlations between baseline characteristics of patients and cisplatin-induced AEs have led to a consensus of absolute contraindications for cisplatin, which can be used to guide the treatment decision-making process.Although it is often clear whether patients are absolutely or not at all contraindicated for high-dose cisplatin-based treatment, many patients fall in an in-between category of “borderline” unsuitability, for which the optimal treatment decision is not self-evident and must be made based on a physician's clinical judgment. Patients with conditions that may be worsened by the high-dose cisplatin regimen may experience QOL detriment while not reaching the recommended cumulative dose due to treatment interruption or cessation. The level of risk of sustaining irreversible cisplatin-associated toxicities should therefore be weighed against the potential benefit on a patient-by-patient basis. In many cases, these toxicities can be avoided if borderline-unsuitable patients are identified before treatment and preferentially redirected to alternative treatment regimens.Absolute contraindications are outlined in In contrast, the borderline-unsuitable population includes patients with any current organ system dysfunction, especially any history of hearing, neurological, renal, hepatic, or cardiovascular disorders; a compromised immune system ; ≥20% weight loss; or a history of having received platinum agents in addition to taxanes in the induction setting for LA SCCHN  of <60 mL/min as absolute contraindications for cisplatin –69. FinaTo assess whether a patient is contraindicated or borderline unsuitable for cisplatin, careful screening for comorbidities and evaluating the patient's current state of health and available psychosocial setting are necessary before prescribing cisplatin , 41.Sensory symptoms in the extremities—such as weakness, tremor, numbness, paresthesia, and loss of position and vibration sense—are early predictors of severe cisplatin-induced neuropathy . Indeed,Key risk factors for cisplatin-induced ototoxicity are age and pre-existing hearing disorders . BecausePre-existing renal disorders are the most important high-risk factors for cisplatin-induced nephrotoxicity and can be assessed by urinalysis and estimating GFR , 38, 40.2. Low hematocrit (anemia) resulting from cisplatin treatment can increase the risk of severe hematologic AEs and should be measured in the blood  before treatment. However, because anemia resulting from cisplatin therapy is rare and can be treated per ESMO guidelines , and history of motion sickness and/or pregnancy-induced vomiting . PatientIn addition to the level of difficulty associated with managing cisplatin-induced late toxicities, limited preventive management options exist, and careful patient selection remains the most effective method to reduce overall risk. Because of the high incidence of toxicities, all available prophylactic measures should be applied when treating eligible patients with cisplatin, and patients should be closely monitored during and after therapy. Furthermore, patients with SCCHN should be managed by a multidisciplinary team , 5, 41.2 and pretreatment hydration  , 86. NumDehydration through nausea and vomiting is one of the most serious and unpleasant side effects of chemoradiotherapy with cisplatin, and keeping a patient sufficiently hydrated is an effective and widely used method to counteract associated nephrotoxicity . The recRecently, the long-term impact of treatment-related toxicities on the QOL of responders has come into focus in populations with a favorable prognosis. Specifically, overall, patients with HPV-positive OPC have a very good prognosis and tend to be younger and have little or no smoking history, fewer comorbidities, and improved locoregional control and OS compared with patients with HPV-negative tumors –94. ResuPatients with LA SCCHN who are strictly contraindicated to receive cisplatin depend on alternative treatments and/or future advances in this field, and those who are either cisplatin borderline unsuitable or have favorable prognoses may strongly benefit from them. To find the optimal regimen for each patient, the benefits and disadvantages of alternative regimens need to be carefully balanced. Despite the lack of phase III trials demonstrating the efficacy of alternative treatments vs. high-dose cisplatin–based chemoradiotherapy in the overall LA SCCHN population, several non-cisplatin regimens are currently recommended by international guidelines, of which only two do not include a platinum agent: radiotherapy plus either 5-fluorouracil [5-FU] and hydroxyurea or cetuximab , 5.Data from a recent meta-analysis by the Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck (MARCH) Group demonstrated that concomitant chemoradiation is significantly superior to altered fractionation radiotherapy alone in terms of OS . Althoug2 every 3 weeks into weekly doses of 20–50 mg/m2, which also allows the physician to monitor the patient weekly and hence potentiates supportive care. Weekly cisplatin 40 mg/m2, the most commonly used weekly regimen, has not been evaluated in a large randomized study vs. concurrent