One strategy that has gained much attention in the last decades is the understanding and further mimicking of structures and behaviours found in nature, as inspiration to develop materials with additional functionalities. This review presents recent advances in stimuli-responsive gels with emphasis on functional hydrogels and microgels. The first part of the review highlights the high impact of stimuli-responsive hydrogels in materials science. From macro to micro scale, the review also collects the most recent studies on the preparation of hybrid polymeric microgels composed of a nanoparticle , encapsulated or grown into a stimuli-responsive matrix (microgel). This combination gave rise to interesting multi-responsive functional microgels and paved a new path for the preparation of multi-stimuli “smart” systems. Finally, special attention is focused on a new generation of functional stimuli-responsive polymer hydrogels able to self-shape (shape-memory) and/or self-repair. This last functionality could be considered as the closing loop for smart polymeric gels. Gels have pervaded our everyday life in a variety of forms. The wet soft solids that we encounter in the form of commercial products such as soap, shampoo, toothpaste, hair gel and other cosmetics, as well as contact lenses and gel pens, etc., are all gels derived from polymeric compounds. Polymer gels have been known for centuries and used for application in fields as diverse as food, medicine, materials science, cosmetics, pharmacology, and sanitation, among others. In general, gels are viscoelastic solid-like materials comprised of an elastic cross-linked network and a solvent, which is the major component. The solid-like appearance of a gel is a result of the entrapment and adhesion of the liquid in the large surface area solid three-dimensional (3D) matrix .Pierre-Gilles de Gennes during his Nobel lecture in 1991 recognized the place of gels among the broad category of ‘‘soft matter’’. Focusing on the phenomenological characteristics, polymer gels are 3D networks swollen by a large amount of solvent. Solid-like gels are characterized by: (i) the absence of an equilibrium modulus; (ii) the presence of a storage modulus, G’(u), which exhibits a pronounced plateau extending to times at least of the order of seconds; and (iii) the presence of a loss modulus, G’’(u), which is considerably smaller than the storage modulus in the plateau region. The presence of liquid-like behavior on molecular length scales combined with solid-like macroscopic properties makes them very unique systems. Polymer gels are classified as chemical and physical gels, depending on the nature of crosslinks  2]..2].Considering the current needs in the field of materials science, the strategy that has gained attention in the last decades is the understanding and further mimicking of structures and behaviours found in nature in order to develop materials with additional functionalities. These materials will have the ability to respond to several stimuli and could be used for biomedical purposes or in everyday life applications. In this context, the so-called “smart” or responsive polymers are becoming increasingly important. This kind of polymer is able to transform external stimuli into shape change or movement by taking advantage of the surrounding environment. The interest in the stimuli-responsive polymers has continued over many decades and it is still a hot topic in materials science. Indeed, researchers’ interest in the ability that this kind of gels present when subjected to external stimuli can be seen in the literature since the early 1990’s a and is The nature of the stimulus can be classified as physical, chemical or biological . PhysicaIn this review, we focus attention on recent advances found within the field of stimuli responsive functional polymeric gels. In the first section of the review, we will devote our attention to earlier (last year) developments on stimuli-responsive polymer hydrogels. Some examples are presented where stimuli as temperature, pH, light and redox, or analyte-responsive hydrogels and 3D printing applications are highlighted. The second section of the review will focus on the most recent studies regarding multifunctional stimuli-responsive microgels, in particular hybrid microgels systems. Special attention will be paid to (multi)responsiveness induced by inorganic nanoparticles incorporated within the microgel matrix, such as, metallic, magnetic, or carbonaceus particles. Finally, the last part of this review aims to highlight the new generation of functional stimuli-responsive polymer hydrogels—self-shape (shape memory) or self-healing hydrogels, as a step-forward in the field of “smart” materials.Hydrogel (water containing gels) can be defined as a polymeric 3D network insoluble in water. This polymeric network is composed of a polar and hydrophilic natural and/or synthetic polymer that is physically or chemically crosslinked and can uptake a large amount of water. If within the polymer hydrogel network, one element can act as a receptor unit or is spectroscopically active, this gel is called a stimuli-responsive or smart material ,2. The eN-isopropylacrylamide) (PNIPAAm) and biomedical applications 2+ luminophore. The redox activity of this system can be reversed by changing the sequential stimuli (fructose and temperature), thus controlling the swelling and deswelling of the hydrogel [PNIPAAm also finds application in this type of stimuli-responsive systems. A PNIPAAm matrix incorporating covalently-bound phenylboronic acids was produced to be used as a saccharide sensing unit and a redox-active [Ru(bpy)hydrogel .In a different study, Zhang and coworkers  producedAnalyte-responsive systems are a scientific research interest since they mimic nature’s ability of molecular recognition. To design these 3D polymer networks, biomolecules capable of recognizing target molecules are incorporated in the hydrogel. These molecules can be enzymes, peptides and nuclei acids. Target analyte can be used to induce hydrogel’s assembly, disassembly, syneresis, swell and also to prompt molecular reorientation and displacement . With thGlucose-responsive hydrogels have been widely studied for its use in diabetes’ treatment. Moreover, the design of enzyme-responsive hydrogels is very attractive since this can act directly upon the target molecule. More recently, the production of hydrogels using a template molecule created molecularly imprinted polymers. The use of the templated molecule produces binding sites in the polymer, leading to its recognition by the desired target. Peppas’ group has recently published a review about these three classes of analyte-responsive hydrogels . The reaPujol-Vila et al.  developeN,N′- diacrylamide. This crosslinker act as a NO scavenger and when expose to NO gas the gels react with the diffuse-in NO molecules to form a benzotriazole group moiety that is then hydrolyzed, resulting in swelling of the hydrogel. The authors also showed that this system can incorporate an enzyme-triggering NO donor.Keeping in mind the importance of nitric oxide (NO) as a signaling molecule in neurons and in the immune system, Park and co-workers  recently2-responsive hydrogel based on CNC, where to a suspension of positively charge nanoparticles, an imidazole solution is added. The presence of the analyte CO2 triggers the gelation of the hydrogel in a pH-responsive fashion, since CO2 reacts with water to form carbonic acid decreasing the pH of the solution and imidazolium salt. The authors showed that if the gel was exposed to N2, the 3D network collapses. The combination of CNC characteristics and its response in the form of the responsive hydrogel allowed the authors to envisage a wide range of applications, starting from switchable absorbents, and flocculants to tissue engineering.Cellulose nanocrystals (CNC) obtained from the acid hydrolysis of cellulose fibers have attracted a lot of attention from the scientific community as they are renewable, biocompatible, have low density, with high specific surface area and present interesting liquid crystalline and mechanical properties, among other . OechsleEuprymna scolopes can alter the thickness of its iridophores by stretching it, leading to a change in its iridescent coloration as a form of camouflage. In addition, structural coloration variation can be observed on the longhorn beetle Tmesisternus isabellae, since they change their coloration from green to red when the ambient relative humidity increases. Inspired by such examples, Qin et al. [co-AAc) deposit on top of a reflective substrate. The resulting colors arise from the interference of light waves reflected from the air–hydrogel interface and the hydrogel–substrate interface. The authors were able to demonstrate a color change in the presence of volatile organic compounds (VOC) as acetic acid, acetone, ethanol, ethyl acetate, hexane among others, as shown in Nature has several interesting examples where animals adapt their coloration in response to the changes in its environment. For instance, Cphalopods n et al.  developeAnalyte-responsive hydrogels can be key versatile diagnostic tools, as they can also create systems that are easy to use. As an example, one can see the use of a photonic biosensor array based on a interpenetrated cholesteric liquid crystal/hydrogel polymer network . This syIf the interesting characteristics of stimuli-responsive hydrogels presented above are considered, one can envisage its use in 3D printing systems or bioprinting or biofabrication, in which one can accurately develop structures, as scaffolds for tissue engineering, or printing cells or even organs ,65. The 2. In this set-up, the authors use the liquid-to-solid phase change to obtain 3D hydrogel structures, by rapidly cooling the ink below its freezing point. When coated with collagen type I, the hydrogels show good cell attachment and viability. The use of cryogenics to obtained printed super soft hydrogels led the authors to postulate several possible applications, which range from soft tissue for surgical training and simulations to mechanobiology and tissue engineering.Tan et al.  recentlyb-PEG-b-PiPGE with the cross-linkable functionality of PAGE-b-PEG-b-PAGE and form a series of PiPGE-stat-PAGE-b-PEG-b-PiPGE-stat-PAGE macromolecules. These polymers can self-assemble in water and give rise to hydrogels that respond to temperature, pressure, and UV light. These features help produce a robust free-standing 3D printed object.Multi-stimuli-responsive hydrogels inks for direct-write 3D printing were developed by Karis and co-workers . In this2/Al2O3)-based gel matrix, were able to obtain a hydrogel that can take up to 70 wt. % in water, respond to temperature and electric stimuli, and be printed using a commercial 3D printer. The hybrid hydrogel is transparent below PNIPAAm’s LCST and opaque above, due to the gels’ dehydration. Using this feature, the authors printed this hybrid system into a flexible electro-thermochromic device. This device allows the authors to display the electric/temperature tunable transmittance of the systems, with lower response times when compared to other reported systems, as well as its bending properties (the system sustain bending angles of 180° without feature failure).Yang et al.  recentlyco-acrylic acid) (PAAm-co-AAc) copolymer, which swells upon heating due to the breakage of hydrogen bond interactions  [Polymeric microgels are in an intermediate state between the branched polymers and macroscopic networks, with a molecular weight (Mw) comparable to that of a linear high Mw polymer, however with a structure resembling that of a macroscopic network. This indicates that in an appropriate solvent, they swell instead of dissolving, forming a colloidal dispersion . Dependi effect) .PNIPAAm is undoubtedly the most studied thermo-responsive microgel ,75,76,77N-vinylcaprolactam originate pH-responsive microgels [Although plain PNIPAAm microgels are often used in several applications, the