The National Institute of Health has mandated good clinical practice (GCP) training for all clinical research investigators and professionals. We developed a GCP game using the Kaizen-Education platform. The GCP Kaizen game was designed to help clinical research professionals immerse themselves into applying International Conference on Harmonization GCP (R2) guidelines in the clinical research setting through case-based questions.Students were invited to participate in the GCP Kaizen game as part of their 100% online academic Masters during the Spring 2019 semester. The structure of the game consisted of 75 original multiple choice and 25 repeated questions stemming from fictitious vignettes that were distributed across 10 weeks. Each question presented a teachable rationale after the answers were submitted. At the end of the game, a satisfaction survey was issued to collect player satisfaction data on the game platform, content, experience as well as perceptions of GCP learning and future GCP concept application.There were 71 total players who participated and answered at least one question. Of those, 53 (75%) answered all 100 questions. The game had a high Cronbach’s alpha, and item analyses provided information on question quality, thus assisting us in future quality edits before re-testing and wider dissemination.The GCP Kaizen game provides an alternative method for mandated GCP training using principles of gamification. It proved to be a reliable and an effective educational method with high player satisfaction. ICH E6 (R2)). In September 2016, National Institute of Health (NIH) determined that all NIH-funded investigators and staff involved in the conduct, oversight, or management of clinical trials must be trained in GCP, and this became an official NIH mandate in January 2017 (https://grants.nih.gov/grants/guide/notice-files/not-od-16-148.html). Most institutions, Institutional Review Boards (IRBs), and clinical trial sponsors have adopted this requirement as policy, regardless of funding source. In addition to federal laws and local institutional policies, ICH GCPs are key guidelines that sponsors, investigators, and clinical research staff should know and follow to ensure study safety, efficiency, and reliability. Notably, the Clinical Trials Transformation Initiative developed recommendations for GCP training practices, including an emphasis on exploring methods for case-study approaches to help learners incorporate application of GCP requirements in study activities [citiprogram.org), available through individual and institutional subscriptions.Good clinical practice guidelines (GCPs) are a broad set of recommendations and requirements that have been developed to assure the ethical conduct of research, increase the protection of human participants, and to ensure collection of credible, rigorous, and reproducible data. The International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has existed for 25 years, focusing global pharmaceutical regulatory harmonization in a centralized venue for best practices in medical product development and research. The harmonized guidelines are divided into four categories: Quality, Safety, Efficacy, and Multidisciplinary. Found within the Efficacy Guidelines, Section 6 (R2), the GCPs are internationally accepted guidelines describing responsibilities and best practices in accordance to the Declaration of Helsinki  and extrinsic motivators  –5.The purpose of this paper is to describe and evaluate GCP Kaizen, a GCP learning method utilizing internet-based gamification to supplement required GCP training. Developed by the Center for Clinical and Translational Science program at the University of Alabama at Birmingham (UAB), the Kaizen-Education software platform provides online game manager tools to develop multiple-choice questions and schedule those questions within games as well as mobile- and computer-based interfaces to play the games. The Kaizen-Education software platform is named after the Japanese concept of continuous incremental process improvement, a concept analogous to the higher education goal of creating lifelong learners. Several games have been developed using this system, including games aimed at reinforcing graduate medical education in internal medicine and otolaryngology ,7. The KWe created the GCP Kaizen game to provide a fun and applicable gamification approach to learning GCPs. This paper details the construction of the game and evaluation of the game quality using item analysis. We also report measures of player satisfaction and propose opportunities to improve future games based on player recommendations.A series of brief, fictitious vignettes followed by multiple-choice game questions formed the structure of the game. A total of 75 original and 25 repeat questions were included in the game to measure knowledge retention. The game was tested in two graduate clinical research courses offered at OSU during the Spring 2019 semester: one in its Masters of Clinical Research program and another in the Masters of Science in Clinical and Translational Pharmacology. This study project was determined exempt by OSU IRB. Case studies and associated questions were drafted by the course instructors (CJ and PJ) and reviewed by an external consultant (CR). Once questions and associated illustrations and rationales were completed, question content and reward parameters were uploaded to the Kaizen platform and scheduled for release. Table ® (Instructure) Course Announcements. At registration for game participation, players used their campus email address and were provided a standardized game password. They were instructed to create an alias, for privacy purposes. The invitation to participate in the game included prestudy links to associated GCP documents, and participants were advised to review the documents prior to answering the Kaizen questions. In addition to providing links to the ICH E6 (R2) GCPs, we also provided links to the Belmont Report [Players were provided a document titled “Welcome Overview and Informed Consent” for instructions and consent for participation in the game and a final game evaluation survey via emails from the study team and through OSU’s online Learning Management Platform, Canvast Report , Declarat Report , Title 2t Report , and a ht Report .Players were informed that game participation was voluntary and that data gathered from the game would not affect their academic course scores or class standing. The game was comprised of 100 total questions that were released on a schedule of 10 questions per week, for 10 weeks. We estimated that it would take players up to 20 minutes to answer 10 questions. Weekly email announcements were issued about the release of new questions and to remind players to participate. Additionally, the course calendar also included reminders to complete game questions. Another motivating strategy included reports about game progress, individual status, and team ranking, which were sent to players via the online course announcements/email mechanism. Players also had access to leaderboards when they signed onto the Kaizen-Education software platform to answer questions which displayed their individual and team rankings in real time.Since the ICH GCPs are “internationally accepted,” we designed an Olympic Games-inspired theme to provide in-game rewards. Teams were named by Country. Northern Hemisphere countries represented team names for one course and Southern Hemisphere countries represented teams for the second course. Players were assigned to teams by their instructors. Players from the two courses participated in the game.Reward badges and points were automatically issued to players based on predetermined participation and answer thresholds, and these data were used to populate the leaderboard. Level badges were issued at 20-point increments based on total points accrued. Hot Streak badges awarded for consecutive right answers were issued for at 15, 20, and 25 correct questions in a row.All player interactions with the Kaizen-Education software platform, including number of questions answered, responses, and timing of answers are captured by the software database. The data captured by the Kaizen-Education software platform were used to complete the analyses below.To access question difficulty, the proportion of students answering correctly was calculated per question for the 75 original questions . To measPoint biserial correlations range from −1 to 1. A correct interpretation of point biserial correlation is that it compares the average total score from the game for all players who answered that specific question correctly to the average total score from the game for all players who answered that specific question incorrectly. To avoid overestimation of the point biserial correlation, it is common to adjust the total scores by removing the points earned from the question under investigation. A positive point biserial correlation indicates the highest scoring players answered the question correctly while the lowest scoring players answered the question incorrectly . TherefoMcNemar’s test was used to compare the paired proportions for the 25 repeated questions to determine if re-exposure to the questions might indicate students who missed the question previously remembered/learned the material and answered correctly, while those who answered correctly the first time maintained the knowledge.xm survey software. The survey asked players about their satisfaction with their experience, including the Kaizen platform, course content and materials, time commitment, as well as perceptions of GCP learning and application. The survey was distributed to all players via course announcement and email a week after the final set of questions was issued. Reminders were sent weekly for 3 weeks.We issued a postcourse evaluation using QualtricsAll analyses were conducted using SAS 9.4 . Player participation and percentage of questions answered were calculated.n = 63, 89%) had previously acquired GCP Certificates from CITI. Additional descriptive data are provided in Table A total of 71 players participated and answered at least one question. Of those, 53 (75%) answered all 100 questions . A total of 55 (77%) answered all of the 75 original questions. Most players (n = 55), the percentage of correct answers ranged from 3.6 to 100 (median 83.5). Point biserial correlation  ranged from a high of 0.61  to a low of −0.42 (the first question asked in module ICH 4: Investigator Responsibilities). The median point biserial correlation for the 75 questions is 0.16 with 83% of all questions either having a point biserial correlation of 0 or greater. The percentage of questions with a point biserial correlation within specified ranges is summarized in Fig. Cronbach’s alpha for the 75 original questions indicated a reliability of 0.74. Across the 75 original questions  responded to the survey. Unanimously (100%), respondents felt that 10 Kaizen questions per week were reasonable and were somewhat satisfied 23%) or very satisfied (68%) with the ease of use of the GCP Kaizen questions. Most (89%) stated that they viewed the leaderboard as a player and team member. In terms of overall satisfaction with the GCP Kaizen game, 34% were somewhat satisfied and 55% were very