Click chemistry has emerged as an effective polymerization method to obtain thermosets with enhanced properties for advanced applications. In this article, commonly used click reactions have been reviewed, highlighting their advantages in obtaining homogeneous polymer networks. The basic concepts necessary to understand network formation via click reactions, together with their main characteristics, are explained comprehensively. Some of the advanced applications of thermosets obtained by this methodology are also reviewed. The development of novel thermosets with requirements of high mechanical and thermal performance for new technologies has moved researchers to incorporate new chemical processes into the preparation of these polymeric materials. Considering the concept proposed by Sharpless , click rThe most notable click reactions that have been previously employed in published studies are depicted in The crosslinking process in these reactions follows a polycondensation or step-growth mechanism, which is advantageous in comparison to polyaddition or ring-opening mechanisms. One advantage is the homogeneity of the material. The network is formed in consecutive steps starting from the initial formulation; then, branched structures are generated in the entire polymer matrix with reactive groups as chain ends, until gelation is reached. The polymerization continues until full crosslinking is achieved as long as no vitrification occurs. The homogeneity of the material is enhanced because of the high yield of these reactions which occur without side-reactions or the formation of byproducts.The monomers that react are of type 2O, HCl, etc. leads to the formation of bubbles, cavities and irregularities that deteriorate the appearance and properties of the material. For this reason, the use of click reactions to form thermosets is highly advantageous. It is no surprise that epoxy resins are usually cured by amines, which involves a nucleophilic ring-opening reaction; this is the oldest and the most widely used procedure to cure epoxy resins.The step-growth characteristic of this polymerization makes it easy to predict the conversion at gelation and the network parameters . It is nThe curing of thermosets is a complex process from the structure, kinetics and properties viewpoints ,12,13. AFrom a structural point of view, the system evolves from a viscoelastic liquid mixture of monomers to a more or less densely crosslinked network. A critical point during this process is gelation, which corresponds to the incipient formation of a 3-dimensional network. Precise knowledge of conversion and time at gelation is essential from a processing point of view, since, at gelation, the bulk of the reacting system starts to become insoluble and ceases to flow. The evolution of the molecular and network architecture during processing will have a deep impact on the rheological and mechanical properties during processing. In consequence, the structure and network build-up process need to be characterized experimentally, but relevant knowledge can also be obtained from a theoretical analysis using suitable mean-field methods.The molecular and network build-up process is accompanied by an increase in the glass transition temperature of the system, tructure . This wintrolled , slowingThe transformations taking place during curing processes are commonly represented in conversion-temperature-transformation (CTT) diagrams  or time-In consequence, it is essential to have a set of basic tools that can be used to characterize a curing process and have a comprehensive picture of it, which can be exploited for the efficient design of curing processes and to tailor the final structure/properties. In the following subsections, some common methods will be outlined.As mentioned, the stepwise mechanism of click polymerization is highly beneficial in thermoset curing in terms of structure and network build-up. Unlike chain-wise polymerizations in which monomer units are added sequentially to the growing chain, stepwise processes proceed ideally by successive and random coupling of fragments with gradually increasing size by reactions between complementary As seen in The evolution of the molecular and network structure during a stepwise polymerization process can be easily analyzed making use of well-established mean-field methods, based on combinatorial  or recurThe starting point of the recursive method is to define a set of structural fragments which are representative of the different states of reaction that can be found for the different monomers. For instance, for an Reactive groups expected mass pending from an arrow bond is finite. In other words, the probability that the path starting from an arrow is finite, or the extinction probability, is equal to 1. The expected mass increases as the reaction advances, and diverges to infinity when gelation takes place. Pregel parameters such as expected mass. Once gelation takes place, the presence of a gel fraction with infinite molecular weight causes the extinction probability to have a value lower than 1. Structural parameters after gelation such as extinction probability. The value of the extinction probability decreases as the reaction advances, and in consequence, Now, the key is to understand that all the reactive fragments carrying at least an arrow can be randomly recombined with any other fragment carrying another arrow. In this way, a most probable distribution of polymeric species within the reactive system can be created, as indicated in expected mass and extinction probability, are determined before and after gelation, respectively, using a recursive procedure that takes into account the probability of picking any fragment issuing a connecting arrow, and the remaining connections with other fragments, if any . Th. Th52]. Aliphatic amines have higher nucleophilicity than aromatics; therefore, the former cure at lower temperatures ,54. ResiThe rate of curing of epoxide with amines depends not only on the amine structure, but also on the epoxide characteristics. The most commonly used diglycidylether type resins easily cure at room temperature with aliphatic amines, but hindered epoxies such as cycloaliphatic epoxide and epoxidized rubbers hardly cure in these conditions see .Epoxy resins based on renewable starting materials have also been cured by a variety of amines ,58. AmonEpoxy-amine reaction was also used in off-stoichiometric mixtures, as a first curing stage in dual curing processes. Therefore, these systems are only click in the first stage, as epoxy homopolymerization reactions (which occur in the second stage) do not fit the click criteria. As the secondary epoxy homopolymer network imparts high crosslink density to the pristine epoxy-amine network, this dual-curing strategy is useful to obtain materials with superior mechanical properties. Secondary epoxy homopolymerization, with well-defined curing kinetics, is usually carried out using anionic initiators such as imidazole derivatives ,64. SincAlthough not as common as amines, thiols are also employed as epoxy curing agents. Thiol-epoxy reactions require the presence of an amine as the catalyst. The amine can act directly as a base, extracting the thiol proton and enhancing the nucleophilicity by forming thiolate active groups, or as a nucleophile, attacking to the epoxide and finally generating thiolate functions, as depicted in The higher nucleophilicity of thiolates in comparison to amines facilitates their reaction with cycloaliphatic epoxides  and inteThe fast thiol-epoxy reaction in the presence of tertiary amines, together with the high fluidity of the thiol monomers, has been utilized to obtain self-healing materials by the addition of two types of microcapsules. One microcapsule contains a thiol/amine mixture and the other the epoxy resins. When a crack occurs in the polymer film, the microcapsules break open and release their components which react and heal the crack instantaneously . This seThiol-epoxy curing based on renewable monomers like eugenol ,71, phloThe thiol-epoxy reaction has been used in the preparation of polymer matrix in nanoclay  and boroSimilarly, off-stoichiometric thiol-epoxy formulations can also be dual-cured using adequate initiators. Our research group has prepared such materials, described their curing kinetics and fully characterized their shape-memory capabilities ,36,77. WMichael-type additions have long been utilized in organic synthesis and more recently in materials science, but relatively few implementations have been demonstrated in the preparation of cross-linked polymer networks. In the last twenty years, the Michael reaction has been more frequently encountered in this field, due to its click nature that yields uniform and homogeneous thermosets in mild and environmentally friendly conditions.Michael additions are 1,4-addition reactions of α, β–unsaturated carbonyl compounds and α, β–unsaturated nitriles with resonance-stabilized carbon nucleophiles, such as enolate ions and enamines. In this thermodynamically favored reaction, during the strong nucleophilic attack on the β-carbon of an α, β-unsaturated carbonyl, a negatively charged intermediate is formed, which subsequently yields the Michael adduct by protonating the catalyst. The α, β–unsaturated compound undergoing Michael addition is called Michael acceptor, the nucleophile is called Michael donor and the product is called Michael adduct. The most typical Michael donors are thiols (thiol-Michael), primary and secondary amines (aza-Michael), alcohols (oxa-Michael) and acetoacetates (carbon-Michael) that easily generate C-S, C-N, C-O and C-C bonds, respectively.enes such as maleimides, vinyl sulfones, acrylates/acrylamides and methacrylates, in decreasing order of reactivity, among others non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) ; howeverThe fast thiol-isocyanate reaction has been exploited to develop an original autonomous self-healing system for epoxy thermosets. The addition of separate capsules containing either isocyanates or thiols facilitates the extrinsic self-healing of epoxy, during which the amine groups present in the matrix act as a basic catalyst .Crosslinked poly(thiourethane)s have been widely used in optical materials thanks to their high refractive indexes . From coThermosetting poly(thiourethane)s have also been prepared from renewable resources  using di3 and DBN with  cycloaddition reaction proposed in 1928 by Diels and Alder is one of the most popular reactions in organic synthesis. In this reaction, an electron-rich diene and an electron-poor dienophile react without the need of catalyst see . This reDiels-Alder reaction (D-A) was also used in the preparation of thermosets by modification of polystyrene with maleimide groups .The reversible D-A process has made it possible to prepare new types of recyclable or self-healing thermosets, such as epoxy resins ,158, polSome of the so-called covalent adaptable networks (CANs)—i.e., are cross-linked polymers in which the crosslinking strands within the polymer material can undergo reversible rearrangement reactions—have D-A adducts in their structure. The D-A rearrangements provide a microscopic mechanism for achieving macroscopic flow and stress relaxation in thermosetting polymers for which this was previously impossible ,168,169.Including an adequate selection of dienes and dienophiles, a lot of studies have been published with different types of thermosetting materials. As a diene, furan derivatives have been widely used, e.g., in the work by Gandini et al. ,171,172.Four-arm star-shaped end-functionalized PCLs have been modified to introduce furan, maleimide and anthracene final groups that are able to undergo Diels–Alder cycloaddition with maleimides to produce thermosets . The antModified novolac epoxy resins with furan pendant groups were prepared from novolac epoxy resin and furfuryl alcohol and then crosslinked by bifunctional maleimide via Diels-Alder reaction to obtain thermally reversible and self-healing novolac epoxy resins .Thermosets were also obtained by crosslinking linear polymers with furan and maleimide functionalized dangling chains  or with It is worth mentioning that biobased materials, namely vegetable oils ,184 or tBenzocyclobutene-functionalized monomers are able to react at elevated temperatures (up to nearly 