incorporation of additional functional monomers gives raise to more complex and interesting microgels. The addition of co-monomers usually affects the swelling behavior of the microgel. PNIPAAm, in particular, is often functionalized with organic acids  (PNIPMAAm) as the inner shell, and PNIPAAm as the outer shell. In addition, by dissolution of the silica core, the authors produced hollow microgels, which enable the production of a series of microgels with diverse thermal response from the initial composition. Zha et al. [Core-shell microgels of PNIPAAm have also been explored due to the possibility of combining the different characteristics of both the core and the shell. For example, core-shell microgels composed of a polystyrene core and a PNIPAAm shell  have beea et al.  producedUsing these few examples, we tried to give the reader a glance of the multiple possiblities of homo- and co-polymeric microgels constructs. It is not our intention to cover every type of microgel and its application. Several reviews have been published recently covering different aspects of microgel design and synthesis, and their applications ,92,93,94Gold nanoparticles (AuNPs) have been used since 1857 when Faraday discovered the different properties of colloidal gold and bulk gold . Nowaday4 aqueous solution based in Au-thiol chemistry. By using this methodology, the authors were able to obtain control over the distribution of AuNPs within the microgel. In another case [co-allylamine)), which responds to both temperature and pH stimuli. With this hybrid system, the authors were not only able to modulate the catalytic activity of AuNPs, but also allow label-free in situ localized surface plasmon resonance (LSPR) monitoring of the catalyzed chemical reaction. The modulation is performed by varying the solution temperature, while the monitoring is made through stimuli-responsive volume phase transitions of microgels, thus changing the immediate physicochemical microenvironment of AuNPs, resulting in an alternation of the LSPR. Similarly, Rehman and coworkers [N,N′–dimethylaminoethylmetacrylate (DMAEMA) in water to obtain microgels responsive to temperature and pH. The poly(NIPAAm-co-DMAEMA) microgels were used as nanoreactor for the synthesis of AuNPs. These microgels demonstrated catalytic properties for the reduction of toxic 4-nitrophenol (4-NP). Moreover, the catalystic activity can be tuned using the microgels’ thermobehaviour. Chen and his team used photoluminescent gold nanodots with 1.8 nm in diameter incorporated into PNIPAAm microgels for the detection of mercury ions (Hg2+). This detection is based in the formation of Au-Hg amalgam and hybrid microgel aggregates in the presence of Hg2+, leading to decreased photoluminescence of the hybrid microgels. By using these hybrid microgels, the authors were able to sensitively and selectively detect Hg2+ ions in environmental and biological samples [2+ by using poly(NIPAAm-co-2-(dimethylamino)ethylmethacrylate) microgels [The most common organic component of a hybrid polymer gel with gold nanoparticles is PNIPAAm. Several research groups have recently used AuNPs incorporated into PNIPAAm microgels for catalytic applications. Shi et al.  used AuNher case , the autoworkers  crosslin samples . Tang eticrogels . Mackiewicrogels  producedOther authors used gold nanorods (AuNR) located at the surface of the microgel instead of spherical nanoparticles incorporated into PNIPAAm microgels b. In botMourran et al.  used theco-MAAc) to obtain thermo-, pH-, and light-responsive hybrid microgels. The authors produced the polymeric microgels, then thiol-functionalized them and obtained the hybrid microgels by in situ reduction of the gold precursor in the presence of the microgels based on Au-thiol chemistry, achieving a fluff-like structure due to the numerous AuNPs distributed in the interior of the microgel [N-vinylcaprolactam/acetoacetoxyethyl methacrylate/acrylic acid-based microgels (P(VCL-AAEM-AAc)) as a polymer template for in situ reduction of the gold precursor. The colloidal gold nanostructure is selectively formed in the core of the microgel and the hybrid structure is used as a noble metal catalyst [A common strategy for the incorporation of gold NPs into polymeric microgels is through the in situ reduction method. Liz-Marzán and coworkers ,112,113 microgel . In a dicatalyst . PVCL hacatalyst ,118.co-MAA-co-2-hydroxymethylmethacrylate) with homogeneously dispersed Ag and AuNPs. These microgels exhibit sensitivity towards temperature and pH. In addition, terpolymer microgels are efficient catalystics for the reduction of 4-NP, congo red and methylene blue in waste waters.In a different study, thermoresponsive PNIPAAm-metal hybrids were produced using PNIPAAm microgels as a microreactor. Metal NPs of different shapes were embbebed in the microgel: Au nanorods, Au nanospheres, and silver (Ag) nanospheres d. These Silver nanoparticles (AgNPs) being one of the noble metals, have unique optical, electrical and surface properties. These nanoparticles are commonly used as sensor, optical switches, antimicrobial agents, and catalysts ,121.+ coordinated into monodisperse PNIPAAm microgels, in which the catalytic activity can be tuned with four stages of change versus temperature. With the same purpose, Tang et al. [co-DMA) for in situ reduction of Ag+ ions pre-dispersed into the microgels. These hybrid microgels possess thermo- and pH-responsiveness, as well as catalytic activity. In a different study, Khan et al. [co-allylacetic acid) (P(NIPAAm-co-AAAc)) with AgNPs incorporated into the microgel by in situ reduction to be used as catalysts for reduction of nitrobenzene into aniline, exploring various conditions of temperature, catalyst dose and concentration of the reagents. The authors found that the catalytic activity of the hybrid microgels can be tuned by changing the temperature of the medium.Similarly to AuNPs, silver-based hybrid microgels are generally composed of thermosensitive polymers, most commonly PNIPAAm. In addition, a copolymer is often used to obtain a dual-stimuli-responsive microgel, for example, a temperature- and pH-sensitive microgel. Liu et al.  preparedg et al.  used P microgels as a template, while Zhou et al. [co-acrylamide-co-4-vinylphenylboronic acid) (P(NIPAAm-co-AAm-co-VPBA)) as a glucose sensing element. Another research group used AgNPs incorporated into poly(3-acrylamidophenylboronic acid-co-2-(dimethylamino)ethyl acrylate) microgels as glucose sensors. The glucose-sensing performance of the hybrid system was improved by tailoring the phase behavior from monotonous shrinking upon adding glucose, as well as the following change in the signaling manner from “turn-off” to “turn-on” [As previously stated, AgNPs can also be used in sensor devices. For example for glucose sensing, Khan et al.  performeu et al.  used AgNturn-on” .2O2 colorimetric sensing. Han and coworkers developed P(NIPAAm-co-AAc) microgels with AgNPs incorporated that went through autocatalytic oxidization in the presence of H2O2. The authors found that the absorbance at 400 nm was linearly dependent of H2O2 concentration and that was selective [PNIPAAm-based hybrid microgels are also used as sensors for other molecules, for example Helective .+ ions were fluorescent, while the AgNPs produced from conventional method do not exhibit this property [Kumacheva’s group produced AgNPs in pH-responsive microgels of P(NIPAAm-AAc-2-hydroxyethyl acrylate) and found that the AgNPs produced in situ, i.e., through photoreduction of Agproperty . Similarproperty ,130.Finally, AgNPs-based hybrid microgels are also used for plasmonic sensing due to the coupling between the oscillating electromagnetic fields on the AgNPs surface originating from plasmon resonance, which provides significant enhancement of the local electromagnetic fields. As such, these systems can be used as substrates for surface-enhancement raman scattering sensing. For this application, the plasmonic properties and surface electromagnetic field enhacement effects of the AgNPs present in the hybrid microgels are tuned by temperature and pH, for example, thus resulting as mobile plasmonic or SERS microsensors to detect environmental temperature or pH variation ,131.3O4, SPIONs) are widely used for biomedical applications due to their biocompatibility and interesting magnetic properties. The main biomedical applications of this type of nanoparticles are magnetic hyperthermia agents or contrast agents for magnetic resonance image [3O4 NPs allows the construction of a composite system with the properties of the polymer with magnetic-responsive properties. For example, several authors incorporated Fe3O4 NPs into PNIPAAm microgels, obtaining a thermo- and magnetic-responsive system. In some cases, the iron oxide NPs act as a crosslinker for PNIPAAm microgels, assuring a higher dispersibility of the NPs in the polymeric network [3O4 NPs may provide an in vitro burst release of chemotherapeutic drugs [Magnetic nanoparticles such as superparamagnetic iron oxide nanoparticles  methyl ether methacrylate-co-methacrylic acid) microgels, obtaining thermo-, pH-, and magnetic-responsive microgels. For the same purpose, other authors used different polymers for the production of the microgels, such as P(VLC-co-IA) based microgels [co-oligo(ethylene glycol) methacrylate-co-AAc) incorporated with attapulgite/Fe3O4 NPs [Boularas et al. ,143 wereicrogels , poly drug delivery systems of zuclopenthixol and phenazopyridine hydrocholride as models drugs; and (ii) absorbents for removal of organic contaminants such as 4-NP, 1,1′-dimethyl-4,4′-bipyridinum dichloride (Paraquat), methylene blue, and rhodamine 6 G from aqueous media [Other authors produced poly(vinyl phosphonic acid) nanogels with silica-coated Feus media .3O4 NPs can also be used for catalytic applications. Liu et al. [3O4-P(MBAAm-co-MAAc) microspheres that contained carboxyl groups for application as magnetic catalyst support to load a series of metallic nanoparticles such as Ag, Pt, and Au. The Fe3O4 NPs loaded into the microgels were able to maintain their superparamagnetic behavior, together with their high saturation magnetization, providing a convenient way for separating metallic nanoparticles from a solution. In a different study, Nabid et al. [3O4 NPs into P2VP microgels where the magnetic NPs acted as crosslinkers. These hybrid microgels are able to trap metal ions such as Pd2+ via complex formation of P2VP with metal ions, and the reduction of the Palladium ions by sodium borohydride led to the formation of PdNPs@P2VP-Fe3O4 hybrid microgels. These systems may be employed as nanocatalysts toward oxidation reaction of alcohols, which can be modulated by the volume phase transitions of the microgel.The combination of polymer gels with Feu et al.  preparedd et al.  incorporCarbon nanotubes (CNTs) are often used as reinforcement agents to create porous hydrogels with tunable mechanical properties. The incorporation of CNTs into hydrogels increases not only later elastic modulus, but also the thermal stability and electric conductivity of the resulting composites ,152.Shin et al.  used reiZhou et al.  used theAmong carbon-based materials, graphene oxide (GO) obtained from chemical modification of graphite is considered a molecular two-dimensional (2D) platform with a high aspect-ratio, also being water-dispersible. This material has several advantages such as high mechanical strength, pH sensitivity, photosensitivity, and low toxicity. In fact, GO shows higher photothermal sensitivity than CNTs, and is capable of efficiently converting optical energy into thermal energy ,156.Lu et al.  incorporFinally, Girard et al.  synthetiAmong the different inorganic materials used to produce hybrid polymeric microgels, silica nanoparticles are of great interest for the production of smart self-catalyzing systems. Agrawal et al.  producedco-acetoacetoxyethyl methacrylate) PVCL/AAEM microgels loaded with different metal NPs: Pd2+, Au+, Pt+. The results showed that some of the