high-dose cisplatin chemoradiotherapy or radiotherapy alone and is currently supported by a category 2B level of evidence in international guidelines   . An evalne study  showed sne study , 15, 16.2 have failed to show superiority or non-inferiority to radiotherapy alone or to high-dose cisplatin in terms of efficacy and treatment compliance in multiple trials  with LA SCCHN showed improved 5-year OS with cisplatin. Toxicity profiles of the two agents were similar, although fewer gastrointestinal and renal toxicities but more frequent hematologic toxicities were observed with carboplatin. Because of the lack of randomized phase III trials, however, treatment of LA SCCHN with carboplatin and concurrent radiotherapy is not currently considered an evidence-based option in LA SCCHN ; h; h109); Cetuximab in combination with radiotherapy is an efficacious treatment option in LA SCCHN and can be used as an alternative in patients who are unsuitable to receive high-dose cisplatin plus radiotherapy. The randomized phase III trial by Bonner et al. that is discussed above included a large number of patients who would be considered fit and cisplatin eligible. There are no phase III data showing benefit of cetuximab in combination with radiotherapy in the non–platinum-eligible population. Notably, combinations of cetuximab with non-cisplatin chemoradiotherapy agents, such as carboplatin plus paclitaxel or 5-FU, are currently being investigated and have thus far shown promising results –119. A rImmune checkpoint inhibitors are hypothesized to synergize well with radiotherapy . Immune High-dose cisplatin-based concurrent chemoradiotherapy is the preferred treatment for fit patients with LA SCCHN. Because high-dose cisplatin is associated with a considerable number of toxicities, it is not recommended for patients aged >70 years or with an ECOG PS of ≥2 . PreexisAlternative chemotherapy regimens and administration schedules, targeted agents, and emerging immunotherapies provide possible treatment options for cisplatin-contraindicated or borderline-unsuitable patients with LA SCCHN. HART alone could also be a reasonable alternative for cisplatin-contraindicated patients . HoweverThe reference tools provided in this review should facilitate the treatment decision-making process in LA SCCHN for oncologists and healthcare professionals before prescribing high-dose cisplatin chemoradiotherapy for their patients.SP, FS, MA, SS, AC, VL-V, and LL contributed equally to manuscript development in terms of manuscript preparation, manuscript review, and final approval.SS discloses employment with Merck KGaA, Darmstadt Germany. 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.


Mobile phones have been actively used in various ways for diabetes self-care. Mobile phone apps can manage lifestyle factors such as diet, exercise, and medication without time or place restrictions. A systematic review has found these apps to be effective in reducing blood glucose. However, the existing apps were developed and evaluated without a theoretical framework to explain the process of changes in diabetes self-care behaviors.This study aimed to evaluate the diabetes self-care app that we developed by measuring differences in diabetes self-care factors between before and after using the app with the Information-Motivation-Behavioral skills model of Diabetes Self-Care (IMB-DSC).We conducted a single-group pre- and postintervention study with a convenience sample of diabetes patients. A total of 38 adult patients with diabetes who had an Android smartphone were recruited. After conducting a preliminary survey of those who agreed to participate in the study, we provided them with a manual and a tutorial video about the diabetes self-care app. The app has functions for education, recommendations, writing a diary, recording, goal setting, sharing, communication, feedback, and interfacing with a glucometer, and it was applied for 4 weeks. We measured the general characteristics of participants, their history of diabetes self-care app usage, IMB-DSC factors, and blood glucose levels. The IMB-DSC factors of information, personal motivation, social motivation, behavioral skills, and behaviors were measured using an assessment tool consisting of 87 items extracted from the Diabetes Knowledge Test, third version of the Diabetes Attitude Scale, Diabetes Family Behavior Checklist, and Diabetes Self-Management Assessment Report Tool.P=.02) and diabetes self-care social motivation (P=.05) differed significantly between pre- and postintervention, but there was no significant difference in diabetes self-care information (P=.85), diabetes self-care personal motivation (P=.57), or diabetes self-care behavioral skills (P=.89) between before and after using the diabetes self-care app.The mean age of the participants was 43.87 years. A total 30 participants out of 38 (79%) had type 2 diabetes and 8 participants (21%) had type 1 diabetes. The most frequently used app function was recording, which was used by 34 participants out of 38 (89%). Diabetes self-care behaviors (Diabetes self-care social motivation was significantly improved with our diabetes