This review is focused on the recent developments of nanocomposite materials that combine a thermoplastic matrix with different forms of graphene or graphene oxide nanofillers. In all cases, the manufacturing method of the composite materials has been melt-processing, in particular, twin-screw extrusion, which can then be followed by injection molding. The advantages of this processing route with respect to other alternative methods will be highlighted. The results point to an increasing interest in biodegradable matrices such as polylactic acid (PLA) and graphene oxide or reduced graphene oxide, rather than graphene. The reasons for this will also be discussed. The fabrication of nanocomposites by the incorporation of nanofillers into polymer matrices originates materials with new functional properties while the excellent processing and manufacturing abilities are retained due to the flexibility in polymer matrices . In receIndustrial thermoplastic polymers and composites are usually melt-processed by extrusion followed by injection molding. The extrusion step combines the application of high temperature and high specific mechanical energy in a short time interval. The optimization of extrusion parameters plays a fundamental role on the final properties of the material. Extrusion elements configuration and parameters such as residence time, screw speed, temperature and energy are even more critical when nanocomposites are concerned ,11. The The original definition of graphene  is that Solvent processing. The use of conventional solvents causes serious health and environmental problems which prevent the large-scale usage of these procedures.In situ polymerization. This is an effective method to obtain small quantities of materials for laboratory research applications but not for industrial scale.Melt blending. Several thermoplastic matrices have been modified by melt blending addition of different forms of graphene oxide (GO) and reduced graphene oxide (rGO) nanofillers. However, this process might cause defects in the GO structure, from wrinkles and rolling, to modification of the initial aspect ratio.Methods for achieving the dispersion of graphene in polymer matrices  usually Methods using a solvent need the previous modification of graphene surface in order to disperse it. In situ polymerization can be more efficient. However, both methods are not readily scaled to industrial processing. In contrast with solvent dispersion and in-situ polymerization processes, melt processing, that is, the direct dispersion of graphene nanophases into molten polymer is a cleaner process that can be readily scaled up for industrial applications. However, in order to achieve uniform graphene dispersion into highly viscous polymers, it is still necessary to modify the surface of graphene flakes. Although this modification can be made by chemical functionalization, with the formation of new covalent bonds , it can Melt-processing is usually performed by twin-screw extrusion, which is an environmentally-friendly method immediately applicable to the industrial scale manufacturing of final parts. The versatility of this process allows tailoring the extrusion parameters for each material and application. This method is widely used for the processing of nanocomposites, since the mixing action is based on an elongational flow. Shear and elongation stresses are as the material is transported through the space between screws  .2, the order of magnitude of the force necessary to exfoliate the graphite is about 300 nN/mm2 [Another advantage of extrusion could be the alignment of planar nanostructures such as those of graphene nanomaterials in one preferential direction. Kim et al.  have dis0 nN/mm2 ,26,27, wResearch interest in nanocomposite materials containing graphene has been present for more than a decade , as it b2 hybridization. As it is depicted in As it is mentioned above, there are several kinds of carbon nanofiller that are commonly called graphene. The basic structure of the different graphenic nanomaterials is graphene . This na3 hybrid carbon atoms with functional groups such as hydroxyl and epoxy groups in the surface and carboxylic groups at the edges [One of the most widely used graphene derivatives is graphene oxide. The structure of this nanomaterial consists in graphene sheets with stoppages of sphe edges ,40,41. The edges ,43. Othehe edges ,45,46. IIn this section we have summarized the recent publications on thermoplastic matrix composites modified by addition of graphene-derived nanofillers, modified graphene nanofillers or blends with other nanomaterials. These new nanocomposites have been obtained by extrusion, in most cases twin-screw extrusion, which can be followed by injection molding.The effect of graphene nanoplatelets (GnP) size on PP nanocomposites processed by twin-screw extrusion and injection molding has been studied  to find Recently, the combination of several nanofillers has demonstrated a useful strategy to obtain new nanocomposites with special properties. Synergy between graphene (G) and synthetic graphite (SG) was studied by Altay et al. , when adIn any case, agglomeration is an impasse in the development of PP-based nanocomposites . During Although PP and PLA (see below) are the most widely studied matrices for graphene nanocomposites, many other thermoplastic materials have also been modified to obtain graphene nanocomposites  21,64,6,92,93,94Polyethylene (PE) and different types of polyethylene-derived materials such as linear low-density polyethylene (LLDPE), high density polyethylene (HDPE), or polyfluorinated ethylene propylene and polyethylene naphthalate (PEN) have been studied as matrices ,67,68,69Polyamides (PA) are another commonly used base polymer for the processing of graphene containing nanocomposites ,75,76,772 processed by using twin-screw extrusion [Other widely used thermoplastics include polystyrene (PS), thermoplastic polyurethane (TPU) or poly (methylmethacrylate) (PMMA) matrices ,78,79. Ixtrusion  have beextrusion  to reducxtrusion . ABS  , PPS  of PLA has been explored ,109,110.Biodegradable nanocomposites have been obtained by different approaches, such as thermal reduction of GO during processing of PLA-PBS (polybutylene succinate)-rGO nanocomposites , and theco-3-hydroxyvalerate)), the selected fillers are a combination of rGO and ZnO nanoparticles [In the case of the biodegradable and biocompatible plastics, different mixtures of graphene and other materials are used as fillers to preserve the sustainability of the composites. Manufacturing of biodegradable plastics can reduce the environmental impact and favor renewable resources. However, some properties of biodegradable polymers cannot often be comparable with petroleum-based plastics and the addition of fillers may enhance the physical, chemical and mechanical properties ,115. Bioarticles , to mainThe present work is an overview on very recent developments in the field of graphene-thermoplastic nanocomposites melt processed by extrusion methods. A wide range of matrices have been studied, from commodity polymers to high resistant engineering polymers. Special attention is being paid at the development of biodegradable and biocompatible nanocomposites.Extrusion is readily scalable to industrial manufacturing of final products; however, in most cases, obtaining homogeneous graphene dispersions within the polymer matrix is not a simple task. Segregation and agglomeration of the nanophases are responsible for the lack of improvement in the thermal, mechanical and electrical properties with respect to the unmodified matrix materials.The results of this review denote that the most widely used techniques to improve the dispersion of graphenic nanofillers are sonication, surface modification and the application of a coating layer of graphene on the polymer surface. However, another promising technique that is beginning to yield positive results is the use of ionic liquids, which should be explored more thoroughly. Other strategies are focused on the modification of the extrusion process, the use of masterbatches and the combination of graphene with other materials as hybrid nanophases.The main factors that affect the characteristics and attributes of these nanocomposites are the nanofiller size and concentration. It has been stated that larger sizes of nanofillers result in a reduction of the mechanical properties but an increase of other functional properties, such as electrical conductivity. However, the effect of graphene concentration is not so well defined, and more studies are necessary.A relevant field, which has received limited consideration until the present moment, is that of the influence of the additives on the deformation and fracture modes and on the resistance to degradation of the final materials.Finally, another line of work that is starting to receive attention is the tribological performance of extruded nanocomposites as a function of extrusion parameters, polymer structure, nanofiller orientation and surface modification.