synthesized microgels are active catalysts for the Suzuki reaction of aryl iodides in a water-rich medium. In a different application, Du and coworkers [® XLS) double-network hydrogels containing neutral PAAm microgels, obtaining a tough and highly stretchable microgel-reinforced hydrogel with superb mechanical strength. In this case, Laponite acts as a physical crosslinker of the hydrogels.Nanoclays such as Laponite have been introduced into microgel systems for the development of responsive scavenger systems due to the cation-exchange capabilities of clays, thus allowing charging of the microgel with (cationic) metal precursors. For this purpose, Contin et al.  developeoworkers  producedco-AAc) microgels by facile electrostatic attractions at room temperature. These hybrid microgels are thermosensitive, with almost fully reversible photoluminescence between 25 °C and 45 °C, and bright fluorescence imaging. Similarly, Cai et al. [co-AAc) microgels. The photoluminescence intensity and color of the hybrid microgels can be tuned by adjusting the QDs content. In a different approach, Lai et al. [Another class of interesting inorganic materials are quantum dots (QDs), a semiconductor nanostructure that can be used for bioimaging and labeling probes. Their combination with polymer microgels extends the range of application for optical sensing, imaging diagnostics, and controlled drug release . For exai et al.  incorpori et al.  used micCui et al.  producedIn a different approach, multi-stimuli-responsive systems can be produced using stimuli-responsive microgels as active sites incorporated into polymeric fibers. Using colloidal electrospinning, it is possible to design multifunctional, highly porous, and biocompatible membranes suitable for several applications.Electrospinning is a simple, fast and easy to scale-up technique to produce functional materials based on polymeric fibers with diameters ranging from 2 nm to several micrometers. Electrospun micro/nanofibers have a high surface-to-volume ratio, tunable porosity, and can be produced from natural or synthetic polymers ,173,174.A variation of traditional electrospinning technique is colloidal electrospinning, where the polymeric solution is replaced by a colloidal dispersion. The presence of particles in the spinning solution allows the formation of core-shell fibers from a single nozzle, offering a simpler setup than that used in coaxial electrospinning, which needs two or more needle-tips ,177. Thel-lactic acid) fibers, in which the production of fibers with a mean fiber diameter of 284 nm connected to bead sizes of 3.4 μm with a spindle-like structure, was reported by Gu et al. [N,N′-methylene bisacrylamide as a crosslinking agent. These thermosensitive microgels were successfully confined in poly(ethylene oxide) (PEO) fibers via colloidal electrospinning, resulting in beads randomly distributed over the fibers with a typical “bead-on-a-string” morphology. Furthermore, by performing a statistical analysis, the relationship of the processing variable over the fiber diameter was evaluated using the response surface methodology. Using the set of optimized parameters, PEO fibers with an average diameter of 63 nm containing PNIPAAm microgels, were produced  is applied above a critical value ,182. ForThe development of shape memory hydrogels faces some difficulties in terms of glass transition temperature, which is usually the phase transition used for the shape stabilization and shape recuperation in SMP. Basically, the presence of a large content of water molecules carries a loss of efficiency in hydrogels. The main strategy to overcome this problem is to promote the formation of new crosslinking in the different deformation states of the hydrogel. Such new links allow the storage of shape. Breaking the new crosslinking points will end up in recovery of the initial shape.co-n-stearyl acrylate) swells with temperature. At temperatures below 25 °C, the gel behaves as a hard system, whereas above 50 °C it, becomes soft and stretchable . Authors suggested that the shape memory effect came from the temperature-induced order-disorder transition associated with alkyls side chains and stearyl acrylate unit interactions. In addition, authors highlighted that the shape “remembered” by the gel was dependent on the container where it was first formed.In 1995, Osada et al.  reportedDespite this pioneer study, hydrogels that can undergo shape transitions (temporary-to-permanent) while containing large amount of water solvent are still scarce. Here, we report some of the most recent and relevant achievements (last five years) in the subject.co-AAc) commercial hydrogel. Authors differentiate two aspects: (i) Shape Change Effect (SCE), which is usually observed in electroactive polymer or piezoelectric materials and (ii) Shape Memory Effect (SME). Both properties were directly related to hydrogel water content. In fact, they found that at low water content hydrogels possessed shape memory effect, whereas at higher water content PAAm-co-AAc commercial hydrogel showed both rubber like shape memory effect and water induced shape change. With these findings, they also understand that programming of the system could be performed through the deformation of the hydrogel above Tg or by dehydration after previous deformation of the rubbery-like hydrogel. Such results indicated that the commercial hydrogel PAAm-co-AAc could be used as an elastic matrix in a hybrid system to induce the shape memory effect [Among the polymer matrices constituting shape memory hydrogels, three are more commonly used: PAAm, PVA and PEG. For instance, Zhang et al.  performey effect . Followiy effect  performey effect .co-AAc) with a characteristic thermoplasticity. More concretely, authors prepared hydrogels by simple ternary copolymerization of AAm and AAc with low amounts of a cationic surfactant monomer, in the absence of organic crosslinkers. The resultant hydrogels could exhibit shape memory effects via two different strategies: (i) From an ionic/complex binding between carboxyl groups and ions, which provided additional physical crosslinking points, necessary to lock a temporary shape; and (ii) By salt-strengthened hydrophobic association that enables the formation of a trapped shape. Such physical hydrogel exhibited novel characteristic thermoplasticity, which allowed the change of its permanent shape upon heating and the storage of the shape after cooling, which is a strong step forward compared to the conventional chemically crosslinked shape memory hydrogels [Fan et al. developed a novel dual-responsive shape memory hydrogel of P, resulting mainly in a loss of mechanical properties and eventually in the failure of structure for the desired application. To avoid the consequences of this event, huge efforts have been made in the past years to develop polymer gels with the ability to self-repair or self-heal and thus restore their initial structure and functionalities. The approaches used for the development of self-healable hydrogels are mainly based on the constitutional dynamic chemistry (CDC) concept, key factors of which are dynamicity and reversibility, involving covalent  and non-covalent chemistry  ,204. SelPhadke et al.  reportedAlong these lines, Tuncaboylu et al. ,208,209 Zhang et al.  worked wAs indicated in previous sections of this review, thermoresponsive polymer PNIPAAm played an important role in the field of polymer gels due to the numerous stimuli-responsive hydrogels and microgels developed involving this polymer. However, approaches to develop PNIPAAm and PNIPAAm-based hydrogels with self-healing abilities are still scarce due to the side groups of PNIPAAm that hinder secondary interactions. Along these lines, Gulyuz et al.  once agaThe evolution on hydrogel research has brought about the development of materials that exhibit improved mechanical properties. However, most of the reported hydrogels that exhibit self-healing properties are in general mechanically weak. To overcome this problem, several authors hybridized self-healable hydrogels with GO, similarly to what was also observed in the previous section regarding shape memory hydrogels ,214,215.At the beginning of this section, we have indicated that the ability of self-repair is desired property in fieldls like aeronautics, coatings, paintings, etc. However, to confer the self-healing ability into smart hydrogels can also be useful in biomedical applications. For instance, when considering smart hydrogels to be used as implants in the body, it should be noted that these implants are under constant movement and thus at risk of mechanical damage. As a consequence, this fact could directly affect the functionality of the implant or even be the cause of an infection. In this regard, as stated by Li et al., developing a hydrogel able to self-heal could contribute to extending the application of the hydrogel and the lifetime of the material. These authors developed a mussel-inspired self-healing injectable hydrogel with anti-biofouling and anti-microbial properties ,219,220.3+ complexes as the multifunctional cross-linkers and AAm as the monomer. The self-healing ability of the obtained supramolecular hydrogel follows a dynamic process due to the re-association capacity of precoordinated metal−catechol interactions.The mussel-inspired strategy and chemistry was also followed by other authors. For instance, Hou et al.  developeIn this field of self-healing polymer hydrogels, it is of importance to highlight the growing interest regarding the use of polymeric microgel and nanogel particles in the development of autonomous self-healing systems ,223. TheLatnikova et al.  proposedIn the field of materials science and engineering, the design, research and development of new and improved smart structures and systems is currently a hot topic. In this context, functional stimuli-responsive gels are of great interest due to their versatility and possible application in fields as diverse as biomedicine, catalysis, or even biosensors.The relevance of the subject dealt in this review is clearly reflected in the considerable number of relevant publications. In this review, we intended to cover the most recent and high-impact publications using functional stimuli-responsive gels. The review started from macro to micro, i.e., from hydrogels to microgels, ending with a new generation of functional gels. Stimuli-responsive functional hydrogels and microgels are used for a broad range of applications, and several publications can be found in literature. PNIPAAm is the most used thermoresponsive polymer. In many cases, PNIPAAm is combined with another polymer to add a new functionality to the hydrogel. In microgels, PNIPAAm is most commonly combined with an inorganic component, ranging from metallic nanoparticles to carbonaceous particles. In the last part of the review, the new generation of functional stimuli-responsive gels, able to self-repair or/and possess shape memory property, are described. Among others, PAAm, PVA and PEG are the commonly used polymers in this new generation of functional gels. The development of Shape Memory Polymers suitable for biological media in a living system is a still a challenge today. In this regard, shape memory hydrogels that are predominantly water stand out as alternative candidates for biomedical applications due to the use of water as a driving force for the desired shape memory effect. The advantages and attributes of functional gels (macro and micro) have been highlighted throughout the entire review, but the most promising is the ability to self-heal, expected in almost all industries in the near future. Self-healable hydrogels go through improvements in their mechanical properties without affecting their intrinsic properties, and importantly, their responsiveness to external stimuli. In summary, this review demonstrates the prominent role of smart functional gels in materials science; its versatility and tunable properties allows usage in a wide range of applications.


Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and  positive symptoms. Within-subjects, substantial variability and co-variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications.Obsessive–compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between-subject comparisons. The aim of this study was to specifically investigate co-variation of symptom domains over time within individuals. Patients with a psychotic disorder (The online version of this article (10.1007/s00406-018-0884-4) contains supplementary material, which is available to authorized users. Meta-analyses estimate that 12% of patients with schizophrenia also fulfil the criteria for obsessive–compulsive disorder (OCD) and that almost every third 30%) patient reports co-occurring OCS 0% patien. Co-occuSeveral studies investigated the relationship between OCS and symptom clusters of schizophrenia . A meta-To overcome the limitation of cross-sectional designs, longitudinal studies investigated the course and associations between co-occurring symptom domains over time. A study of first episode patients revealed high variability of OCS severity over the 5-year follow-up period. Only a minority reported persistence of OCS, whereas the majority reported either remission of the initial OCS or intermittent OCS. No association was found between OCS occurrence and a more severe course of psychotic symptoms . In contThe aim of the current study was to investigate the course of psychotic, obsessive–compulsive, and depressive symptoms over time and associations between these symptom clusters on the between- and within-subject level in patients with psychotic disorders and on a subclinical level in siblings. Based on earlier findings  we expecPatients with a psychotic disorder and un-affected siblings included in the current study, were participants of the GROUP study, who had previously been seen at one of the mental health care institutions belonging to the recruitment site Amsterdam . ParticiFor the current study, potential participants were contacted by phone, informed about the content and time investment of the study, and asked to participate. All participants provided written informed consent prior to their inclusion in the study, which was approved by the accredited Medical Ethics Review Committee (METC)#NL46405.018.13.Sociodemographic data on age, gender, education level, age of onset, duration of illness, and medical treatment were collected.Obsessive–compulsive symptoms (OCS) were assessed with the self-rating obsessive–compulsive inventory-revised . The OCPositive, negative, and depressive symptoms were measured with the three subscales of the Community Assessment of Psychic Experiences . The CASample characteristics at baseline were explored with descriptive statistics.To investigate whether psychopathology ratings changed over time, fixed-effect regression models were conducted with OCS, positive, negative, and depressive symptoms as the dependent variables and time as the predictor. To account for the hierarchical structure of the data, in which repeated observations were nested within-subjects, and to assess between- and within-subject variability, we included random effects in our analyses.Raw scores of investigated variables reflect both, how the individuals differ from other individuals and how individuals differ from their usual level. Because we were specifically interested in the association of intra-individual changes, we followed the recommendation of Wang and Maxwell (2015) to disaggregate between- and within-subject components . TherefoThe longitudinal data set consists of 56 patients*6 assessment times = 336 observations  and 49 siblings*6 assessment times = 294 observations . Sample characteristics at baseline and data on overall, between- and within-subject  psychopathology, are presented in Table 20 of the 56 patients reported relevant OCS at least once during the assessment period. Based on interpretation guidelines, we defined the presence of relevant OCS as an OCI-R score ≥ 14 . BesidesMultilevel models of symptom course were conducted with time as the fixed effect and random effects at two levels: at the upper level, the extent to which people vary from the group average (between-subject), and at the lower level, the extent to which individual data-points vary from the individual fitted regression line (within-subject).t = − 2.93, p = .005), with decreasing OCS severity. Random effects showed significant between-subject variance for the intercept  and significant within-subject variability .Regarding the course of OCS, analysis revealed a significant time effect , negative , and depressive symptoms  with decrease in severity over time. Random effects showed significant between-subject variation of intercept in positive , negative  and depressive symptoms . Furthermore, significant between-subject variability in slope was found for positive symptoms  and depressive symptoms , as well as significant intercept*slope covariance for these two symptom domains . Significant within-subject variability was found in all three symptom clusters .Similar results were found for the three symptom clusters of the CAPE. Analyses showed significant time effects for positive  and CAPE positive symptoms . Random effects showed significant between-subject variety in intercepts of all symptom domains , as well as significant variability in slope for OCS , positive symptoms , negative symptoms  and depressive symptoms . No significant intercept*slope covariance on the between-subject levels was found. Significant within-subject variability was found in all symptoms domains . Figure Within siblings, again, significant time effects were found for OCS , negative  and depressive symptoms , indicating that subjects who reported more positive, negative, or depressive symptoms also reported more OCS over time. In addition, within-subject variability in all three symptom domains of the CAPE  were significantly associated with OCS severity, suggesting co-variation.Mixed-model analyses with between-subject and within-subject variables of the CAPE as predictor variables and OCS as measured with the OCI-R as outcome variable were conducted. Because of apparent time trends, we controlled for the effect of time by including the variable as a covariate (‘detrending’) to investigate the relation between predictors and outcome “above and beyond systematic change in the outcome over time” ( p. 219) Including all predictors in one model resulted in a significant effect of between-subject differences in positive symptoms. Thus, higher scores in positive symptoms across assessment times were significantly associated with higher OCS severity across assessments. Furthermore, within-subject variability in all three CAPE variables remained significantly associated with OCS severity. Random effects still showed significant heterogeneity in intercept and within-subject variation Table .To account for possible confounding effects, we added gender, illness duration, IQ estimate, and type of antipsychotic medication as covariates to the model. None of these variables significantly contributed to the analyses and did not change the results.R2. Therefore, the residual variance of the model with no predictors was compared to the residual variance of the full model including all predictors [To further investigate the quantitative effect of CAPE contribution to the variability in OCS, effect sizes were calculated based on edictors . CompareT = 3.68, p = .001), negative , and depressive symptoms  and within-subject variability in these three domains .Within siblings, mixed-model analyses revealed significant associations between OCS and between-subject differences in CAPE positive .Analyses of a full model including all predictors resulted in a significant effect of between-subject differences and within-subject variability in positive symptoms. Within-subject variability in depressive symptoms also reached significance. Again, random effects still showed significant heterogeneity in intercept and within-subject variability Table . Adding Compared with a baseline model including only the random effects , residual variance was reduced by 8%, whereas random intercept variance was reduced by 21% when within- and between-subject scores were added in a model, where CAPE predicted OCS.t = 8.69, p < .001), negative , and depressive symptoms  were identified as significant predictors, whereas only within-subject variability in depressive symptoms reached significance . When including significant predictors in one model, only between-differences in positive symptoms  and within-subject variability in depressive symptoms  remained significant. Including confounders in the analysis did not significantly change the results.We first investigated these associations in patients. With OCS 4 weeks later as the dependent variable, between-subject differences in positive , negative symptoms , and depressive symptoms  4 weeks later. Within-subject variability in OCS did not significantly predict positive, negative, or depressive symptoms.To investigate possible reciprocal relationships, we included between-subject and within-subject variability in OCS as the predictor of CAPE symptom domains. Between-subject differences in OCS significantly predicted positive symptoms , negative  and depressive symptoms  were identified as significant predictors, with OCS 4 weeks later as the dependent variable. No within-subject variability significantly predicted subsequent OCS severity in siblings. When including significant predictors in one model, only between-differences in positive symptoms  remained significant, even after including IQ and gender as potential confounders.In siblings between-subject differences in positive , negative symptoms , and depressive symptoms  4 weeks later. Again, within-subject variability in OCS did not significantly predict positive, negative or depressive symptoms.Regarding reciprocal relationships, between-subject differences in OCS significantly predicted positive symptoms  or individual characteristics  as well as interactions between them. Furthermore, assessment intervals of 4 weeks might still be too long to detect within-subject causal interrelations. Future studies should involve Experience Sampling Methods (ESM), daily investigation in real life situations, which allow detecting time sequences and predictors of changes in symptom severity on a real-time level . New devSpecific limitations should be acknowledged. Due to the observational nature of our study, the discussion of possible mechanisms and causal interactions remains speculative. Furthermore, participants of the GROUP study represent a relatively high functioning group with mild to moderate symptom severity, which limits the generalizability of our result. Between-subject and within-subject associations in patients with more severe co-occurring OCS and psychosis might differ and should be investigated in future studies. Finally, severity of symptoms was assessed with self-report instruments. Although these have been found valid in assessing psychotic and obsessive–compulsive symptoms, findings should be replicated with interview-based outcome measures.In conclusion, this is the first prospective study investigating between-subject and within-subject associations of OCS and symptom clusters of psychosis in patients with psychotic disorders and their un-affected siblings. Findings indicate that especially severity of positive symptoms is strongly related across individuals and time to OCS in patients and siblings, suggesting shared underlying vulnerability. Furthermore, a specific focus on within-subject variability is necessary to understand interrelations of symptom dimensions. Especially, the associations between depressive symptoms and subsequent change in OCS severity 4 weeks later may have important treatment implications. Further studies are needed to replicate found associations and to investigate proposed overlapping time-varying factors, which may cause concurrent symptoms co-variation within-individuals.Below is the link to the electronic supplementary material.Supplementary material 1 (PDF 382 KB)