200 °C) with dienophiles to form D-A adducts ,187,188.Among the many thermoset preparation strategies, dual-curing stands out as an effective and versatile method. It is based on two polymerization processes carried out either concurrently or sequentially, as depicted in A deep understanding of the underlying reaction mechanisms is crucial to obtain tailor-made materials through curing sequences with well-established kinetics. The material properties at different stages of curing are governed by the choice of monomer. Moreover, the utilization of click procedures contributes greatly to sustainability and efficiency of the method. Several sequential click curing systems have been studied and characterized to date using a variety of techniques, such as calorimetry or spectroscopy. Also, some other dual-curing systems have also been developed simply in order to improve the properties of otherwise single-cure thermosets.The sequentiality in curing provides immense flexibility in the industrial processing of these materials; a chemically stable intermediate material can be stored indefinitely and manipulated whenever desired to process it further. This sequentiality and stability is made possible either by the intrinsic chemistry of the selected monomers, or by employing latent catalysts, which, upon stimulation by heat or light, liberate the active species to initiate curing. This way, complete temporal control of the curing process is facilitated.In some dual-curing systems, some click polymerizations such as stepwise Michael additions are combined with chain-wise homopolymerizations such as acrylate photopolymerization. In such systems, the stepwise polymerization, at the first curing stage, imparts advantages such as network homogeneity, high gel point conversion, and low curing shrinkage to the material. Later, the secondary chain-wise polymerization stage increases the material’s crosslinking density, glass transition temperature and hardness, thereby improving its mechanical properties significantly. Without regard to the utilized curing process, all dual-cured final materials exhibit improved thermal and mechanical properties in comparison to the intermediate materials. These dual-curable materials can be used in a wide array of value-added applications such as high-performance adhesives, shape memory materials, vitrimers, and 3D printing resins see .2PPh). This Michael type reaction was followed by a radical-mediated thiol-yne reaction, which was orthogonal to the thiol-ene stage. This radical thiol-yne reaction quickly and quantitatively yielded the 1,2-addition product.One of the earliest dual-click procedures was described by Chan et al., whereby a sequential curing process was employed using thiol-ene and thiol-yne reactions as first and second stages, respectively . Highly 4) was used, from which TBA was liberated upon light exposure. As the photoinitiator for the thiol-ene reaction, 2,2-dimethoxy-2-phenyl acetophenone (DMPA) was used. Both reactions proceeded quantitatively. Processing flexibility was achieved by the control of curing sequence which allowed tailor-made fabrication of photocurable thin films or thick materials. Furthermore, the incorporation of thiourethane groups in thiol-ene networks improves the physical and mechanical properties thanks to hydrogen bonding. It has been documented that the Versatile thiol chemistry was utilized by another group of researchers to design a thiol-isocyanate-ene dual-curing system . In theition See b followereaction . Taking reaction . They usThey showed that the thiourethane network enhanced the thiol-epoxy properties through an increased rate by hydrogen bonding. The versatility of material properties according to the choice of monomer was demonstrated.ene and excess of thiol groups which underwent UV-initiated click thiol-ene photopolymerization, allowing holographic images to be recorded onto them. The final materials were graded rainbow holograms with high As for interesting applications of dual-curing philosophy, the Bowman group came up with an elegant process for preparing holograms . They fiAnother publication came from the same laboratory describing an image patterning technique based on a different dual-curing procedure, as depicted in Since thiols can also cure epoxy resins, a thiol-epoxy reaction can be carried out as a second curing step, given that an excess of thiols remains from the first curing stage; a covalently-bound interpenetrating polymer network would be obtained as a result. Following this philosophy, Guzmán et al. designed a thiol-ene/thiol-epoxy dual-curing system wherein a photoinitiated thiol-ene reaction took place at the first stage, and an epoxy-thiol reaction followed, initiated by an encapsulated (latent) imidazole catalyst . The act modulus .Another thiol-ene/thiol-epoxy photo/thermal dual-curing system was documented by Acebo et al. . They adbehavior . Similarbehavior .In another publication, a dual-cured thiol-ene/epoxy system was described , whereinepoxides ,205. ThiN,N-dimethylamino)pyridine (DMAP), and 1-methylimidazole (1-MI), and saw that DMAP provided better separation between the two curing stages. In the latter work, the sequentiality of the curing was achieved by employing the same TBD·HBPh4 photobase generator shown in g of the final materials significantly.As a one-pot approach, Jin et al. described a thiol-acrylate-epoxy system wherein a nucleophile catalyzed thiol-Michael addition took places concurrently with a base  catalyzed thiol-epoxy reaction . By usinAs mentioned in Dual-curable epoxy thermosets can be obtained completely in a “click manner” by using a combination of aliphatic and aromatic diamines. By employing these two amines which are reactive at two different temperatures, an epoxide compound (triglycidyl p-aminophenol epoxy resin) was dual-cured without any catalysts . DependiAs mentioned in previous sections, the applications of click chemistry span a broad range of technological fields from optical devices, printing materials (3D printing) and microfluidics to recently emerged shape memory, self-healing or remoldable polymers, also encompassing conventional adhesive materials or coatings.A prominent application of click chemistry, namely thiol-ene/thiol-Michael chemistry, is in the field of optical materials. A thorough review from Du Prez et al.  highlighAs stated in Excellent materials for optical applications were obtained also by Bowman and coworkers . They syAnother interesting market where click chemistry can fit perfectly is flexible bioelectronics. Here, there is an ever-growing need for high performance materials. In the case of thiol-click reactions involving epoxide, alkene, or (meth)acrylate reactive groups, the resultant thioether linkage demonstrates an inherent flexibility that yields a significant reduction in the cure-stress of the final network, a quality that is desirable for low-shrinkage uses, such as the photolithographic fabrication of flexible electronics . HoweverObtaining lithographic printing materials is another field where click chemistry has been applied with success. In the work presented by Bowman’s group , thiol-eAlso based on thiol-ene chemistry, Bowman’s group presented remoldable vitrimers for photopatterning and nanoimprint lithography . These mFollowing a dual-curing approach as presented in Another innovative application of thiol-ene click-chemistry is in microfluidics. Although there is not a “perfect” material that fits all the requirements in microfluidics, the thiol-ene family has enormous potential for organs-on-a-chip applications, droplet productions, microanalytics and point of care testing. The fabrication of microfluidic devices from such materials is typically done by the classical photolithography, replica molding (or double replica molding) or reaction injection molding, and allows very fast prototyping to be performed. This possibility, combined with good mechanical strength, solvent resistance, biocompatibility and the inherently easy surface functionalization are the distinctive features that make thiol-ene polymers suitable for microfluidic applications. Another advantage of thiol-ene polymers for obtaining microfluidic devices with complex shapes is that they can bond using different strategies . In their review, Carlborg and coworkers demonstrated how off-stoichiometric thiol-ene processes are suitable for the commercial production of microfluidic devices to substitute classical poly(dimethylsiloxane) (PDMS). The polymers used were based on versatile UV-curable thiol-ene chemistry, taking advantage of off-stoichiometric ratios to offer important features for a prototyping system, such as one-step surface modifications, tunable mechanical properties and leakage-free sealing through direct UV-bonding . In a moStable and tunable hydrophilic-surfaced materials for microfluidic applications were also obtained by Pojman et al.  via the Khan and Yeo created soft micro- and nano- patterned surfaces based on the thiol-epoxy click reaction  catalyzeThanks to their high refractive index, low oxygen inhibition and minimal polymerization-induced shrinkage, click thiol-enes are well-suited for use as 3D printing resins. In the work presented by Chen et al. , digitalThiol-ene ‘click’ reactions utilizing terpenes and a four-arm thiol have also been employed to produce thermoset 3D-printed structures using vat photopolymerization . The obtShepherd’s group also used thiol-ene click chemistry wisely to obtain tunable materials for soft robotics fabricated via stereolithography . Their mThe self-healing ability, a topic of scientific and technological interest at present, is another outstanding property of some thermosets obtained by click chemistry. Some examples have already been presented in previous sections. The self-healing materials presented in  are baseAnother example, already mentioned in Besides the extrinsic self-healing technique, reversible bonds are also attractive for obtaining a self-healable material. In a work presented by Zhang et al. , smart pFinally, a cutting-edge application of click-based thermosets is Covalent Adaptable Networks (CANs). These constitute a novel material class with the possibility of being reshaped, remolded and recycled, with shape-memory properties and/or self-healing abilities. There are excellent papers in the literature presenting different systems or properties of CANs, of which some have already been cited in the text. However, to summarize them exhaustively is beyond the scope of this paper. Excellent reviews were published by Bowman’s group ,231,232,Given the aforementioned applications, without intending to be exhaustive, this last section has tried to convince the reader that click chemistry opens up a huge world of smart, intriguing and fascinating applications that are (predominantly) technologically available. Being simple, environmentally-friendly and therefore sustainable, click procedures might fully replace conventional thermoset fabrication techniques in the near future to become the go-to approach not only for basic industrial applications, but also complex and delicate, high value-added technological applications. It is the belief of the authors that, with the interdisciplinary efforts that this review will hopefully inspire, a lot of ground can be covered in this promising field rooted in organic chemistry, but rootlets touching many other disciplines such as polymer science and material engineering.Click chemistry is a versatile tool providing extensive control in the preparation of thermosets with tailored structures and properties. The smooth reaction conditions, the high yields achieved and the possibility of performing most of these reactions in air, and even in humid environments, make them ideal for industrial use. In addition, the power of their orthogonality makes it possible to establish novel advanced fabrication procedures.Considering the ever-growing number of applications of click-based thermosets, some of which were outlined in this review, we expect that these efficient synthetic methodologies will be more widely implemented to tackle challenging problems in industry. We are convinced that the application of click chemistry will contribute to improving industrial productivity, mitigating environmental impact and opening up new possibilities in emerging technologies.