Graphene as the 2D material with extraordinary properties has attracted the interest of research communities to master the synthesis of this remarkable material at a large scale without sacrificing the quality. Although Top-Down and Bottom-Up approaches produce graphene of different quality, chemical vapour deposition (CVD) stands as the most promising technique. This review details the leading CVD methods for graphene growth, including hot-wall, cold-wall and plasma-enhanced CVD. The role of process conditions and growth substrates on the nucleation and growth of graphene film are thoroughly discussed. The essential characterisation techniques in the study of CVD-grown graphene are reported, highlighting the characteristics of a sample which can be extracted from those techniques. This review also offers a brief overview of the applications to which CVD-grown graphene is well-suited, drawing particular attention to its potential in the sectors of energy and electronic devices. The gases are then passed through the reactor at a predefined ratio. The partial pressures of the hydrocarbon and the hydrogen can be controlled by changing the reactor pressure or by adding an inert diluent gas such as argon (Ar) or nitrogen (N). After the reaction, the furnace is typically switched off and allowed to cool under a gas flow  until the reactor reaches room temperature. This step is essential in order to avoid aggregation of the deposited carbon, which may result in multi-layer graphene or bulk graphite. It thus contributes to achieving a continuous graphene monolayer on the surface of the metal. In the case of CVD graphene deposition, a metal substrate such as copper (Cu) is placed into a furnace tube made from quartz and heated under a flow of hydrogen at low vacuum or atmospheric pressure. The elevated temperature anneals the substrate which leads to enlargement of its grain size  , as well4 is catalytically decomposed and where the carbon atoms are adsorbed to form graphene film, while, in the high carbon solubility substrate, carbon atoms are diffused into the bulk, and the graphene growth step happens during the cooling step when carbon precipitates to the surface. Fast cooling is thus recommended to avoid the formation of multi-layer graphene. In surface processes (step 6), catalytic decomposition of reactive species occurs in addition to surface migration to attachment sites and other heterogeneous reactions. By-products are then desorbed from the substrate (step 7) after film growth. Finally, by-products are diffused through the boundary layer to the main gas stream (step 8) to be carried away by the force of convection to the exhaust system (step 9) . . 107]. I in 10 s . Furthers growth .2 ..4 ratio In conclusion, SEM has been extensively used as a powerful tool for graphene characterisation, as numerous amounts of information can be extracted from SEM images. Optimising the SEM operating conditions such as acceleration energy, working distance and determining the right detector enables efficient visualisation of surface features in the grown graphene via CVD methods.Atomic force microscopy (AFM) is an extensively used microscopic characterisation technique for graphene characterisation. 3D images obtained using AFM enables the measurement of the thickness of graphene films and the lateral dimensions, which, in turn, allows for accurately determining the number of layers present, thermal conductivity, electric and optical properties of graphene-based products ,195.The necessary component of the AFM instrument is a nanometre-sharp tip created using micro-fabricating technology, which is attached to an adjustable cantilever. The cantilever serves as the transducer to sense the sharp tip on a graphene sample, while a tip acts as a probe that scans over a sample line-by-line . The intThe initial step in setting up the AFM device for spectroscopic and imaging analysis involves mounting the probe in the cantilever, which is typically done with forceps. The removal of the probe for storage is done with vacuum tweezers. Correct mounting is a critical requirement for accurate measurements and ideal laser alignment . The intThe determination of the number of layers is the most common application of the AFM. The procedure typically involves scanning the edges of graphene sheets at the places where the stacked layers form steps . In mostTo date, several AFM-based electrical characterisation techniques are available, a detailed review of which is given in a study by Hussain et al. . ContactThe AFM in nanoindentation mode serves as an effective means of testing the mechanical properties of graphene materials. The procedure involves measuring the intensity of subtle interactions between the sample surface and the probe during the loading stage and the unloading stage and recording them on a force–distance curve. The analysis of such curves enables the determination of numerous characteristics and mechanical properties of graphene-based thin-films, including the hardness, stiffness and Young’s modulus ,201. TheOther morphological features in graphene film can be characterised using AFM such as graphene ripples. Chaitoglou and Bertran have studied the effect of growth temperature on CVD grown graphene where ripples were observed on the surface. AFM was utilized to obtain hight measurements for the ripples; the temperature showed no significant effect on the geometry of the ripples. However, the measured step height gave a value of 5 nm, which is in agreement with the calculated depth value using the model of Mullins  78]. . 78]. 2C. The thickness of the Mo2C hexagonal domains increased with growth time, giving heights of approximately 40, 140 and 190 nm for growth times 20, 60 and 90 min, respectively  is a powerful spectroscopy technique that provides valuable information about the structure of a material at the atomic level . It was The TEM is one of the most versatile and reliable methods for studying graphene edges. The low atomic number of graphene implies decreased scattering of the electron beam, which, in turn, allows for sharper TEM images. STEM and HR-TEM imaging are practical tools for the following objectives: determining the number of layers, studying the atomic structure and characterising the electronic properties of both graphene and graphene doped with heteroatoms . In addiTEM is also used to rotational misalignment between graphene layers using Moire patterns while Fourier transform of the electron diffraction pattern provides information on the nature of the graphene film as demonstrated by Nayak  209]. I. I209]. 2 only, but sp3 hybridization might appear locally.TEM is also considered as an excellent tool to study the structural defects in graphene which have a strong influence on the properties of the produced film that will limit their implementation. Point defects cause undesired electron scattering that drastically reduces electrical conductivity. Bonds around defects become weaker, which decrease the mechanical strength and affect the thermal conductivity. Therefore, understanding of the formation and the nature of those defects in graphene structure is essential in order to tailor the growth conditions and substrate properties to get high purity graphene with no defects. A review on the structural point and line defects in graphene were reported by Banhart et al. as they demonstrated the theoretical defect formation (intrinsic and extrinsic) as well as the utilisation of TEM as an imaging technique for those defects . DefectsSimilarly, adatoms defects can occur by a foreign atom (non-carbon) which affect the graphene properties; the effect will primarily depend on the interaction bond between the foreign adatom and the nearest carbon atoms . SubstitGraphene can also be considered an ideal TEM support film. CVD graphene provides supports of extreme physical stability, periodic structure, single-atom thickness and ballistic electrical conductivity . The ult2/Vs), outstanding flexibility, high transparency in near-infrared and visible light, graphene and graphene-based materials can be applied in a wide variety of applications in electronics, energy, biomedicine and environmental engineering [Due to its unique set of material properties, including exceptional carrier mobility , hence, intensive research is ongoing in order to induce a bandgap in graphene to boost its use digital electronics applications. However, the range of applications for graphene in electronics extends far beyond just digital systems. Here, we briefly review the implementation of graphene in light emitting diodes (LEDs) and nano electromechanical systems (NEMS), highlighting how this helps to develop novel sensing devices and wearable electronics for health monitoring. Since the invention in 1962, LEDs have been used almost universally in a considerable number of different electronic devices. Generally, LED voltage is relatively high because it is required to be equal to or higher than the bandgap energy. These semiconductor light sources necessitate electrodes with high electrical conductivity and high transmittance to enhance their optical and electrical characteristics. However, transmittance and conductivity are mutually contradictory properties, which leads to significant difficulties for simultaneously satisfying both requirements . A set o−1. Although the transmittance of graphene (about 90%) satisfies the requirement, the sheet resistance of CVD-grown graphene exceeds the acceptable level for industrial applications. Several doping methods that employ metal hybrid composites have been proposed to improve the electrical and structural properties of graphene-based materials [Today, indium tin oxide (ITO) remains the most widely utilized transparent conductive electrode (TCE) in optoelectronic devices. However, the scarcity of indium inevitably leads to a constant increase in the cost of ITO, severely limiting its use for low-cost, sustainable and transparent thin-film devices . The synaterials .2+) as dopants from the upper electrode into monolayer graphene films grown by the CVD method through conducting paths formed in aluminium nitride  under the application of an electric field. The authors reported the studied material retained a very high optical transmittance of about 95% after the doping process, while the work function of graphene increased from 4.36 eV to 5.0 eV as a result of p-type doping effects of Ni atoms. The LED with the Ni-doped monolayer graphene demonstrated superior light output power characteristics compared to both LEDs with a 100-nm-thick ITO electrode and LED with undoped graphene without any significant losses in the current–voltage characteristics [A study by Chae et al. describes a novel electric-field-induced doping treatment, which can effectively reduce the sheet resistance of CVD-grown monolayer graphene while retaining its high transmittance. The treatment involves the injection of metallic ions  and industrial mass synthesis makes this metal an especially attractive candidate for use as TCE in optoelectronic devices. However, the application of Cu nanowires in LEDs is severely limited by the low resistance contact and poor stability against oxidation. Huang et al. proposed a CVD method for fast gas-phase encapsulation of the graphene shell layer on Cu nanowire networks to effectively improve the optoelectronic performances of TCEs and enhance oxidation resistance. The authors reported the successful fabrication of fully transparent GaN-based LED chips on a wafer using the Cu graphene nanowire TCEs. The central emission peak of this device is located at 437 nm in the blue region without any additional peaks associated with impurities, which indicates the excellent light transmission and high stability .One of the promising applications of graphene-based material in the field of LED devices is their use as a replacement for conventional sapphire substrates for growing semiconductor materials for LEDs. A study by Li et al. reports the successful growth of an InGaN/GaN blue LED on wet-transferred multilayer graphene. The use of graphene as a substrate allows for releasing the stress during the growth of indium gallium nitride, which leads to a noticeable decrease in the number of cracks. The authors reported that the blue InGaN/GaN multiple quantum wells LEDs grown on graphene exhibit a higher output power and a slightly reduced crystalline quality of GaN compared to that of the LEDs grown on a conventional sapphire substrate .Despite the outstanding set of desirable material properties, the implementation in stretchable electronic applications has been severely inhibited by the tendency of graphene-based materials to crack at small strains . Defects−1 [−1 at room temperature [2 substrate using lithographic techniques, and metal contacts were made of Cr/Au (5/100 nm). The resonant frequency and QR were measured in vacuum condition in a chamber, followed by a set of measurements while a mixture of hydrogen and argon were injected, thus changing the pressure in the chamber. The results showed the change in adsorbed molecules (mass in zeptogram) with the pressure change which proves the efficiency of graphene NEMS-resonators for spectrometry applications for light mass molecules. Another interesting implementation of graphene based NEMS-resonator is the research conducted by Andelic et al. for the detection of chemical warfare agents (CWAs) where they applied mathematical methods and frequency shift method to detect an attached CWA molecule [Nano electromechanical systems (NEMS) are devices that integrate electrical and mechanical functionality. Graphene provides a high surface to volume ratio, which leads to high sensitivity in the NEMS while maintaining a stable mechanical properties. Moreover, graphene’s geometry makes it suitable for standard lithography while its stiff yet flexible material and its electrical conductivity enable its integration in electrical transducers . In anot−1 . On the perature . Their rperature . Graphenperature . The senmolecule . Fan et molecule . 