Salmonella spp. were listed by the WHO in 2017 as priority pathogens for which new antibiotics were urgently needed. The overall global burden of Salmonella infections is high, but differs per region. Whereas typhoid fever is most prevalent in South and South-East Asia, non-typhoidal salmonellosis is prevalent across the globe and associated with a mild gastroenteritis. By contrast, invasive non-typhoidal Salmonella cause bloodstream infections associated with high mortality, particularly in sub-Saharan Africa. Most Salmonella strains from clinical sources are resistant to first-line antibiotics, with FQs now being the antibiotic of choice for treatment of invasive Salmonella infections. However, FQ resistance is increasingly being reported in Salmonella, and multiple molecular mechanisms are already described. Whole-genome sequencing (WGS) is becoming more frequently used to analyse bacterial genomes for antibiotic-resistance markers, and to understand the phylogeny of bacteria in relation to their antibiotic-resistance profiles. This mini-review provides an overview of FQ resistance in Salmonella, guided by WGS studies that demonstrate that WGS is a valuable tool for global surveillance.Fluoroquinolone (FQ)-resistant  Supplementary material is available with the online version of this article.https://amr-review.org/sites/default/files/160518_Final paper_with cover.pdf). In 2017, the WHO published a priority list of antibiotic-resistant bacteria, to support research and development of new antibiotics. Fluoroquinolone (FQ)-resistant Salmonella spp. were listed as a high priority. FQs have broad-spectrum activity and good pharmacokinetics for clinical use, and are important antibiotics for treatment of invasive bacterial infections, such as typhoid fever and invasive non-typhoidal Salmonella (iNTS) infections. Enteric fever  and iNTS (mainly caused by the serotypes Typhimurium and Enteritidis) have the highest impact and mortality in low- and middle-income countries. However, the resistance of Salmonella against FQs has been increasingly reported. The understanding of the FQ-resistance mechanisms and spread in Salmonella has significantly advanced through the implementation of whole-genome sequencing (WGS) during the past 5 years. Here, we review the genetic mechanisms of FQ resistance reported by WGS studies on Salmonella.In 2016, the United Nations General Assembly underlined the threat of antibiotic resistance and committed to join forces to combat this threat. Antibiotic resistance could cause a predicted 10 million deaths and have detrimental economic effects by 2050 if no actions are taken . Typhoidal Salmonella, comprising the Salmonella enterica subspecies enterica  serovars Typhi and Paratyphi A, B and C, cause a systemic disease, also known as enteric fever  to ciprofloxacin from <0.5 % up to 3.5 % since 1996 , South Africa , India  and Nigeria  ,12:i:- ,12:i:- originating from swine , a parC (Ser80Ile) mutation and an additional PMQR gene [aac(6′)-Ib-cr] [Salmonella Weltevreden from Asia  -Ib-cr] . In Asia)-Ib-cr] . PQMR geSalmonella seriously compromises treatment options, especially for invasive salmonellosis. The dominant presence of the Salmonella Typhi H58 clade associated with QRDR mutations jeopardizes effective FQ treatment of typhoid fever in Asia. Recent reports from Nepal indicated that even the fourth-generation FQ gatifloxacin has lost its effectiveness due to high-level FQ resistance [Salmonella. This might be linked to a diverse host niche, including several animal reservoirs, indicative of the need for a ‘one health’ approach to efficiently monitor the spread and source of FQ resistance.FQ resistance in sistance . WGS datsistance , large mSalmonella. Whereas originally predominantly used for research, WGS is becoming more available in diagnostic laboratories across the world and tools are being developed to facilitate the data analyses (such as www.WGSA.net).The increasing use of WGS provides new molecular surveillance approaches to monitor and understand the spread of FQ resistance in Salmonella spp. is rising towards critical levels and there is need for alternatives, such as last resort antibiotics and the development of new antibiotics, as stated by the WHO in 2017 [Salmonella strains and their resistance patterns. Hereto, the implementation of WGS provides new opportunities for surveillance.In summary, FQ resistance in


Cranial arterial air embolism is a rare but potentially fatal complication after computed tomography (CT)-guided pulmonary interventions.A 64-year-old man was diagnosed with a pulmonary nodule (diameter: approximately 1 cm) in the right lower lobe. The patient developed convulsions after CT-guided hook-wire localization.Cranial CT revealed arborizing/linearly distributed gas in the territory of the right middle cerebral artery.The patient was administered hyperbaric oxygen, antiplatelet aggregation therapy, and dehydration treatment.Clinical death occurred 55 hours after air embolism.Systemic air embolism is a serious complication of lung puncture. Clinicians should improve their understanding of this complication and remain vigilant against air embolism. Air embolism is a rare but serious complication of hook-wire localization. We present a rare case of cerebral arterial air embolism after computed tomography (CT)-guided lung puncture and hook-wire localization. The clinical features and treatment experiences of the patient are described.This study analyzes in detail the possible mechanisms by which gas enters the pulmonary veins.1 However, hook-wire localization is an invasive procedure associated with a high risk of complications. Air embolism is a rare but serious complication of hook-wire localization. We present a rare case of cerebral arterial air embolism after CT-guided lung puncture and hook-wire localization. The clinical features and treatment experiences of the patient are described.The diagnosis of nodular pulmonary lesions (NPLs) of unknown origin is sometimes challenging, and a subset of NPL is not suitable for transthoracic needle biopsy. Video-assisted thoracoscopic surgery (VATS) can be used for simultaneous diagnosis and resection of NPL. It is an effective method for diagnosis and treatment of NPL owing to its minimally invasive nature. However, most NPLs are small and located deep in the intrapulmonary tissue, and difficult to localize accurately during VATS thereby reducing its success. The preoperative computed tomography (CT)-guided hook-wire localization technique was 1st proposed by Mack et al.2A 64-year-old man with no significant past medical history was diagnosed with a pulmonary nodule (diameter: approximately 0.7 cm) in the right lower lobe 2 years ago, the patient did not follow the doctor's advice to perform chest CT scan after 6 to 8 months. In a recent health check-up, chest CT showed increase in size of the nodule to 1 cm  for local infiltration anesthesia. Percutaneous lung puncture was performed according to the predetermined puncture point and direction, and a 10-cm needle was quickly inserted into the lung tissue while the patient held his breath at the end of inspiration. The proper location of the needle was confirmed by a thin-section CT scan. The positioning guide wire was then deployed, the puncture needle was removed, and the guide wire was gently pulled outwards to fix the barb at its front end to the lung tissue , intense vasospasm (due to stimulation by gas embolus), and platelet-activated microthrombi . proposed that the scope of the CT scan after lung puncture should include the heart and aortic arch to detect asymptomatic air embolism and to facilitate prompt treatment.Air embolism is easily missed in the absence of any overt symptoms. Brain and chest CT can be used to confirm the presence of gas in the cerebral artery, pulmonary vein, left atrium, left ventricle, aorta, or coronary artery. Kuo et al Early hyperbaric oxygen therapy improves prognosis of patients with cerebrovascular air embolism and reduces their mortality rate to 7%. The present patient was promptly administered hyperbaric oxygen therapy. However, a large cerebral infarct still occurred. This is likely attributable to massive air embolization of the trunk and branches of intracranial arteries and poor compensatory collateral circulation which led to brain cell necrosis and edema in a short time.Hyperbaric oxygen therapy decreases the volume of air bubbles, increases the oxygen solubility in the blood, promotes the release of nitrogen in the air bubble into the blood, attenuates vascular permeability, and reduces vascular endothelial damage. It is currently recognized as the 1st-line therapy for the treatment of systemic air embolism.Systemic air embolism is a rare and serious complication of lung puncture. It is characterized by quick onset, severe symptoms, and high mortality. Clinicians should improve their understanding of this complication and remain vigilant against air embolism, and discover and treat this complication early to reduce its sequelae and mortality.MYW and FW wrote the manuscript; YSL contributed the central idea; XBA and KL contributed to the interpretation of results; YJL revised the manuscript.Conceptualization: Ming-Yi Wang, Yong-Sheng Liu, Xiang-Bo An.Data curation: Ming-Yi Wang.Formal analysis: Ming-Yi Wang, Ke Li.Funding acquisition: Xiang-Bo An, Yong-Jian Liu.Methodology: Yong-Sheng Liu, Xiang-Bo An.Project administration: Yong-Sheng Liu, Xiang-Bo An.Resources: Yong-Sheng Liu, Ke Li, Yong-Jian Liu, Feng Wang.Software: Ke Li, Yong-Jian Liu, Feng Wang.Supervision: Ke Li, Feng Wang.Validation: Ke Li, Feng Wang.Visualization: Feng Wang.