satisfied. When asked if the GCP Kaizen game improved their knowledge of GCP applications, most strongly agreed .I liked that you instantly got answers to questions that were correct.One player completed the internationally recognized Association of Clinical Research Professional (ACRP) Clinical Research Coordinator Certification exam toward the end of the semester and liked that the game provided her with a sound GCP review and contributed to her passing the exam.I felt like this was a great review of the ICH guidelines and definitely helped me to pass my CCRC certification. I am almost hoping to go back and review the questions so I can help some of my colleagues’ review for the SoCRA CCRP exam as well, because it is great that the guideline number and explanation for each question result came with the answer.We also asked what they liked most about the competition features of the GCP Kaizen system. Responses affirmed the motivational aspect of individual and team competition.I liked seeing the leaderboard so I could see how I was doing relative to my teammates and how my team was doing relative to the entire class.Being able to compare scores made it so I wanted to answer more questions and learn more.We also solicited criticisms and asked for other general comments. Players reported that some of the questions were too long, they desired hyperlinked references in the rationales, they wanted more than 10 questions per week, and they wanted the ability to move forward on their own timeframe .I am the type of person who would do more than 10 questions at a time, so having a limit isn’t necessary,Sometimes the wording of the questions was a bit confusing.I wish that there were links the GCP for a reference to the question.One player did not like that some questions were repeated. Another player felt that the questions were too “site focused” suggesting that we modify some questions to include other perspectives, such as sponsors and monitor perspectives.The questions repeated or were very similar. I think that more diverse questions would have helped me learn GCP better.Several players suggested improved clarity in some of the questions. Finally, some felt that there was a lag in the question loading, though wondered if it was possibly related to their browser speed.The system moves pretty slow and there is a decent lag time between pressing “go” and “next” between questions.There was a bit of a lag in the system, but that could have very well been in my browser.The requirement for documentation of GCP training has been a well-established standard to ensure improved quality, safety, and compliance in clinical research. With the revision of the ICH guidelines to include E6 R2 (Step 4), including the emphasis on risk-based approaches for study development, monitoring, and quality improvement, continued calls for GCP training have been issued, especially to address the needs in Social and Behavioral clinical research and in workforce development –19. We hThe traditional training on GCPs has primarily focused on ICH E6 (R2), for example, “GCP Guidelines.” It has been argued that training should go beyond ICH GCP and include statistical concepts  for improvement in trial performance . In the Feedback from players indicated that the GCP Kaizen game provided a welcomed and important review of concepts and increased their knowledge of GCP regardless of experience and prior certification. We dedicated considerable content on investigator and sponsor responsibilities compared to the other topics. An understanding of sponsor roles is important for study operations, but especially when the investigators have sponsor responsibilities . Despite having previous GCP training, participation in the GCP Kaizen game offered important and applicable remediation.In studying the quality, reliability, and satisfaction of the GCP Kaizen game, we identified a number of limitations. GCP Kaizen participation was voluntary in the two courses and some players taking a higher course load or for other reasons opted to not participate fully. This fact could have created a selection bias that affected our item analysis results. Moreover, most, but not all, of the players had prior GCP training which may have impacted our item analysis evaluation. It may be interesting to test knowledge acquisition in clinical research novices exclusively. It may be valuable for a future offering of the GCP Kaizen game to correlate game performance to years of experience and prior GCP training, by including those descriptors in initial game items.https://clic-ctsa.org/diamond).A GCP Kaizen Phase II project is underway to review and edit test items based on point biserial scores. We included a cohort of higher scoring volunteer players in the revision process. We are re-running the revised new test in an Autumn 2019 online course to test question revisions using item analyses. Data on player levels of experience will be collected to compare results of novices verses experienced players. We plan to have the GCP Kaizen game available in a new Kaizen-Education mobile application by 2020 with information about access through the NCATS-funded Diamond Portal (The GCP Kaizen game was developed and tested to meet a need to provide an alternative approach for mandated GCP training using principles of gamification. The Kaizen Education software platform was a reliable and effective mechanism for game delivery with high player satisfaction. GCP Kaizen contributed to new learning, even among participants who had previous GCP training certificates. Finalized versions of the game will offer an excellent supplement to GCP learning and application in academic and training settings. Future games could be produced to offer new case-based scenarios, expand the variety of perspectives and roles, and to expose learners to additional ICH content.


In addition, the GRM-based interface between electrode and dielectric can have an effect on atomic diffusion limitation in dielectric and surface effect suppression. Immense amounts of concrete research indicate that GRMs might play a significant role in promoting the large-scale commercialization possibility of RRAM devices.Resistive random access memory (RRAM), which is considered as one of the most promising next-generation non-volatile memory (NVM) devices and a representative of memristor technologies, demonstrated great potential in acting as an artificial synapse in the industry of neuromorphic systems and artificial intelligence (AI), due its advantages such as fast operation speed, low power consumption, and high device density. Graphene and related materials (GRMs), especially graphene oxide (GO), acting as active materials for RRAM devices, are considered as a promising alternative to other materials including metal oxides and perovskite materials. Herein, an overview of GRM-based RRAM devices is provided, with discussion about the properties of GRMs, main operation mechanisms for resistive switching (RS) behavior, figure of merit (FoM) summary, and prospect extension of GRM-based RRAM devices. With excellent physical and chemical advantages like intrinsic Young’s modulus (1.0 TPa), good tensile strength (130 GPa), excellent carrier mobility (2.0 × 10 With the popularization of information technologies, digital problems with increasing amounts of data are receiving considerable attention in the industry. Until 2020, the digital world is expected to be over 40 zettabytes  with continuous expansion . The rapx, TiOx, TaOx, and NiOx) [2 and WS2) [Currently, with the rapid development of solid-state devices and their excellent combination with emerging NVM technologies, impressive achievements of emerging NVM devices such as FeRAM, PCM, MRAM, RRAM, and STT-RAM were made due to the continuous improvement of fabrication processes, as well as through the performance of enhanced devices stimulated by the application of new materials at the nanoscale ,13,14,15nd NiOx) ,17,18,19nd NiOx) , chalcogand WS2) ,22, orgaand WS2) ,24, and and WS2) ,26,27. Iand WS2) ,29. In tThe aim of this work is to provide a comprehensive overview of the state of the most significant advancements of graphene-based memristive devices. A brief introduction of the basic properties and synthesis methodologies of graphene-based materials (mainly graphene and GO) is presented in 5 cm2∙V−1∙s−1) [−1∙K−1) and electrical conductivity (1.0 × 106 S∙m−1) [During the fabrication and operation processes of electronic devices, the inherent properties of available materials receive paramount attention ,32. As oV−1∙s−1) , and hig6 S∙m−1) ,37 make 6 S∙m−1) ,39, sens6 S∙m−1) ,41, ener6 S∙m−1) ,43, and 6 S∙m−1) . 3 on/off ratio [Apart from the properties of graphene and cost consideration, memory devices developed with high-quality materials, a sophisticated nano-fabrication process, and sufficient prediction may demonstrate enhanced performance. However, in practice, a tradeoff among device performance, nano-scale fabrication process, and suitable cost is necessary, which indicates that it is essential to investigate novel memories that are adaptable to modern electronics. As the most representative category among 2D materials, graphene and related materials (GRMs) are expected to promising materials for the development of modern NVM devices due to their intriguing physical and chemical properties. For instance, the high mobility of graphene may contribute to faster operation speeds and lower operation times for NVM devices; the atomically thick structure of graphene can be helpful to realize the compact integration density of single devices; the solution-processable compatibility of graphene improves the successful probability of flexible memory devices with lower cost and a simpler fabrication method. Based on these considerations, GRM application for NVM devices with properties of higher density, faster operation speed, and lower energy consumption is receiving increasing interest. Hong et al. demonstrated a silicon (Si)-based flash memory device with graphene as a floating gate, which presented a wide operation window and low cell-to-cell interference with low operation voltage . Qi and ff ratio . These r2-based composites, which presented excellent performance in the application of memristive devices, similar to that using graphene-based materials [It is over 10 years since Geim and Novoselov firstly found a way to fabricate graphite thin flakes, and several processes for the synthesis of graphene-based materials are mainly investigated using thin films. In general, it is easy to complete the deposition of a graphene monolayer onto a metal substrate, and the progress of this approach demonstrates the great potential of large-area single crystals ,46,47,48aterials .