2 [2 sensing [2 concentration and the sensor response, while the performance of the graphene-based sensor was evaluated in dry and humid conditions (0% and 50% humid environment) showing a less than 5% degradation in humidity, which is much lower than those of metal oxide gas sensors under the same conditions. Some excellent dedicated reviews about graphene in NEMS have been reported, discussing both NEMS and MEMS applications [Another interesting property in graphene is that it exhibits an excellent piezoresistive effect, which makes it ideal for piezoresistive pressure and strain sensors. In 2013, Smith et al. developed a highly sensitive pressure sensor using monolayer CVD grown graphene membranes that were suspended over the patterns on SiO2 . The sen2 . The res2 . Both se sensing . They prications ,239,240.As aforementioned, it was demonstrated that the implementation of CVD grown graphene in conventional NEMS structures where they still consist of transistor-like nanoelectronics shows superior performance and sensitivity . TraditiChen et al. reported the implementation of PECVD grown graphene nano walls (GNWs) in the fabrication of flexible electromechanical biosensor for real-time measurement of lactate . In the A combination of superior mechanical strength, flexibility, high optical transparency and superb carrier mobility makes graphene a great candidate to be used in energy applications. Here, we discuss three examples of using CVD grown graphene in this category, briefly reviewing the utilisation of graphene in solar cells, batteries and supercapacitors. 24 J of solar radiation per year, which is approximately 10,000 times the current global energy consumption. Thus, as solar energy has great potential in providing energy security, research is continuously tackling the main challenges in solar cells and photovoltaics (PVs) in order to reduce the cost and find novel approaches to increase their efficiency. The current market of conventional solar cells is dominated by crystalline silicon which is a well-established technology. Recent research reported Si-based solar cell with an efficiency of 26%, which is close to the theoretical limit of 29.1% [Solar energy is the most abundant sustainable form of energy on the planet. Earth receives 3 × 10of 29.1% . Howeverof 29.1% , CIGS [2of 29.1% , perovskof 29.1%  and CZTSof 29.1%  showing of 29.1% . Researcof 29.1% . Howeverof 29.1% .x dielectric layer which was deposited using PECVD with a designed lithography mask on the front surface of GaAS. The exposed area in the dielectric layer is considered as the active area for the graphene/GaAs solar cell, where the CVD graphene was transferred to the active GaAs area. The performance of the fabricated solar cell was tested using a solar simulator giving 18.5% power conversion efficiency (PCE) while drift–diffusion simulation was utilised and higher PCE was predicted with over 23.8% shedding the light to great potential of utilising graphene in PVs by investigating more dielectric materials [3) and antireflecting coating of PMMA were performed on the optimum graphene thickness in order to increase the PCE, reaching an efficiency of 9.18% [Since then, many studies have been made in order to increase efficiency by using an interfacial layer, doping and antireflective coating. Song et al. in 2015 reported a drastic increase in efficiency after using an optimal oxide interfacial layer, followed by a further increase to reach 12.4% after chemical doping followed by 15.6% efficiency by applying an antireflective coating, demonstrating a method for the combination of the three aforementioned techniques . Later, aterials . Furtheraterials . Graphenof 9.18% . Another type is the Perovskite solar cells, especially combining crystalline silicon in the design of the solar cell, is predicted to have high PCE using a hybrid of perovskite/silicon tandem devices. However, such a design requires the use of transparent conductive electrodes. Conventional transparent conductive oxides cannot be directly deposited on the top surface of the perovskite cell, requiring buffer layers leading to current losses. Promising alternatives are electrodes made of the silver nanowire (AgNW) as they have low sheet resistance, giving an efficiency of 17%; however, their optical transmission is 87%, which is far below that of graphene . Lang etOrganic solar cells (OSCs) have gained a worldwide interest due to their potential of having flexible and cost-effective solar cells. Organic solar cells consist of substrate, anode, hole transport layer, absorber, electron transport layer and a cathode. The anode layer is typically a transparent conductive layer made of indium tin oxide (ITO) for its electrical conductivity and optical transparency. However, ITO is brittle, making it unsuitable for the next generation of flexible devices. Additionally, since indium is a strategic material, alternatives are very desirable for the industry. Graphene has been proposed as the ideal replacement for ITO due to its properties. The efficiency of flexible OSCs is still low compared to other types of solar cells. However, efforts are ongoing to develop their efficiency further. Kim et al. investigated the use of CVD grown graphene as the transparent conductive electrode on flexible PET substrates . They sh2Sx, x = 4, 6 and 8) are highly soluble that they dissolve and shuttle through the electrolytes [Batteries are usually categorised as rechargeable, which mainly consists of lithium and non-rechargeable such as alkaline and zinc-based batteries. Briefly, the non-rechargeable contain two electrodes and an electrolyte where the charges flow in one direction and usually have a short lifespan. While rechargeable, it also consists of two electrodes, where the cathode is made of lithium-based metal oxide, and the anode is a porous carbon and having lithium ions flow in both directions (charging/discharging). The increasing demand of mobile electronic devices  requires high energy and power density storage systems that provide fast charging and stable performance. The traditional lithium-metal oxide batteries have many limitations, making them unable to meet those requirements . A suggetrolytes  and betwtrolytes .2S2/Li2S, which suppressed the shuttle effect. Therefore, this decreased the self-discharge compared to a conventional Li-S battery using a standard PP separator without sacrificing energy density. In another study, Assegie et al. reported an anode-free Li-metal battery consisting of a Cu current collector that is modified and coated with multilayer CVD grown graphene [Therefore, the need for a conductive material that is thin with negligible weight and yet flexible to be used as separator coating, CVD grown graphene film arise as the most promising candidate to enhance the power and energy density of Li-S batteries. Du et al. prepared a Li-S battery with polypropylene (PP) separator that is coated with two layers of CVD grown graphene . Enhancegraphene . They foMore studies showed the potential of using nanoscale silicon in anodes for lithium-ion batteries since they have high cycle stability and reversible capacity compared to bulk silicon . The siz−1 if the entire surface area is utilised [Supercapacitors have attracted enormous interest in research communities due to their outstanding potential in terms of high power density, high charge/discharge rates and long lifespan performance. They are mainly divided into two categories based on the mechanism of their energy storage; (1) electric double-layer capacitors (EDLCs) and pseudo-capacitors . The EDLutilised ,274, but2So4 electrolyte, while Ag/AgCl was used as a reference anode. The supercapacitor performance showed an excellent charge/discharge cycling stability, and it sustained 84% of its initial capacitance after 1000 cycles. This revealed that graphene/Ta wire electrode is such a promising electrode material for high energy storage devices since it exhibited the highest capacitance of 345.5 F g−1. A recent study on reducing the equivalent series resistance (ESR) was reported by Kwon using optimised CVD grown graphene on Ni foil using different cooling rates  [−1). This was explained by the reduced ESR, thus providing a better interface, enabling more contact points between the electrode and the current collector. This shows advancement of the implementation of G-based electrodes in a supercapacitor for devices that require faster scan rates.Li et al. were the first to report the capacitance of graphene/tantalum (Ta) electrodes . They sy °C/min) . Graphen2. This was followed by more efforts indirectly use self-assembled and chemically modified graphene sheet to fabricate graphene-based fibres employing facile and spinning processes [2. The results showed remarkable porous structure (uniform pore distribution) and electrochemical performances in terms of discharge capacitance and cycling stability shedding light on its potential use as an electrode in supercapacitors. Later, the same research group , studied the implementation of their previously reported graphene fibre structure derived from CVD grown graphene into a flexible all-solid-state supercapacitor using gel electrolyte made [2 nanoparticles) structure worked as the active electrode and electron collectors. The areal capacitance of the graphene-based supercapacitor was reported to be 42.02 mF cm−2, which was considerably high compared to other fibre-based supercapacitors. In addition, the structure withstood mechanical bending and exhibited stable galvanic cycling as well as electrochemical performance.Another interesting implementation of 2D grown graphene films via CVD is their ability to be used in flexible solid-state (the electrolyte is non-liquid) supercapacitors. All-solid-state supercapacitors attracted the most attention due to their simple design, flexibility and efficiency in energy storage, enabling their use in wearable devices . Early srocesses ,279. Li rocesses . The novyte made . The gra2SO4) dropped cast to the supercapacitor design. The reported area specific capacitance of 5.0 µF cm−2 using the fabricated micro-supercapacitor was comparable to other reported supercapacitors based on CVD has grown graphene [More recent study was reported by Kim et al. in 2017, a novel roll-based patterning technology for CVD grown graphene was presented using highly durable Ni stamps to pattern the graphene at room temperature . The metgraphene ,284.An in-depth review was conducted on the synthesis of graphene using CVD methods  and the main characterisation techniques to study the characteristics of the produced graphene . A detailed review on the used growth substrates including the morphological effect and the nucleation and growth mechanism in solid and liquid substrates. Finally, an overview on graphene integration in applications, highlighting electronics and energy sectors in particular.In this review, the various factors affecting the quality of graphene film and its growth process were discussed, including the system total pressure, partial pressure of hydrogen and hydrocarbon species, growth temperature, source of power, etc. Knowledge of the effect of growth conditions and their correlation with the physical and chemical properties of the growth substrate is essential in creating a fundamental understanding of the process. In addition, it gives a powerful tool for tuning the growth parameters accordingly to achieve the desired graphene film, whether, monolayer, bilayer, few layer, or doped graphene which directly influence the electronic properties of the resulted graphene film. The progress in synthesis techniques and exploring wider range of parameters space in order to gain control over the deposition process to have the ability for large scale production while maintaining high quality graphene properties. Growth substrates were discussed in terms of the effect of pre-treatment methods and the surface morphology on the uniformity of the grown graphene film. Liquid substrates show the most potential to grow uniform, single crystalline monolayer graphene with no or a negligible amount of defects due to the absence of grain boundaries and other morphological defects when the growth starts on liquid state substrate. However, more investigations need to be done to explore other substrates such as low-melting point metals and precisely monitor the shrinkage effect of the substrate on the grown graphene.Overview of the essential characterisation techniques were discussed. Utilising Raman spectroscopy, scanning electron microscopy, atomic force microscopy and transmission electron microscopy reveals a tremendous amount of information about the characteristic properties of the produced graphene film as well as the defects nature and density. In addition, progress in the integration of CVD grown graphene in electronics and energy applications was discussed. Graphene’s role in the impressive performance enhancement of LEDs, NEMS, biosensors, solar cells, batteries and supercapacitors were highlighted. The window for graphene applications is wide open for limitless fields. However, CVD methods produce the best electronic quality for graphene, which makes it ideal for electronics and energy technologies in particular.Future prospects shall include novel designs for cost effective CVD systems that allow the continuous growth of high quality graphene on a large scale. Moreover, synthesising functionalized graphene and other 2D materials need to be researched as it could pave the way for a wider range of possibilities. Such novel materials can be employed and be very beneficial in enhancing the performance of electrochemical and electromechanical micro and nano devices. For example, their integration in ultra-sensitive biosensing for healthcare and medical sector as well as environmental sector  and evaluating the performance under harsh conditions are interesting fields that require further studies.