Rhabdomyolysis is a condition in which skeletal muscle breakdown causes the release of intracellular components into the bloodstream – defined as elevations in serum creatine kinase levels. The etiology of rhabdomyolysis is varied and may be the result of toxin-mediated mechanisms or metabolic derangements, or they may develop secondary to other conditions such as seizures, trauma and prolonged immobilization. In this case, we present a patient with suspected acute toxin-mediated rhabdomyolysis in the setting of trimethoprim-sulfamethoxazole (TMP-SMX) therapy for urinary tract infection. To our knowledge, this marks the fifth case report of an otherwise healthy patient diagnosed with rhabdomyolysis thought to be secondary to TMP-SMX. While not an uncommon diagnosis in the emergency department, rhabdomyolysis is often difficult to diagnose clinically and may present in a variety of contexts and clinical scenarios. Patients often present with non-specific generalized myalgias, aches, fatigue, urine color changes, and/or fevers. Others present without symptoms. Rhabdomyolysis presents on a spectrum from asymptomatic elevations in serum creatine kinase (CK) to life-threatening acute electrolyte disturbances requiring hemodialysis.2Identification of rhabdomyolysis usually begins in the proper clinical context based on history and physical, a suspected mechanism, and elevations in CK detected on laboratory analysis. Although an elevation of CK levels at least five-fold greater than the upper limit of normal is a commonly accepted parameter for definitive diagnosis, no true consensus exists.5In this case, we present a patient with suspected acute toxin-mediated rhabdomyolysis in the setting of new trimethoprim-sulfamethoxazole (TMP-SMX) therapy for urinary tract infection (UTI). While rhabdomyolysis in the setting of TMP-SMX has been well described in the immunocompromised, no widespread association exists with immunocompetent patients. To our knowledge, this marks the fifth case report of an otherwise healthy, immunocompetent patient diagnosed with rhabdomyolysis thought secondary to TMP-SMX with no other clear insult or mechanism to explain elevations in CK levels.A 41-year-old African American male with a past medical history of overactive bladder, benign prostatic hyperplasia, obstructive sleep apnea requiring nocturnal home continuous positive airway pressure, presented to the emergency department (ED) with a chief complaint of increasing proximal bilateral lower extremity muscle pain for five days. Pain was associated with increasing difficulty with ambulation. The patient also noted persisting hematuria, urgency and hesitancy for the prior nine days. He had fever to 101.2° Fahrenheit (F) for the prior five days. Symptoms were associated with intermittent episodes of nausea and vomiting for the prior two days. Four days prior to presentation, the patient reported having seen his outpatient urologist who diagnosed a UTI. He was prescribed TMP-SMX double strength 160 milligrams (mg)/800mg. and endorsed medication compliance.On ED arrival, the patient was found to be febrile to 102.3°F and hemodynamically stable. On exam, he appeared grossly uncomfortable. The bilateral lower extremity proximal muscle strength was 4/5 without point tenderness. There was no evidence of lower extremity edema, erythema or rash. Distal pulses were intact. The patient was also noted to have mild left lower quadrant abdominal and suprapubic tenderness to palpation; there was no costovertebral angle tenderness to palpation. Physical exam was otherwise unremarkable.3 per cubic millimeter (mm3), which resolved prior to ED arrival, a urine analysis consistent with UTI: positive large blood with greater than 50 red blood cells per high-powered field, 50 white blood cells per high-powered field, and positive leukocyte esterase. A urine culture was positive for Escherichia coli sensitive to TMP-SMX per the outpatient urologist. The outpatient provider did not request CK levels at initial visit, but at that time AST/ALT levels were 22 u/L and 30 u/L, respectively.Initial laboratory analysis showed an aspartate transaminase (AST) 274 units per liter (u/L) , alanine transaminase (ALT) 102 u/L , CK muscle/brain 3.11 nanograms per milliliter (ng/mL)  with a CK 60,665 ng/mL . Labs obtained from the patient’s outpatient urologist from four days prior to presentation showed an initial leukocytosis to 14.4 10Chest radiograph and computed tomography of the abdomen and pelvis in the ED were negative for acute pulmonary or intra-abdominal pathologies. In the ED, the patient received one gram of ceftriaxone for UTI, two liters of normal saline, acetaminophen for fever, and morphine for pain control. TMP-SMX was discontinued. He was admitted to the inpatient internal medicine service with a concern for non-traumatic acute rhabdomyolysis and pyelonephritis. Further workup by the inpatient medicine team excluded other possible causes for acute rhabdomyolysis. Respiratory viral panel and human immunodeficiency virus studies were negative. Urine toxicology was positive for opiates. Epstein-Barr viral studies were consistent with a prior infection with immunity. Thyroid and glucose-6-phosphate dehydrogenase studies were normal. CK and AST levels peaked on days two and three of admission, respectively .The patient continued to receive intravenous and oral fluids as well as pain control. Over the eight days of admission the patient continued to improve. He reported decreasing muscle pain and was increasingly able to ambulate without difficulty. During the course of his hospital stay, the patient sustained no electrolyte abnormalities, and creatinine and blood urea nitrogen were within normal limits. There was no evidence of acute kidney injury. The patient was discharged on day eight with resolution of symptoms and a down-trending of CK and AST/ALT.What do we already know about this clinical entity?Rhabdomyolysis may develop secondary to metabolic derangements, seizures, trauma, or prolonged immobilization, or via a toxin-mediated mechanism.What makes this presentation of disease reportable?We present a case of trimethoprim-sulfamethoxazole (TMP-SMX) induced rhabdomyolysis in an otherwise healthy patient.What is the major learning point?In otherwise unclear etiologies of rhabdomyolysis in applicable patients, recent TMP-SMX use should be considered as a possible precipitating insult.How might this improve emergency medicine practice?Early recognition of this possible emerging association between TMP-SMX and rhabdomyolysis in immunocompetent patients may alter emergency department management and treatment.Trimethoprim-sulfamethoxazole is a bacterial folic acid synthesis inhibitor used to treat a variety of conditions including UTI, skin and soft tissue infections in healthy patients, and pneumocystis pneumonia or toxoplasmosis in the immunocompromised patient. Side effects generally are mild and include rash, fever, muscle aches and diarrhea. TMP-SMX is also known to have an association with more severe side effects including Steven-Johnson syndrome and toxic epidermal necrolysis, although these are quite rare.In 2014 Ainapurapu et al. reported a case of a previously healthy 40-year-old Hispanic female. She initially presented with two days of bilateral lower extremity muscle aches and weakness. She reported she was prescribed TMP-SMX for a UTI two days prior and had taken four doses. She presented with an initial CK of 20063 u/L, with an otherwise negative workup for other etiologies explaining her rhabdomyolysis.8A second case in 2015 by Petrov et al. was that of a 64-year-old male, active smoker, who also presented complaining of bilateral lower extremity pain and a decreasing ability to ambulate secondary to discomfort. The patient reported self-treating a presumed UTI with TMP-SMX left over from a prior episode of UTI. He reported taking TMP-SMX 40mg/800mg three times a day for two weeks. On first presentation to the ED, the patient was found to have a CK of 1524 u/L, and he was referred to a neurologist with suspicion for polymyositis. TMP-SMX was not discontinued and the patient’s pain continued to worsen. The patient also was prescribed ibuprofen, celecoxib, piroxicam, ketorolac, and meloxicam. On subsequent presentations to the ED, the patient was found to have a CK of 614,691 u/L, elevated transaminases, and multiple electrolyte derangements. Muscle biopsy was suggestive of muscle fibers without striations and a loss of homogeneity. Other causes of rhabdomyolysis were ruled out. TMP-SMX was discontinued, and over the course of admission the patient reported improvement in all symptomatology and was subsequently discharged.9In 2017, Moye et al. presented a case of a 43-year-old African American female with a past medical history of depression and alcohol-use disorder who presented to the ED after eight days of bilateral lower extremity leg pain in the setting of taking five doses of TMP-SMX 160mg/800mg for a UTI. She reported a history of daily alcohol consumption and 10mg vortioxetine. She first began to experience leg pain two days after initiation of TMP-SMX when she re-presented to her primary care provider. There she was switched to ciprofloxacin. The patient continued to experience worsening leg pain, which prompted her visit to the ED. There she was found to have a CK of 26,231 u/L with elevated transaminases AST/ALT of 352/111 u/L, respectively.Also in 2017, Goyal et al. presented a case of an 18-year-old female with a past medical history of Arnold-Chiari malformation presenting from her primary care provider (PCP) complaining of severe weakness and diffuse muscle pains in all extremities for two days. She endorsed recent completion of a course of TMP-SMX for UTI from her PCP. At time of admission, she was noted to have severe proximal muscle weakness in all four extremities and diffuse muscle tenderness. On admission her CK level was 20,418 u/L, which peaked the next day to greater than 42,670 u/L, the maximal quantifiable limit per the institution’s laboratory. She initially received aggressive fluid resuscitation without improvement. Ultimately, she was started on IV immunoglobulin G with eventual resolution of elevations in CK.There are a few concerning similarities with each of these presentations. In each case TMP-SMX was initiated for a presumed UTI. Subsequently, each patient presented complaining of bilateral lower extremity proximal muscle weakness or pain. Each case demonstrated elevations in CK consistent with rhabdomyolysis. TMP-SMX was discontinued resulting in improvement of clinical status and resolution of CK levels. Each patient had a negative workup for other etiologies of rhabdomyolysis and was without concern for immunocompromised state.There are certainly possible confounding factors in each patient presentation. Confounders