self-care app by sharing experiences and sympathizing with other diabetes patients. Diabetes self-care behavior was also significantly improved with the diabetes self-care app by providing an interface with a glucometer that removes the effort of manual input. Diabetes self-care information, diabetes self-care personal motivation, and diabetes self-care behavioral skills were not significantly improved. However, they will be improved with additional offline interventions such as reflective listening and simulation. Diabetes mellitus is a chronic disease caused by an absolute or relative deficiency of insulin . The numAntidiabetic medication such as an oral hypoglycemic agent plus insulin is used as an active regimen for blood glucose control to prevent diabetes and diabetes complications; however, drug therapy alone is not sufficiently effective . DiabeteMobile phones have recently been actively used for changing diabetes self-care behaviors. According to a health report from Intercontinental Marketing Services in 2015, diabetes self-care mobile phone apps were the second most common type of chronic disease management apps . DiabeteProviding information in various formats such as text, images, and videos.Allowing users to record their diabetes self-care behaviors.Displaying diabetes self-care behaviors in charts and diagrams.Providing tailored recommendations based on the history of diabetes self-care behaviors entered by users.Providing reminders to perform diabetes self-care.Enabling real-time communication between the medical provider and patient.Diabetes self-care apps that manage lifestyle factors such as diet, exercise, and medication adherence have been shown to be effective in reducing the blood glucose level. A systematic review and meta-analysis of diabetes self-care apps found that they had a significant improvement in glycemic control ,9.However, existing diabetes self-care apps were developed without a theoretical framework to explain the process of changes in diabetes self-care behaviors . Even thThis study developed a diabetes self-care app based on the information-motivation-behavioral skills (IMB) model, which is a behavioral change theory for explaining the process of changing diabetes self-care behaviors and user requirements determined through focus group interviews. The app provides evidence-based tailored information, provides reminders, utilizes social media, and has an interface with a glucometer . The AmeThis study evaluated the diabetes self-care app by measuring knowledge about diabetes and diabetes self-care as an information factor, individual and social motivation as a motivational factor, diabetes self-care skills as behavioral skills, and blood glucose levels as the outcomes.We conducted a single-group pre- and postintervention study with a convenience sample of diabetes patients to evaluate the diabetes self-care app developed in this study . ParticiThe research process consisted of the following steps :We recruited study participants by posting a call for participation on 5 self-help websites for patients with diabetes from August 1 to 17, 2016.We surveyed patients with diabetes who agreed to participate using a questionnaire to obtain information about their personal motivation, social motivation, behavioral skills, and behaviors.We provided the subjects with a manual and tutorial video on how to use the diabetes self-care app.The diabetes self-care app applied for 4 weeks provides educational material with recommendations about writing a diary, recording, goal setting, sharing, communication, feedback, and interfacing with the glucometer.We surveyed the IMB-DSC factors after the 4-week intervention using the same questionnaire used in the first step.We used an open-ended questionnaire to survey the subjects’ experiences with using the diabetes self-care app and identify how functions of the app influenced the changes in IMB-DSC factors.This study was approved by the institutional review boards at the Seoul National University .The theoretical framework used in this study is presented below . The appThe app used in this study for intervention was developed by the authors, and the technical aspects such as its algorithm, heuristic, and usability were tested . Our diaEvidence-based education and personalized recommendations were included to facilitate the provision of information.Self-reflective diary writing, recording diabetes self-care behaviors, and individual goal setting were included to increase personal motivation.Sharing with other patients and communication with health care providers were included to increase social motivation.Feedback and visualizing blood glucose trends were included to improve behavioral skills.Finally, a wireless glucometer interface (via Bluetooth) for receiving blood glucose data automatically was included to promote diabetes self-care behaviors.We measured the general characteristics of the study participants, their history of diabetes self-care app usage, IMB-DSC factors, blood glucose levels, and surveyed their experiences with using the diabetes self-care app. We pilot tested the readability of the tools measuring 5 IMB-DSC factors