PREcise and Fast Method of Ambiguity Reinitialization/Resolution (PREFMAR) for L1 and L2 in GPS measurements. The method determines This paper presents a  Attempts to determine the total ambiguities in phase measurements in GPS observations date back to the late 1970s—i.e., GPS satellites were first placed in Earth orbits in 1978 . The firThe combination of L1-L2 frequencies of a GPS system is a special one, available in every multi-frequency GNSS receiver and probably the most effective double-frequency combination of GNSS data. A detailed description of mathematical functions used in the PREFMAR approach was investigated earlier for the use of L1-L5 or E1-E5a GPS/GALILEO data , but eacions see . In SectLet us make double-difference equations for two satellites, two measurement points and two frequencies: L1 and L2. For a very short baseline, the ionospheric and tropospheric delays have been ignored. Then, for the two frequencies, double-difference (DD) equations for carriers ; included .This means that for the frequency L1-L2, we should try to obtain code accuracy of less than 0.86 m, and then for short vectors we give only four sets of ambiguities—i.e., The dependence of the number of ambiguity sets on the accuracy of code measurements below 0.86 m using the PREFMAR method is shown in In In addition, in the case of reinitialization in time (t), we use the function values from the time before the disturbance in the reception of the continuity of phase signals—i.e., from time For the DD observation at time (t) during reinitialization, we can, therefore, write the following functions:The developed algorithms were tested on real L1-L2 observations, for a 10-min session with an interval of 1 s, and a baseline length of 3.6 km. The L1-L2 GPS measurements were performed with the Topcon HiperPro (M) receiver on 13rd August 2010, from 10:30:00 to 10:40:00 UTC, with reference to the OLST reference station. There were five GPS satellites available above the horizon: G09, G12, G15, G17 and G27, for which the following double-difference (DD) observations were created: G27-G09, G27-G12, G27-G15 and G27-G17. For every double-difference carrier phase observation and correctly determined ambiguities, the relative errors 2 mm see . The ambIn the second stage of the numerical tests, in the case of reinitialization at rvations , and, thThe properties of the functions iguities . TherefoThis work presents the new PREFMAR method for determining ambiguities in phase measurements for single measurement epochs, for GPS observations performed at L1 and L2 frequencies. Its efficiency mostly depends on the values of relative errors in DD phase observations. Ambiguity is selected based on a proprietary search function that uses the correlation between precisely determined ambiguity values depending on the frequency of satellite signals. The PREFMAR method allows determining ambiguities for individual measurement epochs without using a variance–covariance matrix with a float solution. For relative errors of 73 m see . Thus, tIn the case of relative errors of GPS float solution;Global code GPS/GNSS solution XYZ  and single-epoch double-differenced L1-L2 GPS measurements;A single-epoch of double-differenced L1-L2 GPS measurements.The developed PREFMAR method indicates ambiguity sets (Note that for case III, the PREFMAR method shows ambiguities even for a single DD observation, for any pair of satellites, but the accuracy of the code measurements is of key importance as we use double-difference observations from only two satellites. However, for much more accurate P5 code measurements transmitted at the L5 frequency, the III approach can be effectively used in L1-L5 positioning. The approach II seems to be the most universal, because in the global XYZ solution we can use any configuration of GNSS satellites with the most accurate code measurements and Kalman filter, which significantly increases the accuracy of the solution of the approximate XYZ position, both in static and kinematic positioning. Based on preliminary numerical results, the PREFMAR allows instantaneous ambiguity reinitialization if all satellites lost contact with a GNSS antenna.


In vivo tumor targeting studies at 1 h 20 post-injection revealed specific tumor uptake of 1.89 ± 0.40%IA/g for the site-specific conjugate, 1.77 ± 0.29%IA/g for the random conjugate, no nonspecific organ targeting, and excretion via the kidneys and bladder. Both strategies allowed for easily obtaining 68Ga-labeled hPD-L1 Nbs in high yields. The two conjugates were stable and showed excellent in vivo targeting. Moreover, we proved that the random lysine-conjugation is a valid strategy for clinical translation of the hPD-L1 Nb, despite the lysine present in the CDR.Immune checkpoints, such as programmed death-ligand 1 (PD-L1), limit T-cell function and tumor cells use this ligand to escape the anti-tumor immune response. Treatments with monoclonal antibodies blocking these checkpoints have shown long-lasting responses, but only in a subset of patients. This study aims to develop a Nanobody (Nb)-based probe in order to assess human PD-L1 (hPD-L1) expression using positron emission tomography imaging, and to compare the influence of two different radiolabeling strategies, since the Nb has a lysine in its complementarity determining region (CDR), which may impact its affinity upon functionalization. The Nb has been conjugated with the NOTA chelator site-specifically via the Sortase-A enzyme or randomly on its lysines. [ Immune checkpoints, which mitigate immune activities under physiological conditions, can be hijacked by cancer cells, thereby overcoming the patient’s anti-tumor immune response. Amongst the immune checkpoints, programmed death-ligand 1 (PD-L1) and its receptor programmed death-1 (PD-1), have drawn the most attention during the last 10 years and monoclonal antibody (mAb)-based immunotherapies antagonizing PD-1/PD-L1 have revolutionized the cancer treatment paradigm . Recent Pre-clinical and clinical studies with radiolabeled mAbs showed that the assessment of the PD-L1 status by positron emission tomography (PET) imaging is a promising strategy for patient stratification ,12,13. H99mTc-labeled Nb revealed high signal-to-noise ratios, strong ability to specifically detect PD-L1 in melanoma and breast tumors, and surprisingly low kidney retention, unlike many other radiolabeled Nbs.Nanobodies (Nbs), also called single domain antibody fragments, can overcome limitations linked to the use of mAbs for PET imaging. Their high affinity and specificity, as well as their small size ~15 kDa), make Nbs ideal probes for molecular imaging. Their fast blood clearance allows for imaging as early as 1 h p.i. and radiolabeling with short-lived radioisotopes, lowering the radiation burden for the patients . We prev kDa, mak68Ga) , which is commonly used in clinical settings. To allow for chelation of 68Ga, Nbs are typically conjugated with the bifunctional chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NCS-Bn-NOTA) on the primary amino groups of the lysines of the Nb’s structure Ga-citrate solution was purchased from Mallinckrodt .All of the reagents and solvents were purchased from Sigma–Aldrich  or VWR . Buffers used for coupling reactions and for radiolabeling were prepared with metal free water  and purified from metal contamination using Chelex 100 resin. 4OAc Ph 7, at a flow rate of 0.8 mL/min. SEC purification of randomly functionalized Nb was performed on a Superdex Peptide 10/300 GL column while using 0.1 M NH4OAc pH 7, at a flow rate of 0.5 mL/min. For quality control (QC), radiochemical purity (RCP) was assayed with binderless glass microfiber paper that was impregnated with silica gel   using 0.1 M sodium citrate buffer pH 4.5–5 as eluent. RCP was also assayed by SEC on a Superdex Peptide 3.2/300 GL using a 2× Phosphate-buffered saline  at a flow rate of 0.150 mL/min. Serum and urine samples were analyzed on a Superdex 5/150 GL using 2× PBS at a flow rate of 0.3 mL/min.Size-exclusion chromatography (SEC) columns were purchased from GE Healthcare . SEC purification of the site-specifically functionalized Nb was performed on a Superdex 75 Increase 10/300 GL column using 0.1 M NH6-tag and/or a sortag (LPETG) and the Sortase-A enzyme were produced as described before GaCl3, obtained from [67Ga]Ga-citrate, as previously described Ga-NOTA-(hPD-L1) Nbs were obtained with a RCP > 99% and DC-RCY were 87 ± 5% (N = 3) and 86 ± 10% (N = 3), respectively, for a procedure time of 30 min.Besides labeling with 68Ga-labeled Nb remained > 99% after 4 h. After 4 h at 40 °C in injection buffer, 6% of a radiolysis side product was observed, showing an influence of temperature on the radiolysis process.In vitro stabilities of the radiolabeled probes are summarized in 68Ga]Ga-NOTA-(hPD-L1) Nb remained > 98% after 4 h of incubation.In the presence of 1000-molar fold excess DTPA, no transchelation was observed and the RCP of the site-specifically labeled Ga-NOTA-(hPD-L1) Nbs. For both probes, ex vivo analysis 1 h 20 p.i. showed very low uptake in all organs, except in the kidneys due to renal excretion. Notably, retention in the kidneys of the site-specifically labeled hPD-L1 Nb was 10.1 ± 2.4%IA/g, which is, to our knowledge, the lowest ever reported for a radiolabeled Nanobody at an early time-point.POS cells, or hPD-L1NEG cells as a control  than in the hPD-L1NEG tumors for the site-specifically radiolabeled Nb, and about five times higher (p < 0.0001) for the randomly radiolabeled Nb. Both probes showed high uptake variation in the hPD-L1POS tumors, which did not allow to conclude on a potential difference in affinity in vivo between the two radiolabeled Nbs. Using these preliminary data and taking into account variations in tumor size, a larger sample of animals (N = 21/group) was calculated to be necessary in order to make a statistically reliable conclusion. For both probes, the accumulation of radioactive signal in the hPD-L1POS tumors was measured: 1.89 ± 0.40%IA/g for the site-specifically radiolabeled Nb and 1.77 ± 0.29%IA/g for the randomly radiolabeled Nb , as depicted in Biodistribution and tumor targeting in athymic nude mice bearing hPD-L1The tumor-to-blood (T/B) ratio and tumor-to-muscle (T/M) ratio were calculated for both probes. T/B ratio for the site-specific Nb was 6.3 ± 3.0 (N = 21) and 5.4 ± 1.5 (N = 21) for the random Nb (NS). The T/M ratio for the site-specific Nb was 34.5 ± 13.2 (N = 21) vs. 28.0 ± 10.6 (N = 21) for the random Nb (NS).POS tumor cells confirmed the significantly higher (p < 0.0001) % of cells expressing hPD-L1 than the hPD-L1NEG tumor cells, as reported in Ex vivo flow cytometry characterization of the hPD-L1POS tumor and injected with site-specifically [68Ga]Ga-NOTA-(hPD-L1) Nb confirms the low background at 1 h 20 p.i. and high uptake in the tumor lesion . A smaller fragment could be observed at later