Background: Physical activity among those with type 2 diabetes (T2D) is independently associated with superior medical outcomes, but existing behavioral interventions have not led to widespread increases in activity in this population. A remotely delivered intervention that targets well-being constructs associated with greater activity and assists in the creation of specific physical activity goals has the potential to improve activity and outcomes in T2D.Objective: To outline the rationale and methods of two studies designed to assess the impact and optimal duration of a combined positive psychology-motivational interviewing (PP-MI) intervention for inactive persons with T2D.Methods: We conducted trials studying 8-week  and 16-week  phone-delivered interventions, compared to attention-matched control conditions. In a two-step randomization design, participants were allocated randomly first to study (BEHOLD-8 or BEHOLD-16), then to study condition within study. The primary aims in both trials were feasibility (rates of session completion) and acceptability (participant session ratings), with additional aims examining intervention effects on accelerometer-measured physical activity, psychological measures, and health-related metrics . Main analyses, currently being conducted, will utilize mixed effects models between study conditions, and secondary analyses will utilize the same models to compare the 8- and 16-week PP-MI interventions on feasibility and impact.Results: Enrollment and data collection have been completed for both trials , and data analysis is ongoing to assess feasibility and acceptability within study, as well as the relative feasibility and acceptability of the PP-MI interventions across the two studies. We will also explore impact on clinical outcomes between groups.Conclusions: This design will address how intervention content (i.e. PP elements vs. no PP elements) and intervention duration (8 weeks vs. 16 weeks) affect feasibility, acceptability, and impact, allowing intervention optimization before a next-step larger clinical trial.Trial registration:ClinicalTrials.gov identifier: NCT03150199; NCT03001999. Type 2 diabetes (T2D) affects 29 million Americans  is a promising alternative to in-person programs. MI is an evidence-based, patient-centered counseling strategy designed to enhance intrinsic motivation for change  are prospectively and independently linked with greater physical activity in T2D and other populations, independent of sociodemographics, medical factors, and the adverse effects of depression , this intervention was feasible, acceptable, and associated with pre–post improvements in well-being constructs and physical activity , we are testing an 8-week version of the telephone-delivered PP-MI intervention, compared to an attention-matched MI-enhanced behavioral counseling condition. We chose this control condition to assess the incremental benefits of the PP content given that both groups would obtain MI related content and skills. In the second, (BEHOLD-16), we are comparing a 16-week PP-MI intervention to an attention-matched health education condition. We chose this control condition to allow cross-study assessment that would explore the relative feasibility and benefits of PP-MI, MI, and health education. Participants are first randomly allocated to either the 8-week (BEHOLD-8) or 16-week (BEHOLD-16) study, and then are allocated to the PP-MI or attention-matched control condition within that study. To match for attention, all conditions had phone sessions at the same intervals and duration, utilized written treatment manuals specific to the study condition, provided weekly activities for participants to complete on their own, and included the provision of pedometers to promote physical activity.This pair of studies will allow us to examine the effects of intervention content  within the studies, and it will allow us to explore differences in feasibility and impact related to PP-MI intervention duration  We have completed enrollment and follow-up assessments for these trials; results are pending. In this article, we will outline the rationale, specific aims, detailed methods, and analysis plan for these two trials.BEHOLD-8 and BEHOLD-16 are randomized controlled pilot trials designed to examine the feasibility, acceptability, and preliminary efficacy of 8 and 16-week versions of a PP-MI intervention, compared to attention-matched, clinically relevant control conditions. All participants provided written informed consent prior to enrollment, with consent addressing randomization to study/intervention length and allocation to different intervention content within each study. Institutional Review Board approval was obtained prior to initiation of the studies , and both studies were pre-registered on ClinicalTrials.gov (NCT03150199/NCT03001999). The study was conducted at Massachusetts General Hospital, an urban academic medical center in Boston, Massachusetts, USA.In BEHOLD-8, an 8-week phone-delivered PP-MI intervention is compared to a time-matched MI-alone program in 60 inactive adults with T2D. In BEHOLD-16, the PP-MI intervention is delivered over 16 weeks, this time compared to a time- and attention-matched health-education intervention in 70 inactive adults with T2D. Study outcomes are measured at baseline, in a follow-up visit at the end of intervention (8 and 16 weeks), and in a follow-up phone call 8 weeks after ending the intervention .We selected 8 and 16-week PP-MI interventions to attempt to find a balance between feasibility and longer-term impact. Prior PP-based interventions by our team and others in medical settings have had durations between 5–16 weeks . Session completion rates were high, participants rated the PP-MI content and sessions as useful , and PP-MI was associated with improved adherence to physical activity and overall self-care . Physical activity over the past week  was measured using the MVPA-specific questions from the International Physical Activity Questionnaire (IPAQ), a validated tool used in medical cohorts  treated in an MGH-affiliated outpatient clinic with:Patients were excluded due to: (1) cognitive impairment precluding consent or meaningful participation, assessed using a six-item screen developed to assess cognitive capacity to participate in research studies . At this visit, participants received hip-worn Actigraph GT3X+ accelerometers to wear during waking hours for 1 week to measure baseline physical activity and then returned for a second in-person baseline study visit. During this second visit, adequate accelerometer wear time was confirmed, participants were assigned to a treatment condition, and study interventionists introduced participants to their appropriate conditions . All parFollowing receipt of the treatment manual and completion of the in-person session at the second in-person baseline study visit, the remainder of the intervention was completed by phone. Each week, the PP portion of phone sessions (15 mins) was structured to include: (i) review of the prior week’s assigned PP exercise with the participant to explore its impact on well-being, (ii) discussion about how to translate the PP exercise skills from that activity into daily life , and (iii) assignment of the next exercise via co-review of the treatment manual, with a discussion of the rationale and details of the exercise. Participants then completed the PP exercise independently during the week and wrote about the exercise and its effects. The MI portion of calls (15 mins) assessed participant motivation to increase physical activity and then planned action steps or cognitive work to boost motivation, using the structure and principles of MI.PP and MI components were delivered separately within sessions (rather than intertwined) based on our experience, participant feedback, and pilot work  corresponded with each integration session with the PP exercises and were used to further enhance motivation and commitment to physical activity throughout the course of the intervention. Participants also received pedometers and were mailed a graph of their weekly step counts following each review and reflect session.Participants randomized to this attention- and time-matched condition completed weekly readings in a treatment manual and answered questions related to T2D health, self-care, and health behavior adherence See . This coAll team interventionists were psychiatrists or PhD level psychologists. Once the intervention was adapted and refined for T2D, they received additional training from study experts in PP and MI  using a structured training program that involved didactic sessions, role play, review of recorded sessions, and supervised interviews. The same group of interventionists delivered all arms of both studies and all interventionist phone sessions were recorded. During the study, weekly hour-long meetings were led by PP and MI supervisors  to discuss progress of all enrolled participants and to review audio recordings of sessions. Supervising study staff rated a random selection of sessions in a structured manner for fidelity, using scales for the PP and MI components, and provided ongoing feedback to interventionists during the supervisory sessions. Supervisors worked to avoid between-condition contamination  via training, weekly session review, and fidelity ratings.The fidelity scales utilized were derived from existing MI fidelity assessments  were obtained at the initial study visit and repeated at a post-intervention visit (8 weeks [BEHOLD-8] and 16 weeks [BEHOLD-16]). A follow-up phone assessment occurred eight weeks later to obtain final self-report measures (16 weeks [BEHOLD-8] and 24 weeks [BEHOLD-16]). Finally, at both the post-intervention and follow-up assessments, participants were mailed accelerometers to wear during waking hours for one week, to measure MVPA; wear time was confirmed by study staff upon their return, and accelerometers were re-worn if participants had less than 4 days of wear for 8+ hours required for adequate wear, as per published guidelines  of the prior week’s PP exercise and MI topic, for four total ratings per session. These ratings were provided by participants to study interventionists at weekly calls. We chose these specific metrics for feasibility and acceptability to match the same metrics used in several of our team’s prior studies of feasibility and acceptability in medical and psychiatric populations  , participants were assigned to a treatment condition using allocation by minimization  prior to initial contact. Following completion of informed consent, they were then assigned to treatment condition within their study. In BEHOLD-8 (n = 70) were randomly assigned to the PP-MI or diabetes health education condition. Prior to study initiation, a research coordinator not involved in the project used a random number generator to create a random sequence of treatment assignments. Slips of paper were put into opaque envelopes; these were opened in sequence by study staff following the completion of baseline measures and confirmation