with 14 diabetes patients ) and after the intervention  and after the intervention , as in length of condition over the 1-year group differed significantly before (mean 38.15 [SD 8.28]) and after the intervention  and after the intervention , but there was a trend in decreasing the postprandial blood glucose level  and social motivation , and diabetes self-care behavior skills were significantly affected by social motivation . These findings were different from those of the previous study [Diabetes self-care behavioral skills was not significantly affected by diabetes self-care information, which is similar to the findings of Choi . Diabeteus study . Howeverus study .There were significant changes in diabetes self-care behaviors between before and after use of the app, especially in SMBG and problem solving. We provided a wireless glucometer interface to receive data on the blood glucose level automatically to minimize the amount of manual input required, which is in accordance with the suggestion of Intercontinental Marketing Services to improve SMBG . A wirelP=.008) and social motivation  significantly affected diabetes self-care behaviors in this study. The effect of social motivation on diabetes self-care behaviors was consistent with the findings of previous studies [Our path analysis showed that information (coefficient=1.01;  studies ,29. Incr studies ,25,30. T studies .Diabetes self-care personal motivation did not significantly affect diabetes self-care behaviors in this study, which contrasts with the findings of Osborn and Egede . This coDiabetes self-care behavioral skills did not significantly affect diabetes self-care behaviors in this study. This directly contradicts the finding of Choi , which iThere was a trend toward significant changes in physiological outcomes before and after using the app, especially in the postprandial blood glucose level. This is consistent with the systematic review of Liang et al finding that a diabetes self-care app was effective at improving glycemic control ,9. The dThe limitations of this study are as follows: First, it was developed based on Android and so excluded other mobile phone operating systems such as iOS, Windows, and Blackberry OS. Second, although there are some studies that performed a short intervention for 4 to 6 weeks to improve diabetes self-management ,31,32, tWe have developed a diabetes self-care app based on the IMB model that provides personalized education and information to promote diabetes self-care information according to the knowledge level and behavior status of patients, a bulletin board that allows patients to communicate and sympathize with other diabetes patients, and an interface with a glucometer to improve diabetes self-care behavior factors. This study found that the intervention did not produce any significant changes in personal motivation or behavioral skills; these factors could be improved by providing face-to-face counseling or practicing strategies in combination with using the diabetes self-care app.


The investigational scale of the gut microbiome is expanding rapidly. In 2018, the intersection of gut microbiota and immuno-oncology received much attention. While the impact of gut microbiota on the immune system was already established, the year received an exponential expansion of microbiome’s role in the immunotherapy setting. The microbiome research pipeline is ripe for large-scale, prospective trials. Working knowledge of immune-based cancer treatments, heterogeneity in their responses and resistance mechanisms, relevant immunological and microbiological pathways and potential for gut microbiome in enhancing the responses, is critical. Evidence continued to mount in 2018 that the gut flora, also called “gut microbiota,” of cancer patients dictates how they respond to a variety of cancer treatments. The bulk of microbiome evidence emerged from immune checkpoint inhibition (ICI) setting in 2018, primarily due to increasing interest in ICI in general. ICI is considered a breakthrough in cancer therapeutics and most recently has been the theme of the Nobel Prize for medicine. While ICI prolongs lives of cancer patients including those who have failed all other types of cancer treatments, it only works in certain types of cancer and that too, in a fraction of patients. Many more lives could be prolonged if the positive responses to ICI were more homogeneous.The immune system plays a critical role in fighting cancer. Although carcinogenesis is defined by de novo genetic alterations, its sustained progression is dependent upon its ability to evade the host’s immunity –7. With Although the therapeutic release of immune checkpoints has resulted in unprecedented response rates in patients with a variety of cancers, one-third of patients do not respond. The immunotherapy efficacy also varies considerably depending upon cancer types , 3. SeveEvolving evidence suggests that diversity and composition of the gut microbiota influences response to immune-based cancer therapies. The initial evidence so far hints towards a relation between certain gut microbial taxa and responses to cancer treatment and survival in both