include but are not limited to pre-existing medical conditions and past medical history, outpatient prescription medications, home self-medication, substance abuse and non-modifiable factors including gender and age. However, the overarching consistencies – indication for therapy, the temporal relationship to initiation of TMP-SMX therapy, and chief complaint at presentation – are noteworthy and are fairly consistent between cases.After evaluating for and eliminating other possible toxic, biologic or physical and traumatic etiologies of acute rhabdomyolysis in our patient, we concluded that TMP-SMX was the most likely insulting agent. Furthermore, while serum CK was not obtained prior to initiation of TMP-SMX, the temporal relationship of normal AST four days prior to presentation – and parallel trending of AST/ALT with CK at time of presentation and during admission– suggests that our patient’s rising AST/ALT was likely secondary to skeletal muscle breakdown and may serve as a surrogate for CK. TMP-SMX was discontinued and over the course of admission the CK, proximal lower extremity myalgia, ability to ambulate, and overall clinical status gradually improved.In each of the four prior cases, as with ours, the indication for TMP-SMX therapy was a UTI. Our case report adds to a growing body of anecdotal evidence that suggests TMP-SMX may be associated with acute rhabdomyolysis in immunocompetent patients. While the authors are not aware of any large, multicenter study evaluating for a true association of TMP-SMX with rhabdomyolysis, additional larger scale studies are warranted. Providers should be made aware of this possible emerging association between TMP-SMX and rhabdomyolysis in immunocompetent patients.


The European Commission’s recommendation on the definition of nanomaterial (2011/696/EU) established an applicable standard for material categorization. However, manufacturers face regulatory challenges during registration of their products. Reliable categorization is difficult and requires considerable expertise in existing measurement techniques (MTs). Additionally, organizational complexity is increased as different authorities’ registration processes require distinct reporting. The NanoDefine project tackled these obstacles by providing the NanoDefiner e-tool: A decision support expert system for nanomaterial identification in a regulatory context. It provides MT recommendations for categorization of specific materials using a tiered approach (screening/confirmatory), and was constructed with experts from academia and industry to be extensible, interoperable, and adaptable for forthcoming revisions of the nanomaterial definition. An implemented MT-driven material categorization scheme allows detailed description. Its guided workflow is suitable for a variety of user groups. Direct feedback and explanation enable transparent decisions. Expert knowledge is held in a knowledge base for representation of MT performance criteria and physicochemical particle type properties. Continuous revision ensured data quality and validity. Recommendations were validated by independent case studies on industry-relevant particulate materials. Besides supporting material identification and registration, the free and open-source e-tool may serve as template for other expert systems within the nanoscience domain. For this, a newly developed tiered approach of suitable characterization methods (henceforth referred to as methods) has been proposed. In this context, these are defined either as screening or as confirmatory methods. Beside the measurement technique (MT), a method also comprises suited sample preparation and data analysis procedures. The validation of methods has been established by using well-defined quality control materials (QCMs) and representative test materials (RTMs) [The European Commission’s recommendation on the definition of nanomaterial 2011/696/EU) (EC NM recommendation) [1/696/EU 590:2019 .A major project outcome is the NanoDefiner: A decision support framework, capable of assisting expert as well as non-expert users in the categorization and registration process of potential nanomaterials for regulatory purposes. Specific materials are described using a Material Categorization Scheme (MCS) ,5. MTs sNanoDefiner e-tool as an implementation of the NanoDefiner framework, following the concepts and terms [Investigating capabilities of MTs, suitable for nanomaterial identification, is necessary for material research and regulation ,9,10. Hond terms  used in https://fh.do/nanodefiner/ (access 2019-08-16)) [The e-tool (-08-16))  was impl-08-16)) . Technic-08-16))  are refeOne important characteristic of the NanoDefiner framework is that it has been developed based on a comprehensive set of representative materials as well as taking into account practically all currently available MTs capable of evaluating particle size distribution. Its implementation, the NanoDefiner e-tool, relies on expert knowledge represented in the NanoDefiner framework which has been cultivated throughout the NanoDefine project.In the following, details on the materials and MTs tested are presented. In addition, approaches for knowledge engineering and knowledge management are outlined.First, a set of six materials has been employed as QCMs  see Tab, i.e., nA set of 11 RTMs  see Tab has beenThe systematic consideration of these challenging particulate materials is one of the most valuable outcomes of the NanoDefine project as well as the NanoDefiner framework and differentiates this project from the large majority of the published studies on nanoparticle size measurement, which are often applied on “user-friendly” spherical, monodisperse particles. Details on NanoDefine materials are given in previous publications . Propert(i)Counting techniques, which are in favor to the application of the EC NM recommendation, i.e., Electron Microscopy (EM) (Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), including also derivatives such as mini TEM (miniTEM)), Atomic Force Microscopy (AFM), PTA, spICP-MS, and Tunable Resistive Pulse Sensing (TRPS),(ii)Fractionation techniques, i.e., Field Flow Fractionation (FFF), centrifugation techniques centrifugation techniques  and Differential Electrical Mobility Analysis (DEMA),(iii)Spectroscopic (Ensemble) techniques (Dynamic Light Scattering (DLS), Small-Angle X-ray Scattering (SAXS), Ultrasonic Spectroscopy (USSP), Angular Light Scattering (ALS)), and(iv)Integral techniques such as X-ray Diffraction (XRD) and Brunauer–Emmett–Teller (BET) for determination of Volume-Specific Surface Area (VSSA) .In particular, for borderline cases for particles with an It should be noted that several researcher groups worldwide are working on different schemes ,25,26 foKnowledge engineering refers to all aspects having an impact on the process of designing, implementing, and maintaining a knowledge-based system. Beside technical and scientific aspects, especially social aspects have a substantial impact. Expert systems, of which MYCIN  is a welIn the widest sense of the word, expert knowledge refers to any kind of knowledge an expert activates to fulfill a specific task, e.g., deciding which MT might be suitable for the analysis of a specific material. This comprises explicit knowledge, for instance acquired from literature such as Standard Operating Procedures (SOPs). Though, also tacit knowledge  manifestIdentification; 2. Conceptualization; 3. Formalization; 4. Implementation; 5. Testing; and 6. Revision:Identification: Experts from academia and industry discussed important aspects, goals, problems, and resources with knowledge engineers. This phase yielded requirements for the e-tool and drafted an idea on how to implement them. Beside the experts themselves, the main sources of knowledge were identified as: (i) the NanoDefiner DSFS [ner DSFS ; (ii) finer DSFS  with finner DSFS ,7; and  model [Socialization was performed during tests, single or multiple experts tested the e-tool and gained experience on how it worked.Externalization was conducted during revision meetings, the group of experts were interviewed, shared their experiences, discussed unexpected behavior, and concluded required behavior as a result of tacit knowledge being transformed to explicit knowledge.Combination then took place by achieving a consensus on required behavior of a revision, now relying on explicit knowledge.Internalization was applied revising the e-tool, incorporating prior tacit knowledge as newly gained explicit knowledge. The resulting e-tool version built the base for a new SECI cycle.Knowledge management is a broader term for multidisciplinary approaches to generate, distribute, use, and revise knowledge. When constructing an expert system, a key challenge during the knowledge engineering process is to realize and gather tacit expert knowledge, which experts may initially not be able to articulate and would refer to as intuition. During the development of the NanoDefiner e-tool, alternation of ases see  often reases see  was orieI) model ,34:SociThis cycle was performed multiple times and lead to constant gain and refinement of explicit knowledge as well as to optimized behavior of the e-tool implementation. An example of refinement may be the evolution of the borderline range for a material analyzed via Tier 1 methods ,23.The NanoDefiner e-tool accommodates analysts with different levels of expertise, providing a guided workflow. A tiered approach divides MTs into two tiers: Tier 1 comprising screening MTs, and Tier 2 comprising confirmatory MTs. Information regarding the categorization process of materials with one or multiple types of particles is aggregated in a single dossier for a distinct purpose  ).Physicochemical properties of particulate materials, relevant for an adequate characterization  and reguDetailed descriptions on respective results are outlined further in the following.Dossier creation for a material sample; 2. Particle description of the particle type(s) in the sample; 3. Measurement technique recommendation and method selection; 4. Tier 1/Tier 2 method application of a respective method in the laboratory; 5. Analysis data import of yielded analysis data; 6. Material categorization as nano/non-nano; and 7. Report generation for further use. Following, a workflow walkthrough for a material sample with one type of particles is described that can be tracked by examining the enclosed screencast , applied methods, and a report. In addition to choosing a name for the dossier, users state a purpose  or multiple (multi-type sample) types of particles, both of which determining the availability of MTs in later stages of the workflow. The following steps refer to the mono-type case.gulation ) as wellParticle description: After creating the dossier, the user describes the physicochemical particle type properties