of adequate wear time, ensuring that participants and study staff learned of the study assignment contemporaneously.Participants in BEHOLD-16  will be used to summarize baseline participant characteristics, and between-group differences in baseline characteristics will be calculated using chi-square analyses, Fisher’s exact tests, and independent samples t-tests.a priori for feasibility and acceptability, based on similar interventions and scales  of the 0–10 ease/utility scores of the PP and MI component of each session will be used to assess acceptability, for a total of 4 separate mean scores. We set a benchmark of 70% completion of assigned sessions and mean ratings of 7.0/10 on ease and utility Between-group differences in change from baseline on physical activity metrics and other study outcome measures will be assessed using mixed effects regression models with an unstructured covariance matrix. We selected these models because they allow for the inclusion of all participants, including those with missing data  of PP-MI for each outcome.Alpha for between-group comparisons was set at Additionally, to assess the possible effect of change in positive affect (measured by PANAS) as a mediator of change in MVPA, we will use a series of linear regression analyses to assess the total intervention effect on change in MVPA, the direct effect on change in MVPA, and the indirect effect on change in MVPA mediated through the PANAS. In addition to mediation analysis  to confirm that >70% of sessions were completed, our a priori goal, assuming a moderate standard deviation of 15%,. For acceptability, using prior ratings for ease and utility of sessions (mean 8.1 [SD 2.3])  under the supervision of the study biostatistician (BH).There is a substantial public health need to develop and implement scalable, easy-to-deliver behavioral interventions to promote physical activity in T2D . By comparing feasibility and acceptability measures, along with impact-related outcomes, we can gain an understanding about which intervention design may best fit this large and important population at elevated risk for heart disease and mortality.Specifically, establishing a suitable dose/duration is essential at this stage, as different intervention durations can have implications for participant engagement and retention, budgeting, staffing, and effect. While there is some evidence to support greater efficacy of behavioral interventions with longer intervention duration . Despite these limitations, these studies should provide valuable information about a behavioral intervention designed to promote physical activity among inactive T2D patients, will greatly assist in selecting an intervention duration that meets the needs and preferences of persons with T2D, and will inform further trials that can more definitively answer whether such a program could be successful in this population.Click here for additional data file.


The aim of the current study was to explore protective (resilience) and vulnerability factors  for self-esteem. A total of 725 participants were included in a cross-sectional study. A path analysis revealed five paths to self-esteem. The three main paths were as follows: (1) symptoms −> metacognitions −> brooding −> self-esteem, (2) symptoms −> resilience −> self-esteem, and (3) a direct path from symptoms. The first path corresponds with the metacognitive model of psychopathology and suggests that triggers in the form of anxiety and depression symptoms lead to the activation of metacognitive beliefs, which in turn activates brooding in response to these triggers. When a person engages in brooding, this makes the person vulnerable to experiencing low self-esteem. The second path suggests a protective role of resilience factors. The overall model explained 55% of the variance in self-esteem. Regression analysis found that unique predictors of self-esteem were female sex, symptoms of anxiety and depression, brooding, and resilience. These findings have possible clinical implications, as treatment may benefit from addressing both protective and vulnerability factors in individuals suffering from low self-esteem. Self-esteem reflects how people feel about themselves and is a multifaceted construct related to other psychological constructs such as self-image, self-concept, self-perception, self-confidence, self-acceptance, self-respect, and self-worth. Research suggests that self-esteem is related to psychological well-being and psychological problems . HealthyFindings from prospective studies suggest that self-esteem is relatively stable throughout life . It is gThe association between low self-esteem and psychiatric disorders  indicateThe link between self-esteem and depression may be influenced by perseverative thinking processes such as rumination. Rumination, self-esteem, and depression are closely linked . RuminatThe self-regulatory executive functioning (S-REF) model proposed by The CAS is driven by metacognitive beliefs, and two important domains of metacognitive beliefs are positive and negative metacognitions. Positive metacognitions justify the activation of the CAS, such as “To analyze my flaws will help me sort out my personal problems.” Negative metacognitions concern that engaging in CAS activities is dangerous or uncontrollable, like “I can’t stop thinking negatively about myself.” From a metacognitive point of view, low self-esteem could be understood as the result of a maladaptive coping style, when a person responds to negative thoughts about oneself by ruminating about one’s flaws and shortcomings and engaging in self-criticism and negative self-talk. This response style, influenced by metacognitive beliefs, traps the individual in a vicious circle that further reinforces lower levels of self-esteem. Dysfunctional metacognitions and brooding could be risk factors for low self-esteem. However, protective factors could also play an important role in self-esteem. Resilience is understood as factors that buffer against negative effects of adverse life events . ResilieThere could be some degree of conceptual overlap  between self-esteem and the resilience factor “perception of self.” Resilience involves achieving relatively positive outcome despite experiences with adversity , whereasIt is plausible that self-esteem and perseverative thinking may affect how individuals regard their own future and plan accordingly. Research suggests that individuals reporting higher levels of resilience may have higher self-esteem than those who report lower levels and as such may be regarded as more vulnerable individuals . To summA total of 725 participants were included in the study. Participants were recruited through email lists for university students and social media. There were no set inclusion or exclusion criteria except voluntary participation. They responded to web-based questionnaires, and the survey program allowed no missing data. Participants were anonymous. Demographic information included sex , relationship status , and work status . The sample was predominantly female (81.4%), 25.8% were single, and 89.9% were students or employed. Mean age was 39.6  with ages ranging from 18 to 80 years.The self-report questionnaires used are listed below.Rosenberg Self-Esteem (RSE) Scale  is a widThe Patient Health Questionnaire Anxiety–Depression Scale PHQ-ADS;  was usedThe Metacognitions Questionnaire MCQ;  assessesThe Ruminative Response Scale RRS;  is a 22-The RSA  consistsThe survey program did not allow missing data. Bivariate correlations were used to explore the relationship between study variables. Then, a path analysis was conducted to investigate the role of metacognitive processes and resilience in explaining self-esteem. Three paths were prespecified for the path analysis. The first was based on metacognitive theory in which the generic model specifies “trigger −> metacognitions −> worry/rumination −> emotional disorder” . The secr = −0.46), followed by need to control thoughts (r = −0.39). The weakest correlation was with positive beliefs about worry (r = −0.21).A summary of the scores on the RSE, RSA, RRS, MCQ-30, GAD-7, PHQ-9, PHQ-ADS, and their correlations is displayed in 2(2) = 3.6, p < 0.166, SRMR = 0.0063, RMSEA.033, CFI = 0.999, TLI = 0.997, and explained 55% of the variance in self-esteem. All paths were significant (p < 0.001), whereas the symptoms −> self-esteem path had a p-value of 0.007. Five potential paths were described. The first path was as follows: symptoms −> metacognitions −> brooding −> self-esteem. The second path was as follows: symptoms −> resilience −> self-esteem. The third path was a direct path from symptoms to self-esteem. The fourth path was as follows: symptoms −> metacognitions −> brooding −> resilience −> self-esteem. The fifth and final path was as follows: symptoms −> brooding −> self-esteem. See We tested a model with metacognitions, symptoms of anxiety and depression, brooding, resilience (planned future and perception of self), and self-esteem. The fit of the proposed model was χA regression analysis was conducted to inspect the unique variance of the study variables in explaining self-esteem. All steps added significantly to the model. Demographic variables in the first step explained 4%, whereas symptoms of anxiety and depression on Step 2 added another 35%. Metacognitions, brooding, and resilience on the following steps added another 16%. In the final model, predictors that significantly predicted self-esteem were female sex, symptoms of anxiety and depression, brooding, and resilience. See In the present study, we aimed to explore the relation between symptoms of anxiety and depression, metacognitions, brooding, resilience, and self-esteem. Metacognitions correlated with brooding, which again correlated with self-esteem. These results indicate that self-esteem is associated with perseverative thinking and underscores the importance of metacognitions and rumination for the maintenance of low self-esteem. Clinically, this makes sense as engaging in thinking about one’s flaws and shortcomings and dwelling on comparisons with other persons are likely to lead to lower self-esteem. Furthermore, participants scoring high on resilience were found to be less prone to low self-esteem. This factor comprises the ability to have a positive outlook on the future, being goal oriented, having confidence in own problem-solving abilities, and having realistic expectations. In addition, pathological brooding seemed to interact with resilience.Theoretically, metacognitions maintain pathological brooding, which may contribute to reduced self-esteem. However, our results suggest that this association between maladaptive processes and strategies can be weakened by healthy goal-directed and future-oriented behavior and strategies that in turn can contribute to reducing negativistic mood and attitudes by leading to a more positive apprehension about future events. The results indicate that resilience is an important factor to adjust in a healthy way to negative thoughts and feelings about aspects of oneself