humans and mice, suggesting that its modulation holds substantial therapeutic potential. But the question remains that if the battle against cancer really was situated in the resident taxa, with potential for improved outcomes with simple dietary interventions, then why was not it explored earlier? And, is the existing evidence of manipulating gut microbiome strong enough to be put into clinical practice just yet?It has been known for more than two decades that gut microbiome interacts with the immune system and impact illnesses directly related to the immune system: autoimmune and infectious diseases. Recent developments in genomic and metagenomic techniques allowed a more robust exploration of the gut microbiome , 18. ItsA recent poster presented at the Society for Neuroscience annual meeting was captivating and could be relevant to the interaction between gut fauna and immuno-oncology. The poster showed high-resolution microscopic images of bacteria penetrating and inhabiting the cells of healthy human brains . This hiThe recent genomic exploration of gut taxa allowed stratification of “good or favorable” versus “bad or unfavorable” bacteria in the setting of cancer therapeutics Table . The numThe second proposed mechanism of how the gut microbiome may modulate anti-tumor immune responses is the cross-reactivity between antigens expressed on the commensal bacteria and neoepitopes found in tumors , 35. HowSeveral pre-clinical and clinical studies have highlighted a critical role of the gut microbiota in impacting survival as well as tumor responses to chemotherapy, stem cell transplantation and immunotherapy targeting PD-1, PD-L1, and CTLA-4. The earliest evidence originated from the chemotherapy agent, cyclophosphamide (CYC), one of the most commonly used chemotherapeutic agent for solid tumors and hematologic malignancies as well as for conditioning for the bone marrow transplant (BMT) and for the prevention of graft-versus-host-disease. Part of its therapeutic effect is through the induction of antitumor responses. It became known that CYC alters the composition of gut taxa to stimulate Th17 production which in turn renders the tumor susceptible to CYC . Taur etRuminococcaceae and Faecalibacterium of the Firmicutes phylum) are associated with a superior survival and response to ICI. Whereas, a lower diversity of gut microbiome and the abundance of bacteria of certain phyla (e.g. Bacteroidetes phylum) are associated with an inferior survival and response to ICI. Mechanistic studies and reverse translational evidence in gnotobiotic mice, germ-free mice that lack intestinal microbiota, corroborate that different groups of bacteria impart distinct immune modulating actions [Several human studies in the ICI settings in 2018, performed based on earlier pre-clinical results, have reported positive and reproducible results. Investigators have reported their results in epithelial tumors and hematological malignancies, both in single-agent as well as dual ICI settings. It has been shown that diversity and composition of the gut microbiome mediate response to ICI and improve survival in cancer patients , 38–41.  actions .Faecalibacterium genus and other Firmicutes. In contrast, a high abundance of Bacteroidetes was present in subjects with a poor benefit from therapy [Firmicutes phylum and the abundance of B. thetaiotaomicron was associated with efficacy of combined anti-CTLA-4 and anti-PD-1 immunotherapy [Bifidobacterium longum and Lactobacillus species, were associated with slower growth of tumor in mice models [Several other clinical studies have shown similar results recently , 38–46.  therapy . Frankelotherapy . Similare models , 38–46.Clinical studies in patients receiving concurrent broad-spectrum antibiotics, with immune-based cancer treatments, have shown mixed results , 48. WhiUse of commercially available probiotics is common and has been perceived to be associated with good gut and general health. However, the results of another study presented at the SITC 2018 reported surprising results. In a study conducted in 312 melanoma patients receiving ICI, 42% of patients reported taking probiotics and were found to have a lower diversity of their gut microbiome, in turn, associated with inferior ICI responses and survival . This isThe data from a few underpowered studies on antibiotics demonstrated mixed results in terms of response and outcomes, as discussed above. Furthermore, SITC study above on the use of probiotics in melanoma patients revealing a lower diversity creates a further contradiction. Hence, the role of pro-, pre- and antibiotics still need to be established via larger, multi-center studies.The investigational gamut of the gut microbiome is expanding rapidly. A few in vitro studies have already delineated the suppressive role of Tregs in more advanced immune-based therapies, such as adoptive T-cell transfer (ACT). ACTs mainly include chimeric antigen receptor (CAR) T-cells, tumor infiltrating lymphocytes (TILs) and bispecific T-cell engagers (BiTEs). ACT involves the isolation and ex vivo expansion of tumor-specific T-cells and transfusion back to the patient to fight cancer. CAR