−1, and hole mobility of 233 cm2∙V−1∙s−1 for a single sheet [As typical conventional deposition methods, CVD and ALD are not only used to grow graphene, as well as multicomponent heterostructures of II–VI, III–V, and oxide materials, but they are also applied to the production of large-scale hexagonal boron nitride (h-BN) and two-dimensional transition metal dichalcogenides (2D-TMD) ,60. Currle sheet ,76,77,78In order to produce memory devices with smaller cell size, faster operation speed, lower power consumption, and lower fabrication cost, an FoM assessment of memory devices is always the priority ,80. AparThe random-access time of a single-memory cell and the effective time of write/erase operation performance (latency) are used to determine the operation speed of memory devices. For now, high-performance volatile memory devices, such as SRAM and DRAM, are commonly used in processors, which perform short latencies (<100 ns), but are more expensive and occupy larger chip areas as compared to silicon flash memories ,82. AlthWrite endurance and data retention properties are considered as main characteristics of NVM device reliability. Write endurance is the quantized behavior of the anti-fatigue-degradation characteristic of a single NVM device, which is determined as the highest number of write/erase cycles that can be operated before the NVM cell fails to be reliable. The endurance also demonstrates the number of sustained cycles of the device before reaching the breakdown state ,85. DataDevice power consumption is made up of static power dissipation and dynamic power consumption. Static power dissipation mainly results from the aging process of storage hardware, and the main source of dynamic power consumption is memory data transition ,91,92,932 (F is the technology feature size). For now, the novel program of a semiconductor product with over 64 stacking layers of memory was realized on one microchip, which presents a high bit density of 0.5 GB/mm2 [In order to achieve a memory device with excellent performance, the scalability of the memory cell is receiving more and more attention due to the increasing density of memory devices, which indicates that the memory cell must be scaled. Apart from processing problems introduced by device scaling, another limitation factor, i.e., cross-talk between neighboring cells, cannot be neglected ,96. Typi5 GB/mm2 ,98, whicIn order to determine the commercial feasibility of a product program, during the manufacture of one memory chip with NVM technology, the cost of related materials, the fabrication process, and the integrated system should receive enough consideration. With the development of future semiconductors in the industry, the acceptable cost of a memory device will depend on target applications in terms of embedded hardware design, low-power-consumption environment, high speed, and high capacitor demand ,100. As one of the most promising non-volatile memory devices, the memristor demonstrates great potential in terms of enhanced reliability, fast operation speed, lower power consumption, and lower market cost, which can be observed in ν), current (i), magnetic flux (φ), and charge (q) [ν and i, the capacitor is the connection between ν and q, and the inductor links φ and i. Therefore, in general, the memristor can be used to define the connection between φ and q. To be more precise, the definition of a memristor is related to not only the flux as a magnetic magnitude but also the mathematical magnitude corresponding to the time-integral of the voltage across the device [Chua proposed the existence of another two-terminal component in the circuit, in addition to the resistor, capacitor, and inductor, which operated on the basis of a relationship among voltage (arge (q) . The rese device ,104,106.x, AlOx, and NiOx) [3NH3PbI3 and CsPbBr3) [With the development of memristor research for about half a century, RRAM devices received considerable attention as the most typical memristor. Apart from research on device performance, recent research was directed toward the study of materials with resistive switching (RS) function, such as binary transition metal oxides (TiOnd NiOx) ,110,111,CsPbBr3) ,55,112, CsPbBr3) , biologiCsPbBr3) ,115, andCsPbBr3) ,116. SET and VRESET. In general, two different switching types are defined as unipolar and bipolar [RRAM devices fabricated with a typical MIM  sandwich structure are electrically characterized with two different resistance states, which are generally referred to as the high-resistance state (HRS) and low-resistance state (LRS). The high-resistance value of the device shows the low-conductance state, while the device demonstrates the high-conductance state with the low-resistance value. The on/off ratio is determined by the ratio between HRS and LRS. With the applied voltage bias, the set operation is defined from HRS to LRS, and the reset operation is the transition from LRS to HRS. Stop voltages of the set and reset process are defined as V bipolar ,110,111,− and H+ absorbed on the SiO2/Si substrate induced a chemical modification in the crystal structure of graphene. Bruck et al. reported a graphene-dielectric-layer-based RRAM device with an on/off ratio of ~100 and switching time of ~100 us in 2008, as illustrated in 7) and faster switching speed (~1 us) [In general, graphene and its derivatives are investigated as resistive switching (RS) and electrode materials in RRAM devices. Exfoliated graphene sheets with RS performance in a field-effect transistor (FET) were reported by Tsang and Delgado-Notario et al. ,118,119. (~1 us) . GO can  (~1 us) ,122,123. (~1 us) ,127,128.3 at ~1 V operation voltage and rewritable memory performance with stable resistance states for more than 108 s [3. The write and read cycles could be repeatedly performed in excess of 1000 cycles, and the data sustainment time was beyond 104 s [3, and retention time sustained over 700 s [In addition, various groups investigated graphene-based composite materials, such as combinations of GO/rGO (reduced GO) with polymers, small molecules, and metal nanoparticles (NPs). An Al/TPAPAM-GO/ITO device was proposed by Zhuang et al. . An arylan 108 s . Jin et an 108 s  reportednd 104 s . Cui et nd 104 s  proposeder 700 s . In geneM) of TE and BE [M of Pt is ~5.65 eV, while the фM of Au, Ti, Ag, and Cu is ~5.1 eV, ~4.33 eV, ~4.26 eV, and ~4.65 eV, respectively. The existence of a work function difference (ΔфM) between TE and BE, namely, an asymmetric work function between active and inert electrode, results in the appearance of RS performance in these GO-based RRAM devices [M of ITO is ~4.9 eV, which is very close to the фM of metal Au. Therefore, no effective RS performance can be observed in Au/GO/ITO structure devices [M between Al and Pt is higher than 1.0 eV, successful RS behavior cannot be observed in Al/GO/Pt RRAM devices. However, as illustrated in M exhibit enhanced RS performance. Compared with metals like Au, Ag, and Cu, local oxidation is more likely to occur on Al electrodes at the interface, which might be a decisive influence factor explaining its unique performance [For RRAM devices with a GO-based MIM structure, the choice of top electrode (TE) and bottom electrode (BE) materials always receives the most attention. E and BE ,121,131. devices ,131,132. devices ,133. It formance , the worApart from the choice of TE and BE, other features like surface roughness and obtained thickness of the GO dielectric layer cannot be neglected, as illustrated in Several studies reported that the main reason for RS performance in dielectric layers based on graphene and its derivatives, especially GO layers, is the diffusion of oxygen ions or vacancies ,138,139.x layer acts as an insulating layer and influences the HRS. With the applied negative voltage bias, electrical-field-induced oxygen ions diffuse into the GO layer, which forms local conductive filaments (CFs), resulting in the device switching into the LRS. However, ohmic conduction did not occur at the LRS due to the GO film transforming into an sp3-bonded state without CFs [In 2010, as one of the first examples focused on the oxygen ion-based switching mechanism of graphene-based memory devices, Kim et al. proposed Al/GO/Al crossbar memory on flexible substrate . As illuhout CFs .sp3 hybridization layer between Al and the structure-modified GO layers at the HRS. When a negative voltage bias is applied onto the TE Al layer, the reverse diffusion of oxygen ions leads to LRS CFs near the contact interface under the effect of a negative electrical field [One year later, Panin et al. also reported a device with an Al/GO/Al structure, which presented the importance of local resistance state induced by the contact of Al and GO layers . With thal field . According to a report from Wang et al. , the difApart from the switching mechanism based on oxygen ion diffusion, a metal filament-based mechanism was also used to explain the RS behavior of graphene-based RRAM devices, which mainly depends on electrode materials ,146,147.sp2 cluster density in the switching layer. A simulation program with integrated circuit emphasis (SPICE) model incorporating the proposed compact model was developed for parameter calibration. Firstly, they provided the transport mechanism in GO-RRAM based on hybridization state modulation, as illustrated in sp3 matrix isolates these graphene-like clusters, which introduces a high tunneling barrier and substantially limits the electron tunneling probability between the sp2 clusters. The initial resistance of GO-RRAM is determined by the sp2 clusters. The increasing sp2 density induced by oxygen functional group reduction results in hopping paths for the electron, which completes the set operation (HRS to LRS) [sp2 clusters are hybridized into sp3 bonding, which reduces the sp2 density and switches the device back into the HRS. Acting like intermediate traps, sp2 clusters support continuous electron flow, which can be explored via a multi-phonon trap-assisted tunneling (MTAT) mechanism [In addition to the two main switching mechanisms discussed above, a mechanism affected by GO-based bulk was also investigated. It is worth mentioning that Wah et al. presented a compact model of hybridization state modulation for GO-RRAM, which is one of the most effective explanations for the bulk mechanism ,149,150. to LRS) . Conversechanism . Figure echanism ,151. A sechanism , whose w2/Pt RRAM device with an SLG interlayer [2 layer was fabricated by ALD, and the SLG layer was transferred onto the RS layer with oxygen plasma etching. The inserted SLG layer increased the resistance value at LRS (>1 MΩ) of the HfO2-based RRAM device due to its high out-of-plane resistance, which reduced the reset current 22-fold while decreasing the programming power consumption 47-fold. With the measurement results from Raman mapping illustrated in In addition, some other research teams aimed at an investigation of the contacting relationship between the GRM layer and electrode layer or other RS layers, mainly related to single-layer graphene (SLG) or multi-layer graphene (MLG) interlayers applied in RRAM devices with metal–oxide (M–O) thin films ,155,156.terlayer . The HfOAs one of most representative and competitive graphene-based materials, GO received considerable attention in the industry of large-area flexible electronic devices due to its promising potential for next-generation information storage ,162,163.According to the statistical results from 4 s, and the endurance cycles were more than 110. In addition, with the pulse behavior measurement, they also found that the resistance state switching from LRS to HRS could appear with a 100-ns pulse width, while the switching process from HRS to LRS could only be achieved with a 100-μs pulse width [Wang et al. reported a GO-RRAM device with the structure of Al/GO/ITO/PET, as illustrated in se width . 