e.g., . OverallOur study lends support to the S-REF model to explain the relation between metacognitive processes and self-esteem; metacognitive beliefs influence the degree of brooding, which again is associated with low self-esteem. The current findings dovetail nicely with recent metacognitive approaches to understanding self-esteem by The results of this study are potentially relevant for clinical interventions. Low self-esteem has previously been conceptualized based on the cognitive model proposed by Consequently, there are a limited number of controlled studies on psychological treatment for low-self-esteem, and existing treatments are largely based on cognitive therapy. A meta-analysis by Importantly, the results also demonstrate the importance of resilience factors. Resilience is not explicitly a part of the S-REF model , 1996; hA limitation of the study is its cross-sectional nature, which limits our ability to draw causal conclusions. Also, the convenience sampling procedure  for recruiting participants may have influenced the response rate and representativeness of the sample. Furthermore, although the path analysis achieved good fit, this is not necessarily indicative of a good theoretical model. The model was partly data-driven as indicated with the brooding −> resilience path, in which the opposite direction could be expected. Therefore, the data suggest that brooding could influence the perception of self and future plans. Future research should therefore explore the relationship between resilience and brooding using other designs. Because of the cross-sectional design, the study did not test possible mediation effects, which should be investigated in future research using longitudinal designs. Mediation concerns hypotheses about causal processes. Mediation tests with cross-sectional data imply that causal effects are instantaneous, which is problematic , and lonAnother potential limitation concerns the issue of shared method variance. One limitation relates to choice of measure for metacognitions. In the current study, we used the generic MCQ, which has shown stronger relationships with worry than rumination and depression. However, results could have been somewhat different if the Metacognitions About Self-Critical Rumination Questionnaire  had beenThe present study indicates that metacognitions, brooding, and resilience may have an effect on low self-esteem. Addressing these factors in treatment could be beneficial and should be explored in future studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Regional Committee for Medical and Health Research Ethics in Norway. The patients/participants provided their written informed consent to participate in this study.RH, OH, LK, TR, and SS were involved in study conceptualization and data collection. SS, AH, and OH analyzed the data. All authors contributed to the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 67-year-old female presented to the emergency department (ED) complaining of generalized abdominal pain, nausea, and vomiting. Point-of-care ultrasound (POCUS) demonstrated dilated bowel loops measuring up to 4.1 centimeters and localized free fluid, consistent with a small bowel obstruction (SBO). A nasogastric tube was placed without complications. The patient was admitted to the hospital and conservatively managed with an uncomplicated course.In elderly patients with abdominal pain, POCUS is an excellent initial imaging modality to assist emergency physicians in rapid and accurate diagnosis of a variety of pathologies to expedite management. Point-of-care ultrasound can be used to rule out and evaluate for conditions encountered in emergency medicine, including acute cholecystitis, renal colic, abdominal aortic aneurysm, and intraperitoneal free fluid. As demonstrated in our case presentation, POCUS had an integral role in the early diagnosis and management of a SBO. A 67-year-old female with a history of hypertension, diabetes, and exploratory laparotomy presented with abdominal pain for one day associated with nausea, nonbloody-nonbilious emesis, and normal bowel movements. Abdominal exam revealed a soft, nondistended abdomen with a laparotomy scar and both periumbilical and right lower quadrant tenderness. Point-of-care ultrasound of the abdomen was performed with no acute abnormalities of the gallbladder or kidneys. The “lawn mower” method, scanning systematically across all abdominal quadrants in a horizontal or vertical fashion, demonstrated dilated, small bowel loops containing air and fluid measuring up to 4.1 centimeters (cm)  with locSmall bowel obstruction (SBO) is a common emergency department diagnosis estimated to comprise 2% of all patients with abdominal pain, resulting in 300,000 hospitalizations per year with etiologies including adhesions, neoplasms, hernias, and Crohn’s disease.What do we already know about this clinical entity?Small bowel obstruction (SBO) is a common presenting diagnosis in the Emergency Department (ED) that requires prompt evaluation and intervention.What is the major impact of the image(s)?Point-of-care ultrasound (POCUS) has emerged as a useful, rapid and noninvasive screening tool in the early diagnosis and management of SBO in the EDHow might this improve emergency medicine practice?Early diagnosis of SBO in the ED allows for improved patient care by initiating the appropriate intervention as well as surgical evaluation.Video.Point-of-care ultrasound demonstrating “to-and-fro” swirling of bowel intraluminal contents signifying abnormal peristalsis consistent with small bowel obstruction.


Vascular leiomyosarcoma is an extremely rare tumor and is associated with poor prognosis among leiomyosarcoma. Surgical resection remains the main treatment option. But outcome of definitive treatment with chemoradiotherapy in inoperable patients is not clear. Here, we report treatment and outcome of definitive chemoradiotherapy in a case of vascular leiomyosarcoma. A 64-year-old man with the initial presentation of pulsatile right neck mass was diagnosed with right carotid body leiomyosarcoma. He refused surgical intervention due to risk of carotid body injury and ischemic stroke. Successful tumor control was achieved with carboplatin-based concurrent chemoradiotherapy. Investigational liquid biopsy for circulating sarcoma cells was also performed to analyze drug sensitivity profile of this rare tumor. One year after treatment, the disease remained well controlled and there was no evidence of baroreflex failure or treatment-related late toxicities. To our best knowledge, this is the first case report of right carotid body leiomyosarcoma controlled with definitive concurrent chemoradiotherapy. The approach of personalized multi-modality treatment will be a focus of our future investigation. Sarcomas are a rare type of malignancy that account for less than 1% of all adult cancers. More than 80% of sarcomas originate from soft tissue, with the remaining, less than 20%, of them arising from bone. Soft tissue sarcomas are a heterogenous group of cancers that originate from the embryonic mesoderm and can originate in any part of the body. It usually originates in extremities but can sometimes occur in the trunk, retroperitoneum, or the head and neck region. The most common subtype of soft tissue sarcomas is liposarcoma, undifferentiated/unclassified soft tissue sarcoma, followed by leiomyosarcoma (LMS). LMS comprise 12% of all soft tissue sarcomas, which usually arise from the smooth muscle layers of uterus, gastrointestinal tract, intra-abdomen origin, retroperitoneum, and rarely the blood vessels .Despite a lack of high-level evidence, surgical resection is the mainstay of treatment for these patients. The role of chemotherapy and/or radiotherapy (RT) for vascular LMS remains inconclusive. Clinical descriptions are limited to single case report or case series for vascular LMS of the arterial origin. Due to its rare incidence and poor prognosis, personalized treatment is challenging to multidisciplinary tumor board (MDT). Here, we report our experience of treating one case with primary arterial LMS arising from the right carotid body. Disease control was achieved with carboplatin-based concurrent chemoradiotherapy (CCRT). Relevant literature review on peripheral arterial LMS is also provided.A 64-year-old male presented to the oncology department of our hospital with pulsatile right neck mass for one year. It was associated with dizziness and near-syncope. He was quite healthy without past medical history. On physical examination, a pulsatile mass about 2 cm was palpable over right submandibular region. Carotid bruit was not audible while auscultation and the mass were invisible upon oral cavity inspection. The absence of symptoms of hoarseness or dysphagia indicated no pressure on the larynx or pharynx. Vocal cord paralysis was also excluded after laryngoscopy examination. Magnetic resonance image (MRI) of the head and neck revealed a 2.6-centimeter soft tissue mass occupying the right carotid space and the right parapharyngeal space at the level of carotid bifurcation Figure 1He received biopsy of the carotid body tumor. Pathology reported a high grade leiomyosarcoma with non-limited positive margins. Immunohistochemically, tumor cells are positive for desmin, actin, and h-caldesmon and negative for ER, S-100, CD34, and beta-catenin. Therefore, a diagnosis of right carotid body leiomyosarcoma, high grade, stage IIB was made. After thorough discussion in MDT, platinum-based CCRT was recommended.via 6MV photons  followed by right carotid tumor boost (20 Gy in 10 Fx) was delivered  photons Figure 2In addition to routine clinical workup, an investigational liquid biopsy to analyze circulating sarcoma cells (CSC) was performed if salvage treatment indicated after CCRT. Peripheral venous blood sample was processed for mononuclear cell fraction and was cultured in a binary colloid crystal-coated microfluidic chip to allow clonal expansion. The outgrowth cellular organoids were observed after 4 weeks and cells were stained positive for vimentin and negative for CD45 or EpCAM Figure 5Management of soft tissue sarcoma is challenging to clinical physicians due to its rare incidence, heterogeneity of natural history, and unpredictable response to treatment owing to diverse histology. In addition, special considerations were needed for site-specific tumors. For adult localized disease, surgical resection with appropriate margins is the standard treatment of all adult sarcoma patients. Regional lymph node dissection is not routinely required because the risk of metastatic lymphadenopathies is quite low. However, surgical measure is not always practicable due to the limitations of critical anatomical structures such as major nerve and blood vessels. In addition, positive margins through microscopic examination or macroscopic residual disease imply high risk of local recurrence. Adjuvant treatment, including adjuvant RT, is mandated for microscopic or macroscopic diseases and is associated with improving local control rate from 56% to 74%  as compared with LMS of other origin (9.6 years and 7 years) . AnthracTo our best knowledge, this is the first case report of vascular LMS arising from the right carotid body. Owing to its complexity, the patient received multimodality treatment with carboplatin-based CCRT instead of radical surgery after comprehensive discussion in head and neck MDT. The disease remained controlled after one year of surveillance. The patient lives with preserved quality of life and is satisfied with excellent tumor control during this period. Moreover, investigational liquid biopsy with CSC and molecular and cellular analysis demonstrated potential for personalized drug sensitivity profiling. Although CCRT is associated with promising tumor control, it is not an evidence-based approach owing to the rare disease entity. Furthermore, there are no detailed neurophysiological examinations to clarify neurological function despite the absence of symptoms of baroreflex failure. In conclusion, definitive CCRT is well tolerated and achieved promising tumor control for this patient with right carotid body LMS. Further investigation will be necessary for treating inoperable peripheral arterial LMSs with definitive CCRT.