T-cells are autologous T-cells that are engineered and re-directed towards a tumor-specific antigen , 52. TheTanoue et al. further characterized the critical role of IFNγ-expressing CD8+ T-cells in adenocarcinoma, gnotobiotic mice models treated with PD-1 inhibition. The recent study further identified 11 healthy human-associated microbial strains that acted together to inhibit ICI-mediated tumor growth. This therapeutic efficacy was mediated via an increased abundance of IFNγ-expressing CD8+ T-cells. These taxa are under-represented in the general population and predominantly included members from the Firmicutes phylum . Interestingly, 4 of these strains (3 belonging to the Firmicutes phylum), were able to independently induce CD8+ T-cells. Whereas the other 7 strains, belonging to the Bacteroidetes phylum, performed CD8+ T-cells induction only in conjunction with the other 4 strains. Majority of the remaining strains, that were studied and were found to lack tumor-suppressive effect, belonged to the Bacteroidetes phylum [Tanoue et al. shared critical finding towards establishing a rationally-designed microbial product for future trials. A CD8+ T-cells-based therapeutic design will have broader application towards all immune-based, anti-tumor treatment strategies.s phylum . AlthougBacteroides spp. and augmented the function of adoptively transferred antitumor T-cells, in an IL-12–dependent manner, which is also responsible for an increased abundance of effector T-cells in the TME. To demonstrate a causal effect in humans, they further showed higher levels of IL-12 in those alloHCT patients who had received oral vancomycin [Bacteroides-induced suppression of ACTs demonstrated by Uribe-Herranz et al. was in contradiction with the study results of Vétizou et al. who had earlier shown that the Bacteroides species, specifically B. fragilis and B. thetaiotaomicron, promote the efficacy of CTLA-4 blockade in mice [The role of antibiotics has been studied in the ACT setting as well. In a study on mouse models, Uribe-Herranz et al. showed that vancomycin depleted ncomycin . However in mice . Kuczma  in mice .With an established ability of the gut microbiome in suppressing Tregs, large, prospective studies are being conducted in the ICI, ACT and CAR T-cells settings. Some critical trials that are currently underway include: modification of gut microbiome by dietary intervention (non-absorbable oligosaccharides contained in potato starch) in patients undergoing BMT at the University of Michigan (NCT02763033), FMT from healthy donors in patients undergoing BMT to study survival, post-BMT complications and graft-versus-host-disease incidence at the Massachusetts General Hospital (NCT03720392), concurrent FMT with immunotherapy at the University of Pittsburg (NCT03341143), administration of a rationally-designed bacterial consortia along with immunotherapy (NCT03595683), and transplantation of taxa from responders into non-responders. For instance, a phase-I trial is currently recruiting in Israel in metastatic melanoma patients to study safety and response to FMT from immunotherapy responders to refractory patients (NCT03353402). Groups at MD Anderson and Memorial Sloan Kettering Cancer Centers USA as well as in France are also actively studying, in collaboration with the industry, the potential impact of certain taxa on treatment responses and patients’ survival. These studies will be directed toward averting resistance mechanisms to the novel therapies explored thus far.The immunological evidence behind gut microbiome’s potential to modulate responses to cancer treatments is strong. It is a matter of time that we will be able to show that the gut microbiome modulation works in large, multi-center, prospective trials. Probiotics, narrow-spectrum antibiotics, non-absorbable oligosaccharides contained in potato starch or even a certain diet, fecal transplant from healthy donors, are all potential interventional strategies. These could be employed to strategically modify microbiota, enhance responses to cancer treatment and prolong lives. We are far from that. But we are aware that dysbiosis can increase the representation of deleterious microbiota that produces harmful metabolites and antigens and lead to maladaptive immune responses. Strategically averting gut dysbiosis, preventing alpha diversity crash during treatment, and maintaining desirable taxa are needed to augment response to cancer treatment.Programmable DNA cutters are being utilized to knockout inhibitory proteins. For instance, utilizing CRISPR/cas9-based gene-editing showed an enhanced efficacy of CAR T-cells in the tumor mice model. Ren et al. manufactured potent, universal CAR T-cells with knockout inhibitory ligands, including PD-1, endogenous TCR, and β-2 microglobulin, utilizing CRISPR/cas9 multiplex gene-editing . Rupp etThe field of “onco-microbiome” is evolving. Driven by the era of precision oncology, it is likely to draw greater interest and funding. The impact of gut microbiome on immune-based cancer therapeutics will be a breakthrough in terms of improving patients’ outcomes and the field is certainly ripe to live up to its hype.