4 solution were homogenized into the PVA solution. With a series of chemical treatments, the hybrid thin film was spin-coated onto the ITO/PET substrate. The fabricated device demonstrated a bipolar RS performance with ~1-V operation voltage in the SET process and a ~103 on/off ratio. The resistance distribution result indicated that the device exhibited better performance when the resistance state switched to LRS [Another RRAM device based on an Al/rGO/ITO/flexible substrate with a combination of Au nanoparticles (Au NPs) and polyvinyl alcohol (PVA) was reported by Midya et al. The Au/rGO/PVA dielectric layer was fabricated with a solution-processed method. In this work, in order to prevent Au NP coagulation, GO flakes fabricated via a modified Hummer’s method and HAuCld to LRS . 3), which indicated that the 30-nm-thick GO thin film might be an optimistic choice for their investigation. It is noted that the fabricated flexible GO memory device with 30 nm thickness demonstrated excellent RS performance with no degradation, even when the substrate was bent down to 4-mm radius 1000 times [Apart from Wang and Midya et al., Hong et al. also reported a GO-RRAM device with the same structure, which was a transparent Al/GO/ITO device with a flexible PET substrate. Different GO dielectric layers with three thicknesses  were also fabricated with a spin-coating process, and the device exhibited enhanced performance with a high on/off ratio, low set/reset voltage, and excellent data retention. With the statistical results of GO thickness dependence on fabricated devices, an RRAM device with a 30-nm GO layer exhibited the lowest operation voltage (~2 V) and the highest on/off ratio , and long data retention time (~2000 s). The formation and the rupture of CFs based on metal ion diffusion near the interface layer between TE and dielectric layer were used to interpret their achievements [Liu et al. illustrated their research on an Al/GO/Al/PET structure RRAM device on PET substrate with a spin-coated GO dielectric layer , which sevements ,133,163.2 and h-BN) was also investigated in recent years [2 and GO, they fabricated an RRAM device with a Ti/MoS2-GO/ITO/PET structure. Due to the doping of MoS2, the device worked with a lower operation voltage (~0.3 V). Their bending test results showed that almost no changes in LRS and HRS could be observed during 200 switching cycles, even with 300 bending cycles, which indicated the enhanced reproducibility of RRAM devices [Apart from GO materials, a mixture of graphene-based materials and 2D materials (like MoSnt years ,190,191.nt years , with vi devices . The ele devices . We briefly reviewed recent advances in graphene-based materials used in NVM devices. Reliable systems based on memristors will be a vital technological application in the future development of neuromorphic networks and the AI industry, which are presented with a combined form of RRAM hardware devices and neuromorphic algorithms. Different devices based on graphene-materials mentioned in the recent literature exhibited good switching performance such as low power consumption, enhanced retention and endurance properties, large on/off ratio, and good compatibility with flexible substrates. Despite the great potential of graphene-based materials applied in NVM demonstrated in related research, some limitations cannot be neglected. Firstly, GO as the derivative of graphene was used extensively in electronic device research. The occurrence and organization of oxygen functionalities, the intrinsic variability of the GO material chemical structure, and the random distribution of GO flakes during the fabrication and deposition process directly influence the switching behavior of devices. Secondly, many current synthesis technologies of graphene-based materials are not only mature in the commercial market but also limit the development of large-scale production with good uniformity. Thirdly, the reliability performance of devices, in terms of retention and endurance measurements, needs to be evaluated and improved more accurately in order to meet real application demands in commercial products. In addition, although related switching mechanisms were proposed in the recent literature, definitive evidence in their support remains to be provided.


Chemical vapor deposition of graphene on transition metals is the most favored method to get large scale homogenous graphene films to date. However, this method involves a very critical step of transferring as grown graphene to desired substrates. A sacrificial polymer film is used to provide mechanical and structural support to graphene, as it is detached from underlying metal substrate, but, the residue and cracks of the polymer film after the transfer process affects the properties of the graphene. Herein, a simple mixture of polystyrene and low weight plasticizing molecules is reported as a suitable candidate to be used as polymer support layer for transfer of graphene synthesized by chemical vapor deposition (CVD). This combination primarily improves the flexibility of the polystyrene to prevent cracking during the transfer process. In addition, the polymer removal solvent can easily penetrate between the softener molecules, so that the polymer film can be easily dissolved after transfer of graphene, thereby leaving no residue. This facile method can be used freely for the large-scale transfer of 2D materials. Aications  has beenications . Howeverications ,21,22,23ications ,25,26,27To remove the complications regarding the wet transfer of graphene altogether, recently, we reported the use of polystyrene assisted graphene transfer with the addition of plasticizer named 4, 4′-Di-iso-propylbiphenyl (DIPB) . PolystyIn this study, the effects of the length of plasticizer molecules mixed with polystyrene on the mechanical properties and flexibility were systematically tested and analyzed. It is intended to further develop previous published studies by applying to graphene transfer experiments. We have used polystyrene as base polymer for graphene transfer, due to the presence of multiple aromatic rings in polystyrene polymer chain, which can form strong π-π links with graphene layer for strong adhesion. Since polystyrene does not contain any active bonding links in its molecular structure, any unwanted and permanent bonding between the polymer and graphene can be avoided. Furthermore, polystyrene is readily soluble in wide array of organic solvents, leaving no residues after dissolution. Polystyrene has intrinsically amorphous structure and mechanical properties of polystyrene itself are not very suitable for graphene transfer, due to its rigid structure ,30. So, Polymer solutions for graphene transfer were prepared by dissolving polystyrene beads  in toluene solvent at 5 w.t%. 1-5 hexadiene, 1-7 octadiene and 1-9 decadiene  were used as plasticizers for polystyrene. Polystyrene to plasticizer ratio in the solution was varied from 100% pure polystyrene to 80/20 ratio of polystyrene with plasticizer. The solution was stirred at 500 rpm for 3 h and filtered to remove any undissolved residue from the solution. PMMA solution  was used for PMMA assisted graphene transfer.Graphene was grown on copper foil  after cleaning the foil by nickel etchant . Low pressure CVD method was used to make full coverage graphene, as reported before . Cleaned2/Si by wet transfer method [As prepared polymer solution was spin coated on top of graphene layer at 500 rpm for polystyrene based solutions and 3000 rpm for PMMA solution for 30 s and dried in oven at 70 °C in oven for 10 min. This graphene layer, sandwiched between metal substrate and polymer support layer, was transferred on 300 nm SiOr method  as shown-1, to detect any new bonding links between polystyrene and plasticizer materials. Mechanical properties are measured by nanoindentation test  at loading force from 0 to 30 µN. Surface morphology of transferred graphene was studied by optical microscope , high resolution scanning electron microscope , at accelerating voltage of 10.0 kV, at a working distance of 7.2 mm and atomic force microscope . Raman spectra and mapping data were measured by Raman spectroscopy  at 532 nm laser wavelength and 1 µm spot size. Four-probe station was used to measure sheet resistance of transferred graphene .Pure polystyrene and plasticized polystyrene films were investigated by FT-IR spectroscopy  at room temperature from 3500 to 500 cmThe first step in our work was to prepare and identify a plasticized polystyrene material and its chemical and mechanical properties. The introduction of short chain molecules i.e., 1-5 hexadiene, 1-7 octadiene and 1-9 decadiene in polystyrene polymer structure can provide the necessary mechanical flexibility and improve the hardness of thin polymer film required for graphene transfer . A thin We also tested different molecular weight of polystyrene polymer and the effect of molecular weight on mechanical properties of polymer support film . It was 2 and measuring the film hardness (MPa) and tip penetration depth against a fixed force (30 µN in our case). The main purpose of introducing plasticizer in polystyrene polymer is to increase the mechanical flexibility of the film, as pure polystyrene has an amorphous phase and high hardness value. These properties are studied by spin coating a thin film of polymer on SiO2 substrates, as described in the experimental section  used for polystyrene plasticization process significantly improved the transfer quality of graphene, and retained the intrinsic properties and structure of primarily single layer graphene.Lastly, the electrical properties of these graphene samples were compared by measuring the sheet resistance (average of 5 readings in Ω/sq) of as transferred graphene samples. The plasticized polystyrene however, resulted in much lower sheet resistance values compared to PMMA or polystyrene only, mainly due to the modified physical properties and flexibility of the polymer support layer. Lower sheet resistance values have been reported earlier for PMMA assisted graphene transfer, but that method required the additional process of the annealing of transferred samples, which added extra processing steps and costs .In this work, we present a comprehensive study of the effect of mechanical and chemical properties of the polymer support layer used for graphene transfer, along with a brand-new material combination using polystyrene and low molecular weight softeners . This work demonstrates that flexibility and chemical reactivity of polymers used for graphene transfer play equal role to achieve the best quality of CVD graphene, and will help to overcome the major hurdle of degradation of graphene during the transfer process to desired substrates. Plasticized polystyrene contributes to uniform graphene transfer without sacrificing mechanical and chemical properties of graphene film, as indicated by improved morphology and electrical properties, along with the removal of surface defects and chemical residues attributed to current graphene transfer techniques, like PMMA assisted transfer. This new material combination is expected to be easily scalable to large scale transfer application as well as the transfer of other 2D materials like TMDCs, hBN and black phosphorus.