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Office of Human Research, Taipei Medical University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.Conceived and designed the experiments: L-SL, J-FC, and L-LT. Analyzed the data: C-SL, J-RT, Y-TK, L-SL, Y-JC, TB, and P-YW. Contributed reagents/materials/analysis tools: L-SL, Y-JC, TB, and P-YW. Critical discussion and reading: J-FC and L-LT. Wrote the paper: C-SL, J-RT, L-SL, and L-LT. All authors contributed to the article and approved the submitted version.This project is supported by the National Health Research Institutes, Ministry of Science and Technology, and Taipei Medical University .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The development of the economy has increased the demand for anti-counterfeiting technologies, and with the traditional ones becoming known to the public, new and more effective ones are needed. In this study, a series of liquid crystal mixtures containing side-chain liquid crystal polymers and small-molecular-weight liquid crystals (LCs) were designed and prepared. The phase transition behavior and self-assembling structures of the LC mixtures were investigated by a combination of differential scanning calorimetry, polarized optical microscopy, and small-angle X-ray diffraction. The optical properties of the mixture film were characterized with a UV/VIS/IR spectrum study. The results reveal that the obtained film exhibited different optical modes between transparent, scattering, and selective reflection under finger-temperature control. Therefore, by the introduction of a coexisting thermal- or optical-polymer-dispersed network, a liquid crystal composite film with an integration of apparent optical switching modes and enhanced strength and toughness was successfully demonstrated. This research provides a versatile strategy for the design and preparation of liquid crystal anti-counterfeiting materials for practical use. In this study, a prototype finger-temperature-detecting anti-counterfeiting label was prepared, and its temperature-response property was demonstrated. Due to the fast development of the global economy during the last several decades, counterfeiting is creating more and more profit. Meanwhile, by utilizing continuously upgraded high-resolution scanners and printers, counterfeiters are manufacturing forgeries that are harder to distinguish, and they are stretching their diabolical claws to more profitable areas, such as bills and banknotes ,2,3. ThiFor decades, anti-counterfeiting technologies have been developed to fight counterfeiting, such as holograms , watermaLiquid crystal (LC), which exhibits excellent light-controllable characteristics and a fast response to external stimuli, such as light, electricity, magnets, temperature, and pressure, is regarded as one of the most promising anti-counterfeiting materials and has recently sparked enormous interest in scientists. K. Nakayama and J. Ohtsubo proposed an optical security device using the fingerprint texture in the N* phase, which has both the function of a fingerprint for authenticity and the function of storage for a designed pattern . The stoIn this paper, by the simple mixing of a cholesteric side-chain liquid crystal polymer (ChSCLCP), a smectic side-chain liquid crystal polymer (SmSCLCP), the nematic LC SLC1717, and the chiral dopant S811 with different proportions, a series of LC films with artificially adjustable phase transition behaviors were successfully prepared. Interestingly, the LC film can exhibit different optical modes between transparent, scattering, and selective reflection at finger temperature. Furthermore, by the introduction of a polymer-dispersed liquid crystal (PDLC) network based on urethane acrylate and isophorone diisocyanate/tetraethylene glycol, a LC composite film with an integration of apparent optical switching modes and enhanced strength and toughness was obtained. The resultant composite film is therefore a model system for anti-counterfeiting labels. We strongly believe that it could offer an innovative insight into the design and preparation of LC anti-counterfeiting materials for practical use.The LC materials used in this work are listed in g), LC phase transition, and the isotropic transition from a possible LC phase, were detected in each of the DSC curves for all of the samples during the first cooling and second heating processes. Both the Tg and the clearing point temperature (Ti) gradually increased with the increasing content of the ChSCLCP, while the mesogenic range was narrowed. Furthermore, it is worth noting that the phase transition temperatures of NB1GJ1 were all around finger temperature, which makes its use possible for interesting applications.The phase transition behaviors and phase structures of all the LC mixtures were examined by a combination of DSC, POM, and small-angle X-ray scattering (SAXS) measurements. As shown in To further confirm the phase transition behaviors and phase structures of all the samples, POM and SAXS techniques were utilized. The samples were filled into the cells, whose inner surfaces had been planar orientated, by capillary action in order to perform POM observation and were sandwiched between aluminum films for the SAXS experiment. By combining the results of the DSC, POM, and SAXS experiments, the self-assembly behaviors of the LC mixture NB1GJ1 can be concluded as follows: a simple smectic phase, a Ch phase, and an isotropic state. Similarly, the phase transition behaviors and phase structures of other LC mixtures were also investigated, and the phase transition temperatures could be artificially tuned by changing the content of the ChSCLCP.Due to the abundant LC phase structures with the tunable phase transition temperatures near room temperature, we speculated that there may be interesting optical properties under temperature stimulation. The LC mixture NB1GJ1 was filled into the cells by capillary action to prepare the LC film, and a variable temperature UV/VIS/IR spectrum study was conducted, as shown in According to the results described above, the LC mixture film of NB1GJ1 exhibited abundant optical modes under body-temperature regulation, which could be favorable for application in the intelligent anti-counterfeiting field. Thus, a LC composite film for practical anti-counterfeiting label use was prepared by introducing a coexisting polymer-dispersed network of a photo-polymerization network based on urethane acrylate and a thermal-polymerization network based on isophorone diisocyanate/tetraethylene glycol. Here the coexisting polymer-dispersed network played two roles: (1) the photo-polymer-dispersed network mainly increased the toughness while anchoring the planar texture of cholesteric LC and (2) the thermal-polymer-dispersed network further enhanced the peeling strength of the film. More importantly, the additional polymer-dispersed networks had no effect on the optical properties of the obtained composite film. Cr-N < –40.0 °C, TN-I = 91.8 °C) was purchased from Shijiazhuang Yongsheng Huatsing Liquid Crystal Co., Ltd. . Poly(3-mercaptopropylmethylsiloxane) , ethylparaben , cholesterol , 3-bromopropene , dimethylaminopyridine (DMAP) , N,N0-dicyclohexylcarbodiimide (DCC) , potassium hydroxide , S811 , and anhydrous potassium carbonate  were commercially available and used without any further purification. Toluene  was refluxed over sodium and distilled under nitrogen atmosphere. Azodiisobutyronitrile (AIBN)  was purified by recrystallization from ethanol. The other chemical reagents were used as received.The nematic LC SLC1717  using deuterated chloroform (CDCl3) or dimethylsulfoxide (DMSO) with tetramethylsilane (TMS) as the internal standard at room temperature. The FTIR spectra were recorded using a PerkinElmer spectrum 100 spectrophotometer . A PerkinElmer DSC8000  with a mechanical refrigerator was used to obtain the differential scanning calorimetry (DSC) results and the phase transitions of the polymers under dry nitrogen at a heating and a cooling rate of 20 °C min−1. The temperature and heat-flow scale were calibrated using zinc and indium as standard. Polarized optical microscopy (POM) was carried out on a Carl Zeiss Axio Vision SE64  polarized optical microscope with a Linkam LTS420 hot stage . Spectral characterization was done by an unpolarized UV/VIS/IR spectrophotometer  in transmission mode at normal incidence. The peeling-strength experiment was practiced on a universal tensile test machine .All The LC cells were manufactured with two glass substrates, and polyethylene terephthalate (PET) films of 20 μm thickness were used as cell spacers. To prepare the LC film samples, capillary action was used to fill the cells.A mixture of NB1GJ1 (prepared LC sample), urethane acrylate (photo-polymerizable monomer), isocyanate , a photoinitiator (Irgacure 651), and a thermal initiator (Dibutyltin Dilaurate) was prepared homogeneously in certain proportions. Then the mixture was used to fill between two layers of PET film with a thickness of 20 ± 1 μm controlled by a spacer. After this, the mixture was irradiated by a UV lamp  for 30 min to introduce the photo-polymer-dispersed network and then heated in an oven at 363.15 K for 7 h to introduce the thermal-polymer-dispersed network.In summary, based on the SCLCPs/small-molecular-weight LC mixtures and the coexisting polymer-dispersed networks, a finger-temperature-detecting LC composite film for anti-counterfeiting labels was prepared with the following advantages: easily observed multi-state switchable optical modes, responsive to finger touch; enhanced mechanical properties without the need for a substrate orientation process; and an artificial tunable response temperature. Experiments to further improve the mechanical performance of the composite films for practical application in the anti-counterfeiting field are under way.