Background: The Hispanic/Latino population in the US is experiencing high rates of obesity and cardio-metabolic disease that may be attributable to a nutrition transition away from traditional diets emphasizing whole plant foods. In the US, plant-based diets have been shown to be effective in preventing and controlling obesity and cardio-metabolic disease in large samples of primarily non-Hispanic subjects. Studying this association in US Hispanic/Latinos could inform culturally tailored interventions.Objective: To examine whether the plant-based diet pattern that is frequently followed by Hispanic/Latino Seventh-day Adventists is associated with lower levels of adiposity and adiposity-related biomarkers.Methods: The Adventist Multiethnic Nutrition Study (AMEN) enrolled 74 Seventh-day Adventists from five Hispanic/Latino churches within a 20 mile radius of Loma Linda, CA into a cross-sectional study of diet  and health (anthropometrics and biomarkers).Results: Vegetarian diet patterns  were associated with significantly lower BMI , waist circumference , and fat mass , as compared to non-vegetarians. Adiposity was positively associated with pro-inflammatory cytokines (Interleukin-6) in this sample, but adjusting for this effect did not alter the associations with vegetarian diet.Conclusions: Plant-based eating as practiced by US-based Hispanic/Latino Seventh-day Adventists is associated with BMI in the recommended range. Further work is needed to characterize this type of diet for use in obesity-related interventions among Hispanic/Latinos in the US. For eOverall, in a systematic review of 15 intervention studies (17 intervention groups among them) in multi-ethnic samples, Barnard et al. has shown that interventions with the vegetarian diet contributed to an average of more than 3 kg of weight loss . For diaA recent pilot study at Loma Linda University has shown that a 5-week plant-based, culturally-tailored diet intervention implemented through community clinics and a church significantly improved hemoglobin A1C levels over a 6 month follow-up in 32 Latino diabetics living in a medically underserved area. At Loma Linda University, more than 60 years of NIH-funded prospective cohort studies  and abdominal adiposity [waist circumference (34.8 in vs. 37.5 in)].In the AMEN study, we found that in a sample of Seventh-day Adventist Hispanic/Latino adults, those following a vegetarian dietary pattern had a BMI that was lower , increase hormonal satiety-signaling  and reduce insulin resistance , 33. AmoThe AMEN study has important limitations. The cross-sectional and observational design precludes inferring a causal effect from the association of diet with obesity and obesity-related disease. The purpose of our pilot study was to generate culturally-specific hypotheses for testing this association in longitudinal and experimental designs with novel culturally-tailored interventions.The relatively small sample size limited our statistical power to test more complex food and nutrient models, and for testing interaction and mediation. We note, however, the significant and cross-validating associations between plant-based eating and measures of adiposity that persist despite the limited power to detect these associations.Religiosity could also be a factor since we are studying a faith-based group. It is noteworthy, however, that we observed no difference in religiosity between the vegetarians and non-vegetarians we studied. Measurement error in dietary assessment is always present in observational work, but we note a decades-long track record by our research group validating diet and vegetarian diet survey measures in Adventists , 17, 35.Our findings from Hispanic/Latino Seventh-day Adventists indicate that plant-based diet patterns were associated with adiposity in the recommended range, and effects were consistent across multiple measures of adiposity and obesity-related inflammatory markers. Further studies of how Hispanics/Latinos have culturally tailored the Adventist plant-based eating pattern could potentially inform interventions for the broader population of Hispanics/Latinos.The study protocol was approved by the institutional review board of Loma Linda University and performed in accordance with the ethical standards as laid down in the 1975 Declaration of Helsinki as revised in 2000. All participants provided signed informed consent.PS: designed the study, supervised data collection and analysis, wrote the final version of the manuscript and obtained funding; KJ-S: designed the study, supervised data collection and analysis, wrote a draft of the manuscript; NC: analyzed data; WS: analyzed data and edited manuscript; LL: data collection coordinator and preliminary analysis; KS: analyzed data and edited manuscript; DE: analyzed data; MJ, HF, DH-B, and WM: edited manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.