Sarcoidosis has been associated with co-existing malignancies in several organs, including the breast and thyroid gland as well as lymphomas. However, the occurrence of sarcoidosis with cervical cancer is rare with only nine previous cases reported in the published literature. We present a case of pulmonary sarcoidosis imitating mediastinal lymph node metastases on the staging CT scan and positron emission tomography imaging. The presence of thoracic lymphadenopathy without any pelvic lymphadenopathy prompted histological confirmation of sarcoidosis on endobronchial ultrasound guided biopsy. Misdiagnosing pulmonary sarcoidosis as metastases would have precluded the patient from receiving the curative treatment and likely resulted in suboptimal outcomes. A 31-year-old female presented with a history of post-coital bleeding. She had never had a cervical smear or any other form of screening and did not have any significant past medical history. She had completed her family with two children, worked as a lorry loader and smoked occasionally. There was no shortness of breath, cough or any other respiratory symptoms. A thorough systemic inquiry did not reveal any other significant symptoms. On examination, there was a large fungating polyp on the cervix. Respiratory examination was within normal limits. There were no extra pulmonary manifestations of sarcoidosis.The patient underwent a punch biopsy which showed a moderately differentiated squamous cell carcinoma of the cervix. Routine blood tests including a full blood count, urea and electrolytes, liver function tests and C-reactive protein (CRP) were all within normal limits.1  avid mediastinal and right hilar lymphadenopathy and was therefore unhelpful in differentiating metastatic disease from the other differentials discussed below. Consequently, the patient underwent an endobronchial ultrasound (EBUS) guided biopsy of the mediastinal lymph nodes. Histopathological assessment of the EBUS biopsy showed high cellularity with numerous well-formed granulomas of epithelioid cells with several multinucleated giant cells and lymphocytic cuffs. There was focal necrosis of non-caseating type..In the absence of distant metastases, the patient was staged as FIGO IIB and underwent radical treatment with concurrent chemoradiotherapy with curative intent. The treatment involved external beam radiotherapy to the pelvis with concurrent Cisplatin followed by two fractions of brachytherapy to the cervix.MRI of the pelvis, 3 months after completion of chemoradiotherapy and brachytherapy, showed complete response with no residual tumour. CT scan of the chest revealed no significant changes to the pre-existing lymphadenopathy.5 However, in the UK, cervical cancer accounts for less than 1% of all cancer deaths amongst females and mortality rates have fallen by 74% since 1970’s,5 owing not only to the introduction of a screening programme, but also to the highly effective treatment options available today. The clinical management of cervical cancer is largely dependent on the stage of disease. Patients with FIGO stages I to III and even some with stage IVA disease are offered radical treatment options with curative intent whereas those with distant metastases (FIGO Stage IVB) are offered treatment with palliative intent.6 Thus, accurate radiological staging of cervical cancer, particularly in reporting distant metastases, is critical as it can often be the deciding factor between offering treatment with curative and palliative intent.Worldwide, cervical cancer is the fourth most common cancer amongst females and globally has a high mortality rate, with 90% of cervical cancer-related deaths occurring in low- and middle-income countries.In the case presented here, it was the unusual pattern of distribution of presumed lymph node spread which prompted further investigations into its aetiology. Had the possibility of a non-metastatic aetiology for the thoracic lymphadenopathy not been entertained, the patient would have been inaccurately staged as FIGO Stage IVB and consequently would not have been considered for treatment with curative intent. In a 31-year-old patient with no co-morbidities and good performance status, this would have very likely resulted in an unacceptably suboptimal clinical outcome.7 A previously published review identified 59 reported cases of cancer and co-existing sarcoidosis.7 The most common primary cancer was of breast origin (n = 12), followed by thyroid cancers (n = 8).7 The review identified only 1 case of cervical cancer co-existing with sarcoidosis.7,8 A literature search on PubMed database revealed further studies reporting co-existing sarcoidosis with cervical cancer, as summarised in Sarcoidosis, a multisystem, granulomatous, inflammatory disorder with unknown aetiology has been associated with an increased risk of developing malignancies in several organs, in particular lung, liver, gastric cancers as well as melanomas and lymphomas.13 As there is no definitive diagnostic test for sarcoidosis and it is often a diagnosis of exclusion, further tests are required to exclude other differentials such as tuberculosis, HIV and fungal infections.13 A definitive diagnosis of sarcoidosis requires clinical or radiological manifestations, exclusion of other differentials and histopathological confirmation of non-caseating granulomas.13 Differentiating sarcoidosis from other causes is difficult based on CT alone. Symmetry of hilar lymphadenopathy can be a helpful feature in sarcoidosis, differentiating it from lymphoma, TB and fungal infections.4 In patients with known malignancy PET-CT could be considered. Most of the studies reviewed in 8,10,11 FDG PET imaging is a commonly used modality in a variety of malignancies and often helps with accurate clinical staging of the disease.11 However, as both malignant lesions as well as inflammatory lesions such as sarcoidosis lesions engage in glucose consumption, they can both show FDG avidity and could be indistinguishable on PET imaging.11A thorough evaluation of suspected sarcoidosis warrants detailed history including occupational and environmental exposure as well as a full physical examination, focussing on the pulmonary as well as the extra pulmonary manifestations of sarcoidosis.Consider histopathological confirmation when there is diagnostic uncertainty on imaging, especially if the distribution of lymphadenopathy is not in keeping with the known pattern of lymph node spread for the primary malignancy.Hypermetabolic activity from sarcoidosis on PET imaging is often indistinguishable from malignancy. Misdiagnosing pulmonary sarcoidosis as metastatic disease is a potential pitfall and can result in the patient not receiving the curative treatment and lead to suboptimal outcomes.Despite the rare occurrence of co-existing sarcoidosis with cervical cancer, it is an important differential diagnosis to consider in cervical cancer patients with thoracic lymphadenopathy, especially in those who are otherwise suitable for curative treatment.