N = 17), compared to an age and sex-matched group of healthy control (HC) children (N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC (p = 0.004) and anterior cerebellum / temporo-occipital cortex (p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing  and total  problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children.Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7–12 years) at familial high risk (FHR) for psychosis ( Schizophrenia spectrum disorders are widely considered to be disorders of brain development, even though their most characteristics symptoms do not appear until the first manifestation of psychosis, typically in adolescence or early adulthood , 2. The There are various theories as to why psychotic symptoms take so long to manifest when the underlying etiology is likely neurodevelopmental in nature. On such theory is the “two-hit” hypothesis, which posits that early genetic and environmental risk factors may disrupt certain aspects of brain development, but only to the extent that they render an individual vulnerable to a “second hit.” This second hit, such as exposure to trauma or substance abuse, would then be the catalyst for the actual manifestation of the illness . AnotherTo clarify the developmental trajectory leading up to the manifestation of psychosis, we need to understand the timing of brain and socio-cognitive abnormalities that have been observed in patients with established illness. One consistent finding in schizophrenia is that patients show disturbances in self-related processing, which have been attributed to abnormal processing of the default-mode network (DMN) and related structures –11. The To address this knowledge gap, we investigated a group of children between 7 and 12 years of age who are at Familial High Risk (FHR) for psychosis because they have a parent or sibling affected by psychotic illness. A data-driven analysis of resting-state functional MRI (fMRI) in this sample revealed abnormal functional connectivity of posterior superior temporal gyrus with a set of language and DMN-associated brain regions . In the Moreover, as FHR children show elevated levels of behavioral problems , 19, we A total of 37 children, ages 7–12 years, participated in this study. Our sample included 17 FHR children and 20 age/sex-matched healthy control (HC) children. Three children  showed chance-level performance on the behavioral task  and were therefore excluded from further analysis. The remaining 15 FHR had at least one first-degree relative affected by psychotic illness (see All HC and FHR participants were assessed for current psychiatric disorders using the SCID for Childhood Diagnoses (Kid-SCID) . ClinicaOverall IQ was estimated using subtests from all four domains of the Wechsler Intelligence Scale for Children-IV (WISC-IV) .Behavioral problems were assessed using the Child Behavior Checklist (CBCL) . The CBCDemographic, clinical, cognitive, and behavioral variables are summarized in To assess self-referential processing, participants performed a self-reference task during fMRI, in which they were presented with two lists of 24 adjectives, describing positive  and negative  traits. The lists were presented in six blocks of 4 words each, alternating between a semantic and a self-reference condition. The average number of letters and syllables per word was similar between valences and across the lists.In the semantic condition, participants were asked to determine for each presented word, whether it described a good or bad trait, using a two-alternative forced-choice button press (“good” or “bad”).In the self-reference condition, participants were asked to determine for each presented word whether it described them or not, using a two-alternative forced-choice button press (“me” or “not me”).Semantic performance, measured as the percentage of correct responses during the semantic condition, was assessed for each participant to gauge task engagement and performance. Three participants  were found to perform around chance-level, responding correctly to an average (sd) [range] of 58.3% (4.2%) [54.2–62.5%] of semantic stimuli, and were excluded from further analysis.For each participant, the percentage of semantically good and bad adjectives associated with “me” were computed as a measure of positive and negative self-appraisal, respectively.Semantic performance and positive and negative self-appraisal were compared between groups using Analysis of Variance (ANOVA) and assessed for correlations with clinical variables  in each group separately.3).MRI scans were acquired on a Siemens Magnetom Trio 3T scanner, using a commercially available 32-channel radio frequency brain array coil . A single-shot gradient-echo sequence was used to collect task functional MRI (task-fMRI) data . A 3-dimensional high-resolution T1-weighted structural scan was collected for anatomical localization   and inclpost-hoc testing. All analyses were performed on a whole-brain level. Results are reported with Z-statistic (Gaussianised T/F) images thresholded using clusters determined by Z > 3 and a (corrected) cluster significance threshold of p = 0.01  Version 6.00 . Brain ap = 0.01 , 35 aftepost-hoc analysis.Group-differences in brain activation during self-referential processing were assessed for correlations with clinical variables. To this end, signal intensity values from each participant's contrast parameter estimates for the significant clusters were extracted using Featquery  and assep = 0.13), possibly due to sample size. Approximately 40% of FHR had a DSM-diagnosis (mainly ADHD), while there were no DSM-diagnoses in the HC group . FHR showed more internalizing, externalizing, and total problems on CBCL . See Group-comparisons on demographic characteristics confirmed that the groups were well-matched for age and sex. Average IQ was almost nine points lower in FHR than HC, but this group-difference was not statistically significant  and lower negative self-appraisal   .Assessing main effects of task in each group revealed activation clusters in bilateral MPFC/ACC in HC and precuneus/PCC in FHR , Table 3The FHR > HC contrast yielded two clusters of hyperactivation in FHR. The largest cluster was localized in right precuneus/PCC. A second cluster was found in bilateral anterior cerebellum and inferior temporo-occipital cortex, including parahippocampal and lingual gyrus , Table 3N = 26, including 10 FHR and 16 HC), which confirmed increased activation in FHR vs. HC for both the precuneus/PCC (p = 0.003) and cerebellar (p = 0.019) cluster  and total  problems (p > 0.38).Activation in the precuneus/PCC cluster was associated with CBCL internalizing and total problems in FHR, such that higher activation was associated with increased internalizing , social problems , and withdrawn  subscales  hypoactivation and posterior DMN (precuneus/PCC) hyperactivation during self-related processing in (adult) patients with schizophrenia , 40, 41 hypoactivation for a self-vs.-baseline contrast in schizophrenia patients  self-focus and aberrant activity in self-referential brain circuits , 47. CliThis finding is important as it offers opportunities for early intervention. Mindfulness meditation, for example, has been shown to reduce internalizing symptoms, presumably by promoting a shift from narrative self-focus to present-centered experiential awareness . These To follow up on the observed association between precuneus/PCC activation and internalizing symptoms, we assessed potential correlations with emotion-regulation strategies. Two strategies that are measured with the ERQ were tested: expressive suppression and cognitive reappraisal. Expressive suppression is the process of inhibiting ongoing emotion-expressive behavior; e.g., holding back tears when feeling sad in public. In contrast, cognitive reappraisal is construing a potentially emotion-eliciting situation in a way that changes its emotional impact. For example, viewing a job interview as an opportunity to find out how well a job would fit their person and vice versa, rather than as a test of one's worth. Out of the two, reappraisal has been found to have a more positive influence on affect, relationships, and well-being, and is viewed as the more adaptive emotion regulation strategy , 56. IntIn addition to the precuneus/PCC cluster, FHR children also showed hyperactivation of a cluster encompassing anterior cerebellum and parahippocampal gyrus. High-risk studies have noted that hyperactivity , 59 and This study has a number of limitations to consider when interpreting the current results. The first and main limitation is our sample size, which may have reduced our ability to detect more subtle group-differences. Recruiting children in this age range who have a parent or sibling with a psychotic disorder is difficult, as patients affected by psychosis are less likely to have children  and consIn summary, the results of this study in a unique sample of FHR children between 7 and 12 years of age suggest that hyperactivity of posterior DMN during self-referential processing develops many years before the typical manifestation of psychosis in association with familial (possibly reflecting genetic) risk factors. Moreover, our study links aberrant self-referential processing to increased levels of internalizing problems and less frequent use of cognitive reappraisal for emotion regulation. These findings have implications for our understanding of the developmental timeline of DMN abnormalities in schizophrenia spectrum disorders and may inform strategies for early intervention: aiming to reduce internalizing problems by modulating DMN-related self-referential processing in the early premorbid stage.The data analyzed in this study is subject to the following licenses/restrictions: the raw data from this study is not publicly available because participants did not agree for their data to be shared publicly. De-identified processed data that support the findings of this study are available from the corresponding author, upon reasonable request. Requests to access these datasets should be directed to gcollin@mit.edu.This study involved human participants and was reviewed and approved by the Institutional Review Board (IRB) of Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, USA. Written informed consent to participate in this study was provided by the participants' parents/legal guardians and participants provided assent to participate in the study.LS, MK, JG, HT, and SW-G contributed to conception and design of the study, and the acquisition of funding. EM, RM-G, and HT contributed to data acquisition. LS, RM-G, and MK led clinical consensus meetings. GC and CB performed the statistical analysis. GC wrote the first draft of the manuscript. CB wrote sections of the manuscript. SA contributed to the cerebellar analyses. GC, CB, SA, MS, and SW-G contributed to data interpretation. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Klebsiella pneumoniae (KP) is the primary pathogen associated with pyogenic liver abscesses (PLAs). Moreover, there has been an increase in the proportion of extended-spectrum beta-lactamase (ESBL)-producing KP. However, the clinical and computed tomography (CT) features of liver abscesses caused by ESBL-producing KP have not been separately described. We aimed to compare the clinical and CT features present in patients with ESBL-producing and non-ESBL-producing KP as well as to determine the risk factors for ESBL-producing KP liver abscesses (KPLAs).We performed a retrospective analysis of data obtained from the medical records of patients with a first episode of KPLA admitted to Shengjing Hospital of China Medical University between May 2015 and May 2019. We compared the clinical and CT features between patients with ESBL-producing and non-ESBL-producing KPLA.p = 0.086). The ESBL-producing KPLA group had a greater proportion of patients with a history of biliary disease  and gastrointestinal malignancy . Multivariate regression analysis showed that a history of biliary disease was an independent risk factor for ESBL-producing KPLA. Compared with the non-ESBL-producing KPLA group, the ESBL-producing KPLA group had a significantly higher intensive care unit (ICU) admission rate . All ESBL-producing KP isolates were susceptible to carbapenems and amikacin. Only the presence of multiloculation on CT was found to be significantly different between the groups .We enrolled 100 patients with KPLA . There was no significant between-group difference in the proportion of patients with comorbid diabetes (71.43% vs. 66.2%, The presence of biliary disease was an independent risk factor for ESBL-producing KPLA. Patients with ESBL-producing KPLA had a higher ICU admission rate, with only half of patients having evidence of multiloculation on CT. Klebsiella pneumoniae (KP) is a key pathogen in nosocomial and community-acquired infections [fections –3. Moreofections –7. Severfections –11. One fections . The maifections –15. Bactfections , 16. In fections –19. On tfections . TherefoIn this study, we performed a retrospective analysis of data obtained from the medical records of patients with a first episode of KPLA. We aimed to compare the clinical and CT features of patients with ESBL-producing and non-ESBL-producing KPLA, and to determine the risk factors for ESBL-producing KPLA.We obtained the medical records of patients with a first episode of KPLA admitted to Shengjing Hospital of China Medical University between May 2015 and May 2019. This is a 6750-bed university hospital with 4.46 million outpatient and emergency visits annually. The Ethics Committee at Shengjing Hospital of China Medical University approved this retrospective study. The enrolment process of patients is shown in Fig. The inclusion criteria were as follows: (1) liver abscess symptoms, including fever, chills, and pain in the region of the liver; (2) abdominal CT examination showing liver abscess lesions; and (3) pus or blood bacterial culture indicating KP. The exclusion criteria were as follows: (1) recurrent liver abscess, defined as the presentation of recurrent typical clinical and imaging findings after complete treatment of the first PLA episode; (2) other concomitant bacterial infections, such as the simultaneous isolation of KP and other bacteria on blood or pus cultures; and (3) patients with incomplete or insufficient data.We collected the following patient information: age, sex, the underlying cause , clinical symptoms and signs , concurrent endophthalmitis, treatment methods, antibiotic resistance status, and whether the patient was transferred to the intensive care unit (ICU). A history of biliary disease included that of hepatolithiasis, choledocholithiasis, cholelithiasis, and other benign biliary diseases but not cholangiocarcinoma. A history of gastrointestinal malignancy included that of primary and recurrent gastrointestinal malignancies (including cholangiocarcinoma), regardless of whether the patient underwent the relevant surgery, radiotherapy, or chemotherapy.We only reviewed the contrast-enhanced CT images obtained before drainage of the liver abscess for the purpose of this study. The CT scanning equipment used, scope, and methods are consistent with our previous studies , 20. TwoAll strains were tested for drug sensitivity using the VITEK-compact automatic microbiological analysis system (France BioMérieux) and AST-N334 card. Minimum inhibitory concentration values of 20 representative antibiotics were detected using the micro-release method; these were amikacin, gentamicin, levofloxacin, ciprofloxacin, imipenem, meropenem, aztreonam, ampicillin, ampicillin/sulbactam, cefepime, cefuroxime, cefoxitin, cefazolin, ceftriaxone, ceftazidime, tetracycline, nitrofurantoin, chloramphenicol, cefmetazole, and trimethoprim/sulfamethoxazole. Analyses of drug sensitivity test results were performed using a drug sensitivity test interpretation system. Phenotypic confirmation of ESBL was performed using the double-disk diffusion method in our clinical microbiology laboratories, following Clinical and Laboratory Standards Institute guidelines .2 test or t test was used; if the data were non-normally distributed, the non-parametric test method was used. The underlying diseases related to the pathogenesis of the liver abscess that had statistical differences in the univariate analysis (P < 0.1) were analysed by multivariate logistic regression. P < 0.05 was considered statistically significant.SPSS software  was used for statistical data analysis. The measurement data are expressed as mean ± standard deviation (SD), and count data are expressed as the number of cases and percentages. For data with a normal distribution, the χp < 0.001) and gastrointestinal malignancies . Moreover, the ESBL-producing group had a higher ICU admission rate than the non-ESBL-producing KPLA group. Furthermore, there were no significant between-group differences in the main clinical symptoms, treatment methods, and 30-day mortality. Multivariate analysis revealed that a history of biliary disease was an independent risk factor for ESBL-producing KPLA (Table We enrolled 100 patients with KPLA (14 in the ESBL-producing group and 86 in the non-ESBL-producing group). All patients in the ESBL-producing group had a history of underlying disease and previous hospitalization, whereas 43 patients in the non-ESBL-producing group had no prior history of hospitalization, 19 of these 43 whom were previously healthy and had no underlying medical disease. As shown in Table LA Table . There wThe patients in this study were all treated with antibiotics. We treated them empirically with carbapenems and adjusted the antibiotic based on to the results of the drug sensitivity tests. The resistance rates for ampicillin were 100% for ESBL producing KP and 83.7% for non-ESBL-producing KP. No isolate of this study was resistant to carbapenems. Notably, all ESBL-producing KP and non-ESBL-producing KP were susceptible to amikacin. In general, the ESBL-producing KP showed higher resistance rates to most antibiotics than the non-ESBL-producing KP Table .Table 4P < 0.05). There was no between-group difference in the remaining CT features  are emerging globally, most of which exhibit antimicrobial susceptibility. In an analysis of KP strains in hospitalized patients, 33% were hvKP, of which about 17% expressed ESBL, and this data increased year by year [This study revealed an association between a history of biliary disease and gastrointestinal malignancies and ESBL-producing KPLA. Multivariate analysis indicated that a history of biliary disease was an independent risk factor for ESBL-producing KPLA, which is consistent with the findings of Shi et al. . Howeverhia coli , 27. A shia coli . It is w by year . Under p by year . Patient by year , 31, 32.Previous studies have reported that diabetes is an independent risk factor for KPLA –35. HoweContrast-enhanced CT is an effective method for the diagnosis of a PLA , 36. CT KPLA is often associated with extrahepatic metastatic infections, including endophthalmitis . These mAll ESBL-producing KP in the present study were susceptible to carbapenems and amikacin; this in in contrast to other studies that enrolled more patients with abdominal infection . PreviouWe found an association between ESBL-producing KPLA and a history of biliary disease and gastrointestinal malignancy. Moreover, a history of biliary disease is an independent risk factor for ESBL-producing KPLA. Patients with ESBL-producing KPLA had a higher ICU admission rate, with only half showing multiloculation on CT. Therefore, it should be noted that patients with a history of biliary disease or gastrointestinal malignancy who present with a PLA are likely to have an ESBL-producing KPLA, especially if CT findings are indicative of uniloculation. Future studies with larger sample sizes are needed to confirm our findings.