Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors. Aberrant activation of the Wnt/β-catenin pathway and its downstream β-catenin-T cell factor (TCF) target genes is a characteristic feature of colorectal cancer (CRC) development . Among sTo identify proteins secreted by L1-expressing CRC cells whose levels are increased after L1 transfection, we performed mass spectrometry analysis on proteins in the secretome of LS 174T L1-expressing and control LS 174T cells. As shown in To examine the role(s) of changes in biglycan expression on the growth and motile properties of L1-expressing CRC cells, we isolated biglycan-overexpressing CRC cell clones A and L1-We wished to determine whether the changes in CRC cell proliferation and motility observed in cultured CRC cells in which biglycan levels were modulated can also be detected in mouse models in vivo. CRC cell clones expressing L1 and CRC cells where the endogenous levels of biglycan are suppressed see B were inPrevious studies have shown that the tumorigenic properties conferred by L1 expression in CRC cells require an