Sarcoidosis is a multisystem granulomatous disease, associated with significant morbidity and impaired quality of life. Treatment is aimed at recovering organ function, reducing symptom burden and improving quality of life. Because of the heterogeneity and variable disease course, a comprehensive, multidisciplinary approach to care is needed. Comprehensive care includes not only pharmacological interventions, but also supportive measures aimed at relieving symptoms and improving quality of life. The purpose of this review is to summarize the most recent knowledge regarding different aspects of care and propose a structured approach to sarcoidosis management. Sarcoidosis is a multisystem granulomatous disease of unknown cause, that can affect almost any organ. The past decade we have gained more insights in the dysregulation of the immune system, which is thought to play an important role in the etiology of sarcoidosis . PatientCurrent pharmacological treatment of sarcoidosis is usually immunosuppressive and directed at decreasing granulomatous inflammation . OverallThe aim of this review is to summarize the most recent knowledge regarding different aspects of care in sarcoidosis and propose the “ABCDE model for sarcoidosis”, which is an adaptation of the version in interstitial lung diseases (ILD) ,11.The importance of comprehensive care in sarcoidosis is generally acknowledged ,13. HereIn all sarcoidosis patients, organ involvement should be carefully assessed in the diagnostic process and during follow-up. The degree of organ damage and disease activity is often difficult to quantify, as no gold standards exist and symptoms are often non-specific ,14,15. Rn = 150) considered their general health moderately to severely impaired. Only 7% answered that their health problems had no influence on their social life [n = 755) were partially or totally unable to work due to their sarcoidosis, highlighting the considerable impact of sarcoidosis on daily life [n = 2318), 44% of respondents reported a large effect on household finances, and 31% had to quit their job after the diagnosis of sarcoidosis [Furthermore, organ involvement significantly varies for different ethnic groups. In individual patients, the number of involved organs may change over time and therefore diagnostic assessments have to be performed regularly, particularly if patients express new symptoms ,16. The ial life . Furtherily life . A Swediily life . In a USOverall, sarcoidosis patients have an impaired QoL compared with the healthy population . SeveralQoL can be defined as “an individual’s perception of their position in life” and is influenced by a person’s values, beliefs, culture, physical health, social and psychological state . Qol canOther factors with a potential negative impact on QoL should not be forgotten in the assessment of sarcoidosis patients. For example, medication for sarcoidosis may lead to debilitating side-effects, such as weight gain, diabetes, osteoporosis and psychological problems ,39,40. AAlthough it is increasingly acknowledged that patient perspectives are important for optimizing individually-tailored treatments ,27,42, lSeveral support measures to improve QoL for sarcoidosis patients have been suggested in the past years. Better information and education are vital to optimize care for sarcoidosis ,27,45,46Self-management support is one of the main pillars of the chronic care model, developed to improve care for patients with chronic conditions . Many asWhile activity tracking at home could possibly help to stimulate exercise ,53,54,55The majority of patients would like to have better access to psychological support ,27. In cSymptom relief is a major aspect of sarcoidosis management. Dyspnea is among the most common symptoms in sarcoidosis and is an important indication for treatment . DyspneaNon-organ manifestations or parasarcoidosis syndromes include symptoms as fatigue, depression, anxiety, pain, SFN, and cognitive impairment . As mostNext to fatigue, SFN-related related symptoms were reported by the vast majority of patients (86%) in a recent European survey . SFN is Other common non-organ manifestations of sarcoidosis are psychological problems. Previous studies reported anxiety in up to 33% of patients and depressive symptoms in up to 66% of patients ,83. In aCognitive problems, including memory loss, concentration difficulties and impaired short-term memory are reported by more than 50% of sarcoidosis patients ,81. At pComorbidities may also importantly impact QoL and are more prevalent in patients with sarcoidosis compared to the normal population ,86,87. ANot all patients with sarcoidosis require pharmacological treatment, as the majority will have spontaneous regression of the disease . TreatmePharmacological treatment of pulmonary sarcoidosis should be considered for patients with significant pulmonary symptoms and patients with an impaired or deteriorating lung function ,91. For The current guideline, dating from 1999, states that “the appropriate treatment has not been well-defined for all patients” . PresentThe most frequently used second-line treatment is the folic acid antagonist methotrexate . MethotrIn refractory sarcoidosis, TNF inhibitors can be prescribed as a third-line agent. Infliximab has been studied in randomized controlled trials and may have beneficial effects on both pulmonary and extra-pulmonary sarcoidosis in a subgroup of carefully selected patients ,102,103.Pulmonary physicians play an important role in the management of sarcoidosis patients, as the lungs are affected in up to 90% of patients. Nevertheless, a multidisciplinary team is needed to improve efficiency of care and outcomes for patients, as many organs can be affected and symptoms are wide-ranging ,107. WhiA comprehensive, multidisciplinary approach is essential to treat patients with such a heterogeneous disease as sarcoidosis. Besides aiming at disease modification with pharmacological interventions, patients should also be offered supportive comprehensive care aimed at relieving symptoms and optimizing QoL. Patients’ preferences should be guiding all treatment decisions. To allow for better evidence-based treatment in the future, more research into both pharmacological and non-pharmacological treatment options is highly needed.


Sarcoidosis is a multisystem granulomatous disease with nonspecific clinical manifestations that commonly affects the pulmonary system and other organs including the eyes, skin, liver, spleen, and lymph nodes. Sarcoidosis usually presents with persistent dry cough, eye and skin manifestations, weight loss, fatigue, night sweats, and erythema nodosum. Sarcoidosis is not influenced by sex or age, although it is more common in adults (< 50 years) of African-American or Scandinavians decent. Diagnosis can be difficult because of nonspecific symptoms and can only be verified following histopathological examination. Various factors, including infection, genetic predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are difficult; however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy, high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography has improved our ability to reliably diagnose this condition and accurately forecast its prognosis. This review discusses the causes and clinical features of sarcoidosis, and the improvements made in its prognosis, therapeutic management, and the recent discovery of potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation. Sarcoidosis is a systemic multisystem inflammatory disorder of unknown etiology characterized by the presence of non-caseating granulomas. The first case of sarcoidosis was reported in 1877 by Jonathan Hutchinson at the King’s College Hospital in London (United Kingdom) . Despite its long history, this disease remains enigmatic. Unidentified etiology and the multisystemic nature of the disease have made it more complex. Previous data suggested that at least 90% of sarcoidosis patients have manifestations in the lungs ,4. In adTo identify the studies included in this review, we performed an intensive search of the electronic databases, PubMed and MEDLINE, for relevant studies published between 1980 and the present using the following terms: sarcoidosis, pulmonary sarcoidosis, and extrapulmonary sarcoidosis. Bibliographies of all selected articles were reviewed, and we also included any relevant information from our personal files. More than 100 articles were extensively reviewed for the purpose of this review. The prevalence and incidence of sarcoidosis are not well known worldwide owing to the challenges associated with ascertaining the number of asymptomatic patients. Sarcoidosis affects individuals of all ages irrespective of race or ethnicity, with maximum incidence among people aged 20–39 years, and quite more prevalent in women, non-smokers, and in rural communities . In EuroThe exact cause of sarcoidosis is not known. Many researchers have hypothesized the role of genetic susceptibility, environmental factors, putative antigens, and autoimmunity in the development of this disease, but no single cause has been identified to date. Various studies suggest that genetic factors could play a crucial role in establishing the risk and clinical development of sarcoidosis . Eleven Genome wide association studies have demonstrated that several HLA and non-HLA alleles are associated with the development of this disease . HLA-DRBVarious environmental factors, including exposure to wood stoves, soil, tree pollen, inorganic particulates, insecticides, and nanoparticles, have been associated with an increased risk for developing sarcoidosis. In addition to these factors, some workers, such as those involved in hardware, gardening materials, building supplies, and metal work as well as ship servicemen in the navy, fire workers, and educators, are prone to sarcoidosis ,41,42. ILeptospira species, Mycoplasma species, herpes virus, retrovirus, Chlamydia pneumoniae, Borrelia burgdorferi [Pneumocystis jirovecii [Mycobacterium (M.tb) [Propionibacterium species [M.tb. DNA, from tissue specimens collected from sarcoidosis patients, with sequences specific to mycobacterial proteins, such as ESAT-6, Kat G, and SoD A, illustrate that Mycobacterium is the strongest candidate for infection-mediated sarcoidosis [In addition to all of the factors mentioned above, infectious agents such as mycobacteria, have been suggested to be associated with the development of sarcoidosis, because the production of granulomas is a key factor in the immune defense response against these agents. Studies have identified numerous microbial agents as a potential eliciting agents of the immune response in sarcoidosis including gdorferi , Pneumocirovecii , Mycobacm (M.tb) , and Pro species . Isolaticoidosis ,50,51. Icoidosis ,53. A fecoidosis ,55.Autoimmunity has not been studied as extensively but given the underlying pathological mechanism of sarcoidosis there is certainly potential for these conditions to play a contributing role in disease development. Although no disease-specific auto-antibodies have been observed, it has been shown that the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells possess an autoantigen that is recognized by the T-cell receptor (TCR) of the responding T-cells in sarcoidosis patients ,57. VimeAnother important aspect of autoimmunity is the imbalanced gut microbiome. Gianchecchi et al. reported the associations between the presence of microbiome dysbiosis and the development of autoimmune conditions . SarcoidMany etiological agents, including infectious microbes, as well as organic and inorganic compounds, contribute to the development of sarcoidosis. These antigens are first cleared by the immune system, but this is not infallible and some undegraded antigens may remain in the cells, which can initiate