of the mono-type material sample via the MCS, a multi-page form allowing specification of particle properties. The live feedback on MT suitability and recommendations is one of the core features of the NanoDefiner e-tool, backed by rule-based decision making based on the information of the knowledge base.Measurement technique recommendation and method selection: Methods are performed to document the process of analyzing the described sample with one of the available MTs. In this step of the workflow, users can make use of Tier 1 (screening) or Tier 2 (confirmatory) methods based on a list of configured MTs and their suitability for the material sample, as well as choosing the pre-processing protocol and name for the method.Method application: The next step is performed outside of the NanoDefiner e-tool. The user applies one or more selected methods. Methods may also be applied multiple times.Analysis data import: When analysis results are available the user can upload analysis data or manually state results. Optionally, a percentaged MT uncertainty  can be stated. For supported analysis data formats direct categorization and visualization is available.Material categorization: After uploading analysis results, a nano, non-nano, or intermediate borderline decision , a Portable Document Format (PDF) report can be generated for the dossier. A report contains detailed information on the dossier, its sample, and a custom set of applied methods, including analysis and categorization results. Additionally, The simplified underlying guided workflow for material categorization see  comprisecast see :DossierDuring the whole workflow, the integrated NanoDefine Methods Manual ,44,45,46The spreadsheet-based knowledge base is documented and maintainable by non-computer scientists. Continuous evaluation and multiple revision cycles ensured validity of stored knowledge. MTs were assessed by experts from industry and academia via literature analysis as well as by systematic measurements and analysis on materials . CurrentFor description of MTs, well-defined attributes were derived from filled out templates for quantitative and qualitative description of MT performance criteria ,18, as wstring), value sets (set), decimals , decimal intervals , Boolean values (binary), and value scales .The knowledge base setup consists of dictionaries and associated sheets that form logical pairs. A dictionary defines a set of attributes for which value assignments are made in the related sheet. A set of value assignments represents a profile, multiple of such profiles can be described. An attribute has a unique name, a data type, and a value scope. To describe properties pre-defined data types exist for representation of character strings  the Measurement technique performance dictionary and sheet; (iii) the Material group dictionary and sheet; (iv) the Material property dictionary and sheet; (v) the Priority dictionary and sheet; as well as (vi) the Explanation dictionary and sheet:(i)Measurement technique dictionary and sheet: Administrative component for definition of MTs; contains controlling attributes.(ii)Measurement technique performance dictionary and sheet: Core component for description of default or material group-dependent MT performance criteria profiles; contains controlling and matchable attributes.(iii)Material group dictionary and sheet: Administrative component for definition of material groups for which an MT may show non-default performance; contains controlling attributes.(iv)Material property dictionary and sheet: Core component for description of particulate material property profiles; contains controlling and matchable attributes.(v)Priority dictionary and sheet: Administrative component for individual weighting of MT performance criteria attributes for decision making; contains controlling attributes only.(vi)Explanation dictionary and sheet: Administrative component for description of explanatory text fragments for explanation during decision making process; contains controlling attributes only.In the current version of the knowledge base the setup see  consistsA special feature of the knowledge base lies in its capability of handling missing knowledge and case-specific irrelevances in the description of MT performance criteria and material property profiles. This allows expression of lack of knowledge regarding characteristics of configured MT performance criteria and material properties described via the MCS. Also, it allows the statement that certain attributes of configured MTs are not relevant for the decision making process.https://www.drools.org/ (access 2019-08-16)) rule-processing engine that uses the novel PHREAK algorithm [Recommendation of suitable MTs for a specific material via rule-based decision making is a key feature of the NanoDefiner e-tool. Particle properties stated in the MCS are processed by rules, matching them against MT property profiles described in the knowledge base. Changes in the MCS instantly trigger decision making via the Drools . Another feature is to exclude the influence of specific particle properties that are irrelevant for the recommendation of certain MTs.The decision making itself comprises expert knowledge, present as a combination of production rules  which armono-type sample. The special case of a multi-type sample is approached subsequently. Non-default MT performance is not considered in favor of reduced complexity. It starts with a description of attributes as lowest units of the decision model, brings them into a relation, illustrates how decisions are determined, and finally explains the process towards the final set of recommended MTs for a specific material:The following formal description of the decision making is a bottom-up approach and elaborates the inference process for MT recommendation for a a has data fields ) [https://imagej.net/ (access 2019-08-16)) [https://www.wur.nl/en/show/Single-Particle-Calculation-tool.htm (access 2019-08-16)) for calculation and evaluation of spICP-MS data [The e-tool supports the import of a two-column data format for number-based particle size distributions. The first column consists of the upper limit of the particle size classes, the second contains the cumulative distribution function value. This format is featured by the ParticleSizer -08-16))  (an Imag-08-16))  plug-in -08-16))  and is p-08-16)) . Data ge-MS data  is accep-MS data  can be g)  ) and was published under the MIT license (https://opensource.org/licenses/MIT (access 2019-08-16)).Further support of also proprietary analysis data formats can be established by extending the e-tool with custom analysis data importers, using the provided API. Its source code is available on GitHub (https://www.nanoreg.eu/ (access 2019-08-16)) as a ready-to-use tool [Selection of an appropriate MT for the analysis of a specific material requires expert knowledge that is not always available. Hence, the e-tool can support manufacturers of potential nanomaterials during the process of categorization and registration of their products. It is considered in the NANoREG Toolbox ,56 of thuse tool  for the use tool  and the use tool ,44,45,46use tool .Beside confirmatory Tier 2 MTs, its recommendation of suitable screening Tier 1 MTs provides (under well-defined conditions and within their limits of applicability) alternatives to an analysis with time- and cost-intensive MTs such as TEM that also require their own expertise. Dossier reports generated by the e-tool comprise mandatory and The guided workflow of the e-tool provides information on how to proceed in a walkthrough. The NanoDefine Methods Manual can be accessed anytime for consultation in case further guidance or details on requested input may be necessary. This allows also inexperienced analysts to fulfill a categorization process. Due to the lack of generalizability of SOPs developed during the NanoDefine project ,60,61,62Expert knowledge present in the spreadsheet-based knowledge base can be adjusted and extended by non-computer scientists. For instance, newly added material property and MT performance profiles will be present in the e-tool without altering its source code. It is robust against missing knowledge, allowing it to work efficiently with just the basic set of attributes used for decision making. Manufacturers of materials and MTs may add profiles for their products to test with which MTs their materials can be analyzed adequately, and vice versa, for which materials their MTs are recommended.The decision making on MT recommendation for the analysis of specific materials is transparent and comprehensible due to explanation on all single decision points. Furthermore, user learning is supported as changes on material properties in the MCS result in live feedback on MT recommendations with explanation. This way, linkage of material properties that lead to exclusion of specific MTs from the recommendation can be revealed. Albeit, as an expert system the e-tool is not intended to substitute human experts but to support them. It is not an adequate surrogate to a human expert possessing creativity and intuition.Three independent industrial case studies on different and representative industrial materials were conducted to examine whether behavior, recommendations, and decisions yielded by the e-tool are consistent with the NanoDefine DSFS. All case studies approved its concordance . HoweverThe e-tool is prepared for anticipated re-definitions of the EC NM recommendation and will be kept up to date concerning this matter. This extends to security aspects, reported bugs, and wording. Hence, its users will not be forced to abandon their installations in the future. On the contrary, an active user community including dialogue, participation, and contributions is the goal.As it is based on open-source software see  and is oThe NanoDefiner e-tool provides a guided workflow, based on the NanoDefine DSFS , that suhttps://labs.inf.fh-dortmund.de/NanoDefiner/ (access 2019-08-16)) is available for trial purpose. Installation packages and related documentation can be downloaded for local deployment. A virtual machine as well as a Docker (https://www.docker.com/ (access 2019-08-16)) container with installed software packages and default configuration are provided likewise.Results of e-tool assessments obtained from independent industrial case studies confirmed its consistency with the underlying NanoDefine DSFS in all cases . In OctoManufacturers of materials and MTs may contribute novel material property and MT performance criteria profiles, providing e-tool users an additional perspective to explore their products. As it is free, open-source, and designed to be extensible and customizable, the e-tool itself or parts of it may serve as template for other knowledge-based expert systems of the nanoscience domain, but not limited to it.