time points (4 h) and it is most likely due to radiolysis, which is a result of combined positron emission and high temperatures FDG, implementation in routine patient care should also be very straightforward.Taking together all of the results obtained for each of the functionalization strategies, their high production yields, high purity, specific tumor targeting, and excellent tumor-to-background ratios make them both excellent candidates for future clinical translation. The site-specific coupling method offers the advantage that it yields a homogenous pharmaceutical product, which is not the case for the random lysine conjugation. Its implementation in a GMP radiopharmacy is however less straightforward as compared with the random strategy due to the use of an enzyme. Nevertheless, the use of enzymes in pharmaceutical productions is increasing, for example in antibody drug conjugate production for clinical trials, and such a development might also facilitate the use of the Sortase strategy for radiopharmaceutical production . Since t68Ga-labeled probe. We demonstrated that a lysine present in the CDR did not impact the affinity when randomly functionalizing this particular Nb with NOTA for 68Ga-labeling as compared with a site-specific strategy. Although the site-specific strategy had the advantage of providing a more homogeneous clinical product, the random strategy is more straightforward and less costly for clinical translation. The 68Ga-labeled Nb is a promising PET imaging agent for future clinical assessment of PD-L1 expression and patient stratification. When compared to other PET probes in development, the radiolabeled Nb shows the lowest kidney uptake, enables imaging at early time points after injection, and provides high tumor-to-muscle and tumor-to-blood ratios in a preclinical model, thereby confirming its high potential for successful clinical applicability in the future. In this study, we have confirmed the high affinity and specificity of a lead Nb targeting human PD-L1 as well as fast clearance in vivo of the Bridoux, J.; Broos, K.; Lecocq, Q.; Raes, G.; Keyaerts, M.; Devoogdt, N.; Breckpot, K.; Xavier, C. Human PD-L1-BINDING Immunoglobulins. hPD-L1 Nanobody No. PCT/EP2019/055133; WO/2019/166622; 6 September 2019. Keyaerts, M.; Devoogdt, N.; Raes, G. Radio-labelled Antibody Fragments for Use in the Prognosis, Diagnosis of Cancer as well as for the Prediction of Cancer Therapy Response. HER2-Nb imaging and therapy No. PCT/EP2015/067424; WO/2016/016329; 4 February 2016.


Ageism is unlike any other form of prejudice in that, all things being equal, we are all at risk of experiencing it as we age. Whilst this stands true, many communities experience discrimination in other domains such as gender, race, sexuality and disability. As these communities age they are likely to experience cumulative or intersectional disadvantage due to multiple stigmatized group memberships. Where it is understood that there are negative health  and psychological  outcomes associated with each form of discrimination, the often focused research is less than conclusive regarding the consequences of intersectional discrimination. Using both qualitative and quantitative methodologies from across the US, this symposium explores the impacts of ageism with regard to HIV status, disability status, race/ethnicity and LGBT identification. Exploring the intersections of ageism, each paper will highlight the challenges faced by the respective communities as well as some of the ways to address this using policy, practice and highlighting where additional research would be needed to fully understand the phenomena. Finally the discussant will summarise and collate ideas for a concluding panel discussion.


Background: We studied the effects of a supervised, structured exercise program in a severe sarcoidosis patient. Methods: After being clinically stable for two years, a 52-year-old woman  who originally had irreversible lung fibrosis, pulmonary arterial hypertension (PAH), mild mitral insufficiency, and atrial dilatation, and was candidate for lung transplant, performed a combined high-intensity interval, high load resistance, and inspiratory muscle training for 4.5 years, and was tested  every six months. Results: Cardiorespiratory fitness (CRF) and maximal pulmonary ventilation increased by 44% and 60%, respectively. Ventilatory efficiency also improved . She improved New York Heart Association (NYHA) class (from III to II), and cardiac alterations as well as PAH reversed so that she was not in need of lung transplantation anymore. Likewise, she suffered no more episodes of hemoptysis. Bone health was overall maintained despite the post-menopausal status and the corticoid treatment. Conclusions: A long-term combined exercise intervention safely contributed—at least partly—to improve CRF and NYHA class in a patient with severe sarcoidosis, suggesting a potential coadjuvant effect to attenuate clinical manifestations. Sarcoidosis is an autoimmune disease of unknown etiology , diagnosed in 2007 with the most severe presentation of systemic sarcoidosis according to the American Thoracic Society criteria—stage IV—indicating irreversible scarring in the lungs (pulmonary fibrosis) [The patient is a post-menopausal woman aged 52 years at the start of the study  , in the Beyond pulmonary involvement , she had ocular, dermal, and articular symptoms . She hasShe practiced athletics from the age of 17 to 20 years and adopted an essentially sedentary lifestyle since age 23 until starting our intervention—except for two 12-week respiratory rehabilitation programs performed 4 and 3 years, respectively, before the start of our exercise training intervention.All assessments were performed every 6 months (June and December) at the Exercise Physiology Laboratory at Hospital 12 de Octubre , which she first visited in June 2015. After we studied her medical history in depth (with one of us (A.L.) being a physician with solid expertise in the implementation of exercise interventions, including in-hospital programs, for patients with numerous disease conditions such as PAH ), she unFirst, we measured maximum inspiratory pressure (MIP) . Due to the history of recurrent hemoptysis (some during spirometry) and the fact that performing forced expiration is known to increase pulmonary capillary pressure , we refr2)  and gas exchange data  were continuously monitored. We followed a published protocol [2 decreased below 90%. Other criteria for test termination were chest pain, ECG signs of ischemia, severe dyspnea disproportionate to the effort, tachyarrhythmias, or a drop in BP. The protocol also included a recovery phase, during which the patient pedaled for one minute at 10 watts and one minute without resistance, before finally resting for one minute on the ergometer to prevent post-exercise desaturation. Gas-exchange parameters (10-s averages) where collected for the determination of the peak value of oxygen uptake (VO2peak) reached during the tests, as well as the ventilatory threshold (VT) and respiratory compensation threshold . The VT corresponded to the workload at which the ventilatory equivalent for oxygen (ventilation (VE∙VO2−1) starts to increase with no concomitant increase in the ventilatory equivalent for carbon dioxide (VE·VCO2−1) and with departure from linearity of VE. The RCP was determined as the workload at which both VE·VO2−1 and VE·VCO2−1 increase together with a decrease in end-tidal pressure of carbon dioxide [Thereafter, the patient performed a cycle ergometer  exercise test until volitional exhaustion, during which blood pressure (BP), heart rate (HR), 12-lead ECG, peripheral oxygen saturation  during and after each set of exercises.In the first visit only, the patient performed a circuit strength training session using basic machines , during which we monitored SpO1-L4) and femoral neck was performed as described [After the first year of training, we incorporated body composition analysis  to the battery of assessments. Body mass composition was calculated from a full body study scan, and a specific analysis of bone density in the spine (Lescribed .The patient underwent a combined (HIIT + high load resistance + IMT) program for a total of 4.5 years in her local fitness center under the supervision of a fitness specialist. The patient generally trained five to six days/week. This included two sessions of strength training using machines, two sessions of strength training using “functional exercises”, and two HIIT sessions. When she performed two sessions per day, this consistently included a HIIT and a functional training session, respectively.2 , and rating of perceived exertion  were recorded in each session. During the first three years all the sessions were performed on a cycle-ergometer . To prevent eventual abrupt decreases in SpO2 after exertion, each session ended with a cool-down phase . In the last phase (1.5 years) of the program, the HIIT sessions were performed on a treadmill . The transition from HIIT cycle-ergometer to HIIT treadmill sessions served two purposes: (i) to apply a more functional exercise modality with a greater transference to daily life activities; and (ii) to increase the impact load associated with exercise in order to prevent—or at least attenuate—the loss of bone mineral density that is known to be associated with both post-menopause and corticosteroid treatment [The HIIT program is detailed in reatment ,28.2 consistently >90%. Of note, this race speed was similar to the one corresponding to the active rest periods between intervals in the treadmill HIIT sessions  with SpOsessions .Strength training program is detailed in 2 were continuously monitored in all sessions, as was RPE, using the 0–10 OMNI Resistance Exercise Scale [2 above 90% . This combination was selected since high loads increase maximum force more than low loads [Thereafter, eccentric Russian belt squat  and, alsse Scale  at the eow loads , and a low loads .IMT was done using a mechanical pressure threshold device . It started with two sessions (morning and evening) of 10 maximum inspirations at 42% of MIP, five days a week, increasing gradually to 30 inspirations per session in the sixth month. Thereafter, the number of repetitions was maintained, and the inspiratory load was progressively increased depending on the patient’s intensity perception. She was asked to gradually increase the load of the inspiratory device so that it was always difficult, but not impossible, for her to do all the inspirations. After the second year, she performed two sessions of 60 inspirations per day, increasing the inspiratory load as described.2 dropped below 90% after the HIIT sprints, it consistently returned to baseline levels very quickly (within 10–15 s).During the study period the patient’s functional status improved from NYHA III  to II . At the end of 2016 and throughout 2017 