an immune feedback loop. In response to this feedback loop, the antigen-presenting cells (APCs), such as dendritic cells (DCs), alveolar macrophages (AMs), and alveolar epithelial cells, produce high levels of TNF-α, and secrete interleukins-12, -15, and -18, macrophage inflammatory protein-1 (MIP-1), monocyte chemoattractant protein-1 (MCP-1), and granulocyte macrophage colony-stimulating factor (GM-CSF) . These AActivated CD4+ T-cells can differentiate into two distinct subsets, namely, T helper 1 (Th1) and T helper 2 (Th2) cells, based on their cytokines profile. Th1 cells predominantly secrete interleukin-2 (IL-2) and interferon-gamma (IFN-γ), while IL-4 and IL-13 are the major secretions of Th2 cells. Resolution or maintenance of granuloma is determined by the proportion of Th1 and Th2 cells, respectively. Alveolar macrophages are activated in the Th2 milieu and stimulate fibroblast and collagen proliferation culminating in progressive fibrosis .Incapacitation of Tregs is also a key feature of granuloma maintenance. It is presumed that infiltrating Tregs fail to reduce the exaggerated inflammatory response, thereby contributing to granuloma persistence and integrity. Tregs also release transforming growth factor β (TGF-β) that may contribute to fibrosis and granuloma organization .Th17 and Th17.1 cells have only recently been linked to the pathogenesis of sarcoidosis . These cSarcoidosis is often diagnosed when aberrations are identified on a chest radiograph (up to 50% of patients) during a routine examination. Based on the presence of lung infiltration and/or lymphadenopathies on the radiograph, different stages of sarcoidosis have been described  Box 1)  Box 1) SThe multisystemic nature of sarcoidosis leads to organ specific manifestations . SymptomBox 1Radiographic TypeRadiographic Characteristics0No visible findingsIBilateral hilar lymphadenopathyIIBilateral hilar lymphadenopathy and parenchymal infiltrationIIIParenchymal infiltration without hilar adenopathy in regular chest radiographyIVAdvanced fibrosis with severe distortion of the normal lung architecture predominately in the middle and upper lobes with evidence of bronchiectasis, hilar retraction, bulla, cysts and more rarely “honeycombing”Diagnosis of sarcoidosis always poses a challenge to clinicians. Owing to its multisystemic nature and unidentified etiology, the diagnosis of this condition can be difficult and is often delayed; however, early diagnosis is indispensable for patient management. Sarcoidosis is usually diagnosed when radiological and typical clinical data are reinforced by histological confirmation of non-necrotic granulomas. To establish any confirmed diagnosis, patients should undergo multiple clinical examinations, depending on organ involvement, as a specific diagnostic assay is still lacking . Numerous imaging techniques have also been assessed for their diagnostic utility in the identification of sarcoidosis, but their utility is mostly restricted to specific organs. Despite these limitations, high-resolution computed tomography (HRCT), magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) have improved the diagnosis of sarcoidosis. These techniques are equally effective in evaluating a patient’s response to treatment. All examinations mentioned in A biological marker or biomarker refers to a broad subcategory of medical signs that can be accurately, objectively, and reproducibly measured . SeveralVarious biomarkers, including, serological biomarkers, bronchoalveolar lavage (BAL) biomarkers, and exhaled breath biomarkers, have been proposed numerous studies, but all have been shown to have limited applicability. Serological biomarkers should be the area of most focus for researchers moving forward as these are the least invasive and most accessible . AlthougThe application of biomarkers in the diagnosis and prognosis of sarcoidosis is still in its infancy with relatively few biomarkers appearing to have any real clinical application. However, the advent of “omics” type approaches  and the increasing number of studies applying these techniques suggest that we may soon have more valid candidates to choose from. Thus, while biomarkers are not currently a viable alternative for diagnostic applications, they may soon become effective .1H nuclear magnetic resonance (NMR)-based metabolomic analysis identified metabolites and metabolic pathways that can discriminate sarcoidosis patients from healthy ones. Acetoacetate, 3-hydroxybutyrate, carnitine, cystine, and trimethylamine N-oxide levels are significantly increased in sarcoidosis, with dysregulation of ketone bodies and citric cycle metabolism also being identified as hallmarks of this disease [In the previous decade, transcriptomics have identified novel gene expression profiles underlying the pathogenesis of sarcoidosis . All the disease ,174.In sarcoidosis, a decision on the appropriate intervention precedes the decision of whether or not to treat the patient. Not every patient needs to be treated. The decision to treat a sarcoidosis patient is predicated according to the development of specific symptoms and disease progression evidenced by worsening functional status and imaging abnormalities ,176. PatTreatment is often initiated with 0.5–0.75 mg of prednisolone per kg (body weight) daily for 4 weeks and tapered by 10 mg every 4 weeks, depending on the disease response . It is sFor patients with intolerable adverse responses to steroids, corticosteroid-sparing regimens can also be administered. These are considered second line treatments and rely on therapeutics such as azathioprine , methotrMechanism-based therapeutic treatment is the most advanced and targeted approach for the treatment of sarcoidosis. Different cytokines play a pivotal role in the immunopathogenesis of sarcoidosis. Anti-cytokine monoclonal antibodies are a specific way to modulate cytokine networks, thus influencing disease progression . These cPersonalized medicine is a novel medical doctrine focused on tailoring therapeutic management of various diseases . The goaDespite extensive research over the past several decades, the etiological agents of sarcoidosis remain unknown. Numerous potential etiological agents have been identified and the most recent hypothesis suggests that host-microbe interaction and genetic factors play an important role in the pathogenesis of this disease when they interact with various environmental factors, which results in the clinical presentation of this disease. To cure this disease, timely diagnosis is important; therefore, there is a critical need for clinicians to develop potent diagnostic tools for the identification and prognosis of sarcoidosis. Recently, new diagnostic strategies for sarcoidosis, including HRCT, FDG-PET scanning, TBNA, and EBUS technologies, have reinforced its prognosis. More focus should be concentrated on the development of non-invasive biomarkers. Big data analysis with the integration of ‘-omics’ data might elucidate the etiology and pathogenesis of sarcoidosis. Corticosteroids play an important role in the treatment of sarcoidosis, but they evoke many side effects if used for a long period. Second line and targeted treatments could be promising alternatives for the treatment of sarcoidosis in the near future. Precision medicine is the new hope in this field and should be monitored closely for progress toward targeted interventions. For better disease management, multifaceted approaches remain the best practice to ensure competent and effective patient care.


Three-dimensional (3-D) porous graphitic structures have great potential for sensing applications due to their conductive carbon networks and large surface area. In this work, we present a method for facile fabrication of hair-like laser induced graphene (LIG) patterns using a laser scribing system equipped with a 355 nm pulsed laser. The polyimide (PI) film was positioned on a defocused plane and irradiated at a slow scanning speed using a misaligned laser beam. These patterns have the advantages of a large surface area and abundant oxidation groups. We have applied the hair-like LIG patterns to a humidity sensor. The humidity sensor showed good sensitivity characteristics and a large amount of electronic carriers can be stored. Therefore, the fabrication of sensors using LIG is very simple and cost-effective, showing many advantages over lithographic sensors [Graphene is a two-dimensional 2-D) monolayer of  lattice . Due to -D monola lattice ,4,5,6. B lattice , strain  lattice ,9, solar lattice ,11, bios lattice ,13,14,15 lattice ,17,18,19 PI film . LIG has sensors . This is sensors ,22, gas  sensors ,24, supetivity 5– S/cm. Th sensors  and bio  sensors ,28.In this paper, we present an approach for fabrication of a porous, conductive, 3-D carbon network obtained by direct laser writing onto PI sheets. This is done under ambient conditions with a cost-effective laser scribing system equipped with a 355 nm pulsed laser. Due to the wavelength characteristic of 355 nm pulsed laser, it is effective to manufacture LIG by irradiating the polyimide with a laser. By controlling the alignment, laser speed and focal plane, we could control changes in the LIG pattern’s morphology and chemistry. The most important feature of our LIG manufacturing method is the condition of the laser. We used misaligned and defocused beams when irradiating the PI with a laser. In order to increase the overlap rate of the pulse, the scanning speed of the laser was adjusted to 10 mm/s, and hair-like LIG patterns were made under the conditions mentioned. These patterns have the advantage of having a large surface area and rich functional groups. This results in improving the characteristics of the sensor. Therefore, we propose a new approach to fabricate a humidity sensor in a simple one-step process without the complex fabrication processes used for conventional humidity sensors ,30,31. WIn this experiment, LIG patterns were fabricated using a laser scribing system equipped with a 355 nm pulsed laser . A photograph of the laser system configuration is shown in PI thin film has a very high absorption rate with respect to 355 nm wavelength . Althoug.1 J/cm2 . If the .1 J/cm2 . Recentl.640 µm) . When thLIG, described above, is based on photothermal effect caused by a shown in  is the o® HN, Wilmington, DE, USA) with a nominal thickness of 125 µm was irradiated at defocused plane (+1.5 mm) and misaligned laser beam. Commercial PI film (DUPONT™ KAPTONWe observed the formation of 3-D PGS in hair-like LIG patterns through FE-SEM pictures and predicted the chemical structure through Raman spectra analysis.−1, a G peak near 1580 cm−1, and a 2-D peak near 2700 cm−1. The layer number identification of graphene can be confirmed by the Because the multi-layered graphene with porous structure has many defects, such as abundant oxygen groups, these LIG patterns have the possibility of excellent sensing ability.The facile fabrication of a hair-like humidity sensor is shown uctivity .We conducted several experiments to check the electrical characteristics of the humidity sensor.To fabricate a hair-like LIG patterns, we placed the PI film on a defocused plane and slowly irradiated the laser with a misaligned beam. We confirmed that FE-SEM and Raman spectra showed that hair-like LIG patterns had a porous structure and had abundant oxidation groups. We applied it as a humidity sensor to confirm the applicability of these patterns. For simplification of the process, the pattern was designed with 2-CAD and fabricated using LDW method. This hair-like humidity sensor showed good sensitivity and was also excellent in storage capacity for large quantities of electrical carriers. Therefore, our new form of sensor platform presents excellent characteristics which have potential for fundamental and practical work.


Spirodela polyrhiza (duckweed) under three levels of population density , two levels of nutrient availability (low or high), and two levels of clonal fragmentation (with or without). Clonal fragmentation and high nutrients increased biomass and ramet number, but decreased frond width, frond length, and specific frond area of S. polyrhiza. Increasing population density decreased growth (biomass and ramet number) and frond and root size, and increased frond thickness of individual ramets of S. polyrhiza. The negative effect of population density on growth of S. polyrhiza was greater under high than under low nutrient availability. Furthermore, the negative effect of population density on total mass and frond mass of S. polyrhiza was greater with fragmentation than without. These results suggest that clonal fragmentation, nutrient availability and population density can interact to affect growth and morphology of clonal floating plants. Competition for nutrients and space, rather than light, may be the mechanisms underlying reduced growth of clonal floating plants. As clonal fragmentation can increase biomass and ramet production of S. polyrhiza, disturbance that potentially causes clonal fragmentation cannot be recommended as a measure to limit the spread of clonal floating plants.Connected ramets of aquatic clonal plants are susceptible to fragmentation by disturbance. Such clonal fragmentation may interact with nutrient availability and individual density to affect growth and morphology of aquatic clonal plants. We grew the widespread floating clonal plant  Small floating plants are conspicuous components of many aquatic ecosystems  and playAquatic ecosystems are frequently subjected to disturbance caused by e.g., flooding , human aPistia stratiotes and Eichhornia crassipes  due to loss of the ability of sharing resources  between previously interconnected asexual individuals  . Howeverrassipes . This israssipes . Furtherrassipes .Population density is an important factor for plant growth and morphology because it affects resource availability . High poSalvinia natans , and grew one (low density), four (medium density) or 16 (high density) ramets in containers with two levels of nutrients (low or high). All newly produced ramets were either severed (with fragmentation) or connected to parent ramets (without fragmentation) to test the effects of clonal fragmentation, nutrient availability, population density, and their interactions on growth and morphology of S. polyrhiza. Specifically, we addressed two questions (1) Do clonal fragmentation, nutrient availability and population density affect growth and morphology of S. polyrhiza? (2) Do clonal fragmentation, nutrient availability and population density interact to affect growth and morphology of S. polyrhiza?Duckweeds are a food source of a number of vertebrates , so thatSpirodela polyrhiza (L.) Schleiden is a small clonal plant of the Lemnaceae family (duckweeds) and is widely distributed across many temperate and tropical regions of the world , Zhejiang Province, China. The species was brought to a greenhouse at Taizhou University for propagation, and the plants were washed several times with double distilled water to avoid microbial and other contaminations. They were then rinsed with 0.01 M NaClO for 30 s to prevent algal growth (3)2⋅4H2O, 506 mg/L KNO3, 80 mg/L NH4NO3, 136 mg/L KH2PO4, 493 mg/L MgSO4, 13.9 mg/L FeSO4⋅7H2O, and 18.7 mg/L EDTA⋅2Na.Ramets of l growth , and cull growth . The HoaS. polyrhiza was added in a container. In the medium and high population density treatments, four and 16 ramets were added, respectively. Ramets consisting of two fronds were used in this experiment. Each replicate was comprised of a container that was 24.5 cm in diameter and 11 cm tall, filled with 3 L of either a low (2%) or high concentration (10%) of Hoagland solution.The experiment had three levels of initial population density  crossed with two levels of nutrient availability (low or high) and two levels of fragmentation (with or without fragmentation) in a fully factorial design with seven replicates each. In the low population density treatment, one ramet of S. polyrhiza: 16 ± 0.5 mg, mean ± SE, n = 20). Containers were arranged randomly in the greenhouse.Clonal fragmentation was applied by severing connection between parent ramets and offspring ramets. In half of the containers, we severed stipe connections between the parent ramets and the newly produced offspring ramets; in the other half, the stipe connections were left intact. Severing was repeated every 3 days during the experiment. We randomly selected 200 ramets to measure initial biomass . There were about 14 h of daylight and 10 h of darkness in the greenhouse during the experiment. The mean air temperature was 27.0 ± 0.3°C (mean ± SD), and the mean relative humidity was 85.9 ± 0.6% (mean ± SD), as measured hourly by temperature loggers .The experiment lasted for 5 weeks, starting on 16 July and ending on 19 August 2018. At harvest, plants in medium and high population density treatments covered the entire water surface. Hoagland solutions were completely replaced every week. Photosynthetic photon flux density at the water surface was measured at noon on sunny days  of each ramet. In each container, we obtained an image of 25 randomly selected ramets by a scanner (Epson Perfection V19), and measured frond width, frond length, and total frond area by WinFOLIA Pro 2004a  using this image. These ramets were then separated into fronds and roots, dried in oven at 70°C for 48 h, and weighed to obtain total frond mass and total root mass of these 25 ramets. Specific frond area in each container was calculated as total frond area divided by total frond mass of these 25 ramets, which can be used to reflect frond thickness and light use efficiency of fronds. Mean frond width, frond length, longest root length, mass per ramet and frond area per ramet were also calculated based on the data of the 25 ramets in each container. In each container, we randomly selected another 75 ramets, and separated them also into fronds and roots. Frond mass and root mass of these 75 ramets were obtained after oven-drying at 70°C for 48 h. Based on frond mass and root mass of the 100 ramets , we obtained frond mass ratio  and root mass ratio . The remaining plants in each container were also harvested, but not separated into leaves and roots. They were dried in oven at 70°C for 48 h, and weighed. Total mass in a container was the sum of mass of the 100 ramets and the remaining ones in that container. Total frond mass in a container was calculated as total mass × frond mass ratio in that container, and total root mass was total mass × root mass ratio.By the end of the experiment, we counted the total ramet number of S. polyrhiza. Ramet number and root length were log-transformed to improve homoscedasticity; figures show untransformed data. Statistical analyses were carried out with SPSS 19.0 .Before analysis, values of total mass, frond mass, root mass, and ramet number were divided by the number of parent  ramets , so that values were scaled to the level of per parent ramet. We used three-way ANOVA to test for the effects of nutrient availability (low or high), population density , and fragmentation (with or without fragmentation) on growth  and morphology  of S. polyrhiza by 6.0–50.6% compared to the treatment without fragmentation , except for the treatment of low population density and low nutrient availability  and newly produced offspring ramets are connected to their parent ramet by slender stipes. Also, the duration of the connection between parent and offspring ramets are much shorter  compared to stoloniferous or rhizomatous clonal plants whose inter-ramet connections can maintain from one growing season  or several years  to several decades . For such reasons, resource sharing mediated by clonal integration may be weak and not favored at a relative longer time (3 days in the current study).Unlike stoloniferous or rhizomatous clonal plants, S. polyrhiza. Another possible reason is that maintaining connections between parent and offspring ramets of S. polyrhiza imposed great costs  on the whole clone, which overweighed the benefits of resource sharing  of S. polyrhiza, which could potentially intensify intraspecific competition, particular in high population density.The positive effect of clonal fragmentation on total mass and frond mass of S. polyrhiza, as demonstrated by reduced frond width, frond length, root length, and frond area per ramet. However, they increased frond thickness (as shown by reduced specific frond area) so that they had little effect on mass per ramet. Thus, the increased total mass of S. polyrhiza under high nutrients and clonal fragmentation was solely due to increased ramet production, but not related to individual ramet size or mass.Across other treatments, clonal fragmentation and high nutrients decreased frond and root size of the individual ramets of S. polyrhiza. An increase in frond thickness is likely because S. polyrhiza in unfavorable conditions can accumulate more starch grains (S. polyrhiza because this floating plant lacks vertical growth and can only spread horizontally (S. polyrhiza, it is most likely that increasing population density resulted in increased competition for space or nutrients, rather than light.Increasing population density decreased frond and root size and increased frond thickness of individual ramets of h grains . For terh grains . On the h grains . Also, izontally . TherefoS. polyrhiza were higher under low than under high nutrient availability, and the negative effects of population density on frond length and specific frond area were greater when with clonal fragmentation than without. There was also an interactive effect of clonal fragmentation × nutrient availability × population density on frond width, frond length, root length, specific frond area, and frond area per ramet of S. polyrhiza. This was because the negative effect of population density was greater under low nutrient availability when the plant was fragmented. These results suggest that clonal fragmentation, nutrient availability, and population density can interact to affect morphology of S. polyrhiza. Clonal fragmentation increased biomass and ramet density of S. polyrhiza, likely resulting in increased intensity of intraspecific competition, particular under medium and high population density, which may greatly influence the morphological responses of the plants. However, plants under low nutrient availability and low population density did not occupy the whole surface of containers at the end of the experiment so that intensive competition shaping plant morphology may not occur under low population density.The negative effects of population density on root length and specific frond area of S. polyrhiza. As disturbance commonly results in clonal fragmentation of S. polyrhiza, it cannot be recommended as a measure to efficiently control the spread of this clonal floating plant.Clonal fragmentation, nutrient availability, and population density can interact to affect the growth, ramet production, and morphology of clonal floating plants. Competition for nutrients and space, rather than light, may be the mechanisms underlying reduced growth of clonal floating plants. Clonal fragmentation can increase biomass and ramet production of The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.L-MZ, N-FL, J-SC, and F-HY contributed conception and design of the study. L-MZ, YJ, S-MY, and QZ performed the experiments and collected the data. L-MZ analyzed the data. L-MZ and F-HY wrote the manuscript. 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.