several breaks in training occurred due to exacerbation of the disease likely associated with the progressive reduction in corticoid dosage  until the withdrawal of the drug in May 2017 and reintroduction again at the start of 2018 (due to exacerbation of symptoms) . In addi2 dropped below 90% it normalized very quickly (10–15 s).Strength training was affected by medication withdrawal in the same way as HIIT . Plantar2O). In addition to the interruptions of IMT due to the worsening of her condition after the medication withdrawal, IMT was suspended in March 2019 due to rib pain after a fall while running on the treadmill.The inspiratory load increased from 20 to 40 inspirations per day at 42% MIP of restriction to 120 inspirations per day at 85% of MIP, causing a 19% increase in MIP  at the start of the study to 8.3 MET at the end). This is an important finding because the VO2peak level reflects the synergistic action of pulmonary, cardiovascular and muscle tissue via a suite of physiological actions that effectively transport and deliver oxygen from the atmosphere to mitochondria in working muscles [2peak, is a strong prognostic factor of morbimortality, particularly in relation to cardiometabolic diseases [2peak above this level have a reduced cardiovascular risk [2peak was expressed in either absolute units (mL·min−1) or relative to body mass (mL·kg−1·min−1). Furthermore, the intervention was safe, with no persistent SpO2 drops or syncope episodes.The main finding of our study was that a combined (HIIT + strength + IMT) program, applied for 4.5 years in a patient with sarcoidosis (stage IV) and pulmonary involvement and treated with corticoids for 12 years, contributed—at least partly—to increase functional capacity (improving a class in the NYHA classification) as well as cardiorespiratory fitness  [2 drops in her daily life activities.HIIT induces both peripheral  and central (increased cardiac output) cardiovascular adaptations . Furtherubjects) . ImproveIMT has been shown to improve exercise capacity, functionality, respiratory muscle strength, dyspnea, and fatigue in patients with sarcoidosis . These i2peak (mL/min) and improving the patient’s NYHA functional class. The increase in maximum strength may have allowed her, at least partly, to maintain a higher training work rate and increase the ability to cope with—and adapt to—cumulative HIIT sessions. Resistance training is known to improve work economy [Resistance training may also have played a role in increasing the VO economy  and thus economy . Muscle  economy . Likewis economy , especia economy . Althoug economy . This is economy . In this economy . AlthougIt is widely known that bone and lean mass decrease with age, particularly in menopausal women due to hormonal changes . CorticoThe NYHA class improvement, together with the well-known deleterious effects of chronic corticoid treatment led to the progressive withdrawal of this drug after 1.5 years from the start of the training program. With the exception of the sarcoidosis flare-up caused by medication withdrawal, only one sarcoidosis-related hospital admission (due to respiratory infection) and one medical intervention (capsulotomy) related to sarcoidosis occurred in the 4.5 years. Adverse events related to training were a running fall from the treadmill  and plantar fasciitis. Despite these episodes, the patient maintained her adherence to the training program due to the positive impact that the improvement in QoL and wellbeing early during the intervention (in the first few months) had on her level of motivation, as well as to her strong self-discipline.The present study has several limitations that should be considered. First, as this is a case report, our preliminary results in only one patient must be interpreted with caution and cannot be generalized to all patients with sarcoidosis. In this regard, it would be interesting to conduct a randomized controlled trial with a long-term intervention like the present one, although this type of study might be very difficult to conduct. Second, the 1RM was not evaluated, and thus although an increase in load (kg) was observed with resistance training, we could not quantify the magnitude of the actual improvement in maximum strength. Finally, diet was not controlled.In summary, the results of this study suggest that a long-term combined (HIIT + strength + IMT) exercise intervention might have contributed, at least partly, to safely improve CRF and functional capacity (NYHA class) in a patient with severe thoracic sarcoidosis. Our results also suggest that the intervention could have acted as a coadjuvant treatment that helped to partially reduce the severity of associated pathologies (cardiac involvement and PAH) and attenuate the loss of BMD and muscle mass caused by menopause and chronic corticoid treatment. Randomized controlled trials are needed to confirm our preliminary findings.


We aimed to develop question prompt lists for family caregivers of nursing home residents with advanced dementia to augment advance care planning conversations. In the context of a joint European-Canadian study, we used standardized nominal group methods to create country-specific lists of questions. (Bereaved) family caregivers of persons with dementia read an information booklet about end-of-life care for people with dementia, and generated questions to ask healthcare professionals. They also marked the most important questions from pre-selected questions from other lists. In the Netherlands, 20 participants contributed to a question prompt list of 24 questions that gravitated towards questions about terminating life and the responsibilities of physicians and family involved in decision making. In Canada, 4 participants came up with a question prompt list of 15 questions, related mostly to staff-family communication, with some the same as selected in the Netherlands. Data from the other countries will be presented too.


An easily fabricated Fabry-Perot optical fiber humidity sensor with high performance was presented by filling Graphene Quantum Dots (GQDs) into the Fabry-Perot resonator, which consists of two common single mode optical fibers. The relative humidity sensing performance was experimentally investigated by an interference spectrum drift between 11 %RH to 85 %RH. 0.567 nm/%RH sensitivity and 0.99917 linear correlation were found in experiments that showed high sensitivity, good and wide-range linear responding. Meanwhile, its good responding repeatability was demonstrated by two circle tests with increasing and decreasing relative humidity. For investigating the measurement influence caused by a temperature jitter, the temperature responding was experimentally investigated, which showed its linear responding with 0.033 nm/°C sensitivity. The results demonstrate the humidity sensitivity is greatly higher than the temperature sensitivity. The wavelength shift influence is 0.0198 nm with 0.6 °C max temperature jitter in the experiment, which can be ignored in humidity experiments. The fast-dynamic responses at typical humidity were demonstrated in experiments, with 5.5 s responding time and 8.5 s recovering time. The sensors with different cavity lengths were also investigated for their humidity response. All sensors gave good linear responding and high sensitivity. In addition, the relation curve between cavity length and response sensitivity also had good linearity. The combination of GQDs and single mode optical fibers showed easy fabrication and good performance for an optical fiber relative humidity sensor. Relative humidity (RH) measurements are very important in chemical fields, industrial monitoring, agricultural, pharmaceuticals, environmental monitoring, and so on ,3,4,5,6.2 sputtering deposition was reported with 0.14 rad/%RH sensitivity [2O3-PVA composite films and got a maximum sensitivity of 0.587 nm/%RH, but the response linearity in a repeatability experiment was expected to be better. An optical fiber grating RH sensor was also reported, such as polymer-coated fiber Bragg grating [Many optical fiber humidity sensors with a different structure or sensitive materials have been developed in recent years. The optical fiber coated with Nafion-crystal was used to measure relative humidity from 40 %RH to 82 %RH in 1997 . In the sitivity . In 2019sitivity  proposed grating , which i grating . An arra grating . The LPG grating . Many re2 [Many kinds of optical fiber humidity sensors are fabricated by various materials coating at the periphery of fiber, such as graphene oxide (GO) , MoS2 [22 , poly  every 0.5 s. By analyzing the spectrum shift, we got the dynamic responding data of this humidity sensor. The peak wavelength shift results at a typical humidity value of 54 %RH, which is shown in As The F-P cavity parameters directly affect the interference spectrum, especially the cavity length. To investigate the influence on the humidity response, the humidity sensing experimental results are also obtained. Seven RH optical fiber sensors with a different cavity length are all evaluated. In experiments, the cavity length is 108.41 μm, 152.34 μm, 196.44 μm, 251.23 μm, 302.67 μm, 352.76 μm, and 405.23 μm, respectively. All the humidity responding curves are shown in As According to the previous comparison, this configuration has high sensitivity with good linearity, wide linear responding scale, easy fabrication, and a fast-dynamic response.An optical fiber Fabry-Perot relative humidity sensor composed of QODs and single-mode fibers has been fabricated and experimentally investigated. The interference peak wavelength shift can be tracked by MOI SM125 in the experiments. The humidity responding experiments have been operated in a wide humidity range (11 %RH–85 %RH), and given 0.567 nm/%RH sensitivity and 0.99917 linear correlation. The humidity measurements were repeated at two humidity changing circles, which showed its good responding repeatability. For investigating the influence caused by a temperature jitter, the temperature responding characteristic was also experimentally investigated. The temperature responding curve had 0.033 nm/°C sensitivity and 0.99787 linear correlation. The influence to wavelength shift is 0.0198 nm with a 0.6 °C max temperature jitter in the entire experimental process. The temperature responding sensitivity is greatly lower than the humidity. Furthermore, the sensor has a stable and fast dynamic humidity response, which was discovered through the dynamic measurement experiments. We obtained a 5.5 s responding time and an 8.5 s recovering time at 54 %RH. In short, this kind of sensor has high sensitivity, an easy fabrication process, low cost, a wide linear measuring scale, good repeatability, and a rapid dynamic response. Some applications need a high performance and low-cost relative humidity sensor. This sensor indicated the possibility of easy implementation.


Hybridizing graphene and molecules possess a high potential for developing materials for new applications. However, new methods to characterize such hybrids must be developed. Herein, the wet‐chemical non‐covalent functionalization of graphene with cationic π‐systems is presented and the interaction between graphene and the molecules is characterized in detail. A series of tricationic benzimidazolium salts with various steric demand and counterions was synthesized, characterized and used for the fabrication of graphene hybrids. Subsequently, the doping effects were studied. The molecules are adsorbed onto graphene and studied by Raman spectroscopy, XPS as well as ToF‐SIMS. The charged π‐systems show a p‐doping effect on the underlying graphene. Consequently, the tricationic molecules are reduced through a partial electron transfer process from graphene, a process which is accompanied by the loss of counterions. DFT calculations support this hypothesis and the strong p‐doping could be confirmed in fabricated monolayer graphene/hybrid FET devices. The results are the basis to develop sensor applications, which are based on analyte/molecule interactions and effects on doping. Organic star‐shaped tricationic molecules interact with graphene and a one‐electron transfer from graphene to the molecules leads to strong p‐doping. Both compounds were converted into trications 3+6 through N‐quaternization using alkylation agents to introduce various substituents and counterions . Due to the polar nature of the benzimidazole moiety and hydrogen‐bond acceptor function, it seems likely that water or methanol molecules can be adsorbed under ambient conditions. Although some contaminants are visible on the surface of the flakes of the r‐oxo‐G/hybrid the roughness and measured height is overall homogeneous after functionalization. Thus, the AFM results indicate that molecules form indeed films and do not cluster to aggregates.The non‐covalent modification of graphene was accomplished by incubating a silicon wafer with deposited graphene, either CVD graphene or r‐oxo‐G, in a 12 mx 150 μm of a film of flakes of r‐oxo‐G/3+8  was scanned in positive mode. The most prominent signal observed was m/z 811.16, which can be related to 3+8 through the loss of one of its counterions. As shown in Figure m/z signal all over the flake with almost constant intensity confirms the homogeneous non‐covalent functionalization of the r‐oxo‐G. In addition, no signal is found on the bare SiO2 surface, indicating that molecules are only adsorbed on the r‐oxo‐G flake.The existence of the tricationic molecules on the surface of r‐oxo‐G/hybrid was further studied by time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) analysis. The adsorbed tricationic molecules can be identified by ToF‐SIMS analysis. An area of 150 μm m/z 662.73 and m/z 513.28 corresponding to the mass of the trication without 2 and 3 counterions, respectively, . In addition, ToF‐SIMS was conducted in negative ion mode to detect the triflate counterion with m/z 148.95. The map of Figure ). However, experiments with a blank Si/SiO2 wafer as substrate reveals that the tricationic molecules are not adhering to the SiO2 surface . A Si/SiO2 wafer incubated in methanol also did not show signals from the trication molecules . An optical image of a functionalized r‐oxo‐G sample is included in the Supporting Information .Thus, these observations corroborate the height profiles obtained by AFM measurements. Also, although with lower signal intensity, signals were observed at 2 surface and on graphene surface.N‐methylbenzimidazolyl) benzene 3+8 on SiO2 substrate  or the reduced form 2+8,  on graphene computed on the density functional theory (DFT) level of theory support this interpretation . Reference Raman measurements on r‐oxo‐G/3+8 indicate, in agreement with the ToF‐SIMS results, that molecules are only adsorbed on the graphene flakes and not on the bare SiO2. Raman spectra recorded on CVD graphene and CVD graphene/3+8 reveals that 3+8 is adsorbed on graphene. Analysis of the shift of the position of the G peak, which is sensitive to doping,3+8, respectively . The influence of the solvent methanol on CVD graphene was investigated and did not show any significant influence on the G and 2D band . XPS was used to analyze the composition of the surface of r‐oxo‐G/hybrid materials.2‐hybridized character of the carbon present in graphene, together with minor contribution from certain oxidized states that cannot be completely avoided during the preparation.2‐intersurface in between the graphene layer and silicon substrate. The nitrogen (N) signal observed at 400 eV,3+7), oxygen (O) and sulfur (S),  or boron (B) and fluorine (F) . Comparison among the XPS spectra of pristine graphene, functionalized graphene and the neat molecules on silicon confirms the non‐covalent adsorption of the molecular systems on graphene. XPS samples with the neat molecules on substrates were prepared by drop casting a methanol solution of the respective tricationic molecule on a silicon wafer. The preparation of non‐covalently modified graphene was described previously.For this study, CVD graphene was used because its Raman peaks are sharper compared to the peaks for r‐oxo‐G. Thus, the choice of CVD graphene reduced the interfering overlap with other peaks in the subsequent analysis. Raman spectra from non‐covalently functionalized graphene show the presence of broad and overlapping signals between 1200–1600 cm+ Figure  C. We pr4 on silicon shows two binding energies for nitrogen at 398.6 eV and 400.5 eV  and a secondary amine type of nitrogen atom (R2‐NH). The binding energies for these two nitrogen atoms increase slightly to 399.0 eV and 401.0 eV, respectively, when the molecule 4 is adsorbed on graphene . It shows one major peak at the binding energy 402.1 eV, consistent with imidazolium nitrogen atoms.The XPS spectrum of the neat neutral molecule 3+7 and 3+11 on silicon, it could possibly correspond to an ensemble of tricationic molecules binding to the silicon surface in a distinctly different mode compared to the vast majority. On the other hand, the XPS spectrum obtained for the sample with the tricationic molecule 3+8 on CVD graphene shows one very broad signal that can be fitted by two components of equal intensity  what is consistent with the presence of two sets of nitrogen atoms. XPS analysis of the N 1s components reveals two species. Accordingly, the signal at around 399.7 eV corresponds to an iminium type state and the other component located around 401.7 eV agrees with the expected value for an imidazolium nitrogen state.As this minor peak is also present in the XPS spectra of tricationic molecules y Figure  B what i3+8 on silicon gives a ratio among fluorine, nitrogen and sulfur (F/N/S) of 3:2:1. This is in agreement with an assembly of one trication and three counterions, which corresponds to the molecular formula C36H33F9N6O9S3. After non‐covalent binding of 3+8 to graphene, this ratio changes to 1:3:0. The signal for the sulfur atoms is below the detection limit. The decrease of fluorine and sulfur, which originate from the triflate counterion, indicates that the triflate counterions become more exchangeable and possibly even superfluous.As will be discussed later, the two components may correspond to two various nitrogen atoms either facing or pointing away from the graphene. The change in the ratio of the N 1s signals also gives information about the doping of graphene by non‐covalently bound molecules. Both p‐3+7 and 3+11 on CVD graphene show similar trends . Charge transfer from graphene to the non‐covalently bound molecules could explain this observation. Due to the weaker Coulomb attraction, some of the counter ions could potentially be removed by rinsing the sample with methanol during the sample preparation, or exchanged by some negatively charged species in the methanol solvent, for example, methoxide ions. A summary of all tested molecules is depicted in Scheme 3+9 and 3+12 were investigated by cyclic voltammetry in acetonitrile . Both compounds show several reduction events. The first one‐electron reduction of 3+12 corresponds to a reversible one‐electron transfer at Ered,1=−1.65 V . Such long wavelength bands are usually a sign for the generation of radical species. Figure 3+12 and for the reoxidized species of 3+12. The uniform overlap of both spectra indicates that the same species was analyzed and that the first reduction event is reversible.The XPS data recorded for 3+8 (without counterions) on top of a 9×9 supercell of graphene served as the unit cell in our model system. Density functional theory with periodic boundary calculations was used to study the overall electron distribution in the system. The optimized geometry of 3+8 alone at the same level of sophistication is propeller shaped, characterized by an average dihedral angle of 53.2°  between the central benzene ring and the appended benzimidazolium moieties  of the unit cell  the peripheral benzimidazolium moieties. From a stabilizing point of view the effect of this partial electron transfer is twofold. First, the increased electron density at the central benzene ring decreases the coulombic repulsion between the cationic benzimidazolium moieties via a screening effect. Second, the bonding traits of the LUMO results in a planarization of the overall molecular structure when electron density is fed into the orbital. The later contributes favorably to the bonding interaction by allowing for a shorter bonding distance and an increase in the surface area exposed to graphene by the trication. The denser deposition of molecules in the physical samples compared to the unit cell explored in the calculations may disturb the system causing some molecules on the graphene surface to possess more 2+8 character and others to be more like 3+8. This could explain why the adsorbed molecules display broad/overlapping nitrogen signals in XPS. Another reason could be that the strong binding in combination with the propeller shaped molecular structure results in two chemically distinctly different sets of nitrogen: the set of three nitrogen atoms close to the graphene surface and the set of those on the molecular face opposite to the graphene surface. All six nitrogen atoms in the free cation are chemically equivalent and should, as observed for the pristine silicon/silicate substrate, only give one peak in XPS. The single main peak may in fact indicate that the interaction between the trication and the silicon/silicate surface is so weak that it does not significantly disturb the molecular properties.To identify the effect of electron transfer, calculations were performed with different overall charges  and the ionization potential of graphene (exptl. 7.20–7.30 eV). The mismatch between the two values justifies the partial transfer of charge (not a full electron) between graphene and trication in case of the 3+8 unit cell.The same LUMO orbital, responsible for the stabilization effect discussed for the 3+8 on graphene, r‐oxo‐G was used to fabricate a monolayer field‐effect transistor device (FET)  was constant at 10 mV. Transfer curves (dsI‐dsV) with unipolar character are shown in Figure 2 is observed after sweeping continuously from −50 to 50 V and then back to −50 V. From the dashed lines  of 28.6 cm2 V−1s−1 is obtained at ambient conditions, calculated by Equation To better investigate the p‐doping effect of ) Figure  A. In reoxC=1.15×10−8 F/cm−2. After doping r‐oxo‐G with 3+8dsI‐dsV curves still keep the unipolar character, but these curves lean to a higher p‐doped direction. The hole mobility decreased to 20.7 cm2 V−1s−1. In addition, we found that the hysteresis effect increased indicating that more carriers were trapped between r‐oxo‐G and the SiO2 interfaces. The resistance of monolayer r‐oxo‐G device (with length 3 μm) before and after doping varies only slightly from 6.0 to 5.8 kΩ with a channel width of 20 μm and length of 3 μm. To investigate the influence of the hysteresis on the carrier mobilities deeper, we calculated the carrier mobilities at different slopes for r‐oxo‐G and r‐oxo‐G/3+8, respectively, .in which 4 for non‐covalent functionalization of r‐oxo‐G also results in p‐doping of the underlying graphene  in Figure 4, compared with the measurements from 3+8. After doping with 4, the transfer curves become unipolar, suggesting a stronger p‐doping character of r‐oxo‐G. Hole mobility (hμ) of the r‐oxo‐G before and after doping decreases from 20.4 cm2 V−1 s−1 to 18.9 cm2 V−1 s−1. The corresponding resistance of the r‐oxo‐G before and after doping decreases from 27.2 to 18.9 kΩ at dsV=10 mV, bgV=0 V with a channel width of 10 μm and length of 4.5 μm. Comparing both FET devices with each other, a stronger decrease in hole mobility can be observed for 3+8. This can be explained by a stronger interaction between 3+8 and r‐oxo‐G compared with 4 and r‐oxo‐G, which leads simultaneously to a stronger p‐doping effect on the underlying graphene for 3+8.We note that the reference experiment using the uncharged compound e Figure  C. TransN‐hetero‐π‐systems, which were used to non‐covalently functionalize graphene forming graphene/molecular hybrid structures. The cationic molecules form a stable molecular layer and interact strongly with graphene. This results in a reversible one‐electron transfer between the molecules and the underlying graphene, which leads to p‐doping of the graphene. The functionalization of graphene and the one‐electron transfer was studied by AFM, XPS, ToF‐SIMS and Raman spectroscopy. The performed measurements did not show any influence of the various counterions. DFT‐calculations confirmed the observed effects from the performed experiments. With the reported wet‐chemical method of graphene functionalization, we were able to fabricate monolayer graphene FET devices. Comparing both FET devices with each other, a stronger decrease in hole mobility can be observed for the tricationic molecules 3+8 compared to the neutral precursor 4. This can be explained by a stronger interaction between 3+8 and r‐oxo‐G compared with 4 and r‐oxo‐G, which leads simultaneously to a stronger p‐doping effect on the underlying graphene for trication 3+8.Through a concise synthetic strategy, we synthesized a series of cationic Both the novel series of compounds as well as the described method help to understand the non‐covalent functionalization of graphene in more detail. In the future, novel sensors based on FET devices can be fabricated for selective sensing, if the analyte interacts with the cationic molecules adsorbed to the surface.The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent. Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH Nearly 40% of clinical MRI procedures use a contrast agent to produce enhanced images, and nearly all contrast agents are Gd(III) coordination complexes. Although Gd-based contrast agents are highly successful, there are concerns about potential toxicity and retention from long-term exposure, particularly for patients with renal insufficiency ,4,5,6,7.The Fe(III) complexes that were studied in the early years of MRI contrast agent development were not very effective in comparison to those of Gd(III) . In many6–108 s−1 for Gd(III) or Mn(II) complexes, with optimal rate constants of 107–108 s−1 at moderate field strengths of 3 T Cl for Fe(L1)(OH2) and [Fe(L2)]Cl2 for Fe(L2). The ligands and their protonation states, L1, H-L1 and L2, H-L2, are defined in Key steps in the synthesis of H-L1 and H-L2 are shown in −1∙cm−1 to 3800 M−1∙cm−1 (2) was estimated as 18.1% over 24 h and 53.6% over 72 h based on absorbance changes. For comparison, the dissociation of the Fe(L2) complex in acidic solution (100 mM HCl) was 7.9% over 48 h, and the dissociation of Fe(L3)(H2O) was 14% over 24 h and 38% over 72 h − anion (c-axis. Both monomers have a six-coordinate Fe(III) center with three amine groups and three pendant alcohol groups ° and 39.4(1)°, respectively (The Fe(L2) complex crystallizes in the non-centrosymmetric space group ]− anion . The chll groups . There aectively . Similarectively  .,59.17O-N17O resonance of water and the corresponding transverse relaxivity is low. However, Fe(L1)(OH2) presumably has one bound water ligand, but also shows little resonance broadening at neutral pH (17O resonance peak width of Fe(L3)(OH2) and Fe(L1)(OH2) reaches about 21% and 7%, respectively, of Fe(CDTA) at pH 3 (2), similar to our observations for Fe(L3)(OH2) Cl.+H The H-L1 ligand (0.100 mmol) was dissolved in ethanol (5.00 mL). Then, ferrous chloride tetrahydrate  was dissolved in ethanol (2.00 mL) and was added dropwise to the ligand solution. Fe(L1) complex was isolated as yellow solid  by precipitation with diethyl ether. Fe content was calculated through ICP-MS for [Fe(L1 + H+)Cl]Cl: 11.38%, found: 11.57% ± 0.01%. M: [Fe(L1)]+; LCQ-MS: found m/z 421.2 , m/z 443.2 (M + Na+ − H+), 30%), m/z 841.0 , and m/z 863.0 . FT-ICR-MS: calculated m/z 421.13341, found m/z 421.13273 , calculated m/z 443.11535, found 443.11460 . 2[Fe(L2)]Cl. The H-L2 ligand (0.100 mmol) was dissolved in ethanol (5.00 mL). Then, ferrous chloride tetrahydrate  was dissolved in ethanol (2.00 mL) and was added dropwise to the ligand solution. Fe(L2) complex was precipitated as yellow solid . The yellow solid complex was washed with diethyl ether. Fe content was calculated through ICP-MS for [Fe(L2)]Cl2: 13.08%, found: 12.85% ± 0.09%. M: [Fe(L2)]2+; LCQ-MS: found m/z 357.2 , m/z 713.1 , and 735.1 . FT-ICR-MS: calculated m/z 357.17150, found m/z 357.17820 , calculated m/z 713.33517, found m/z 713.33414 , calculated m/z 735.31711, found m/z 735.31576 .217O water solution and studied at variable temperatures (20–80 °C). 1/T2 was calculated by subtracting the full width at half maximum (FWHM) of the 17O resonance with Fe(III) complex from that in the absence of complex /kg. The Fe(III) complex stock solutions were adjusted to pH 7.2 by addition of meglumine and were injected intravenously via tail vein. MR data were recorded continuously for up to 1 h. Distribution studies and clearance kinetics were studied by using MR data acquired over several time points for up to 1 h, and additionally at 4 h and 24 h. For comparison, The Food and Drug Administration (FDA)-approved MRI contrast agent gadopentetate dimeglumine (Gd(DTPA), Magnevist®) and gadoterate meglumine (Gd(DOTA), Dotarem®) were injected at 50.0 μmol [Gd]/kg into separate group of mice and imaged as above. 2-H+][FeCl4]3 were grown through slow evaporation of solvent from a water/methanol mixture. Data were collected on a Bruker SMART APEX II CCD diffractometer. Data reduction was completed using SAINT version 8.40A, and a multi-scan absorption correction was applied using SADABS version 2016 included in the Bruker APEX3 software suite [2). Hydrogen atoms attached to oxygen atoms were located in the difference Fourier synthesis and had their distances restrained using the DFIX command to an effective O–H distance of 0.84 Å retrieved from the lst file. Anomalous scattering was used for absolute structure determination. The twist angles were calculated as torsion angles using the Olex2 software package [Single crystals of [Fe(L2)]re suite . Space-gre suite . The strre suite  using inre suite  using le package . Crystal1 relaxivity in phantoms at 4.7 T that we attribute to second-sphere water interactions, similar to an analogous complex with a benzyl ancillary group. The addition of an alkyl group with anionic sulfonate has the advantage that it produces a hydrophilic Fe(III) complex of high solubility. However, the replacement of a benzyl group with an alkyl group on the TACN macrocycle produces an Fe(III) complex that is less highly stabilized in the trivalent state. The hydrophilic nature of the Fe(L1)(OH2) complex combined with its relatively low binding to serum albumin leads to a complex that behaves as an extracellular fluid contrast agent. In fact, Fe(L1)(OH2) shows a pharmacokinetic profile that is similar to that of Gd(DTPA) or Gd(DOTA). Future research will focus on the molecular properties of Fe(III) macrocyclic complexes that contribute to serum protein binding and will explore factors that modulate biodistribution of the contrast agents.As shown here, Fe(III) macrocyclic complexes are promising for further development as MRI contrast agents. One of the macrocyclic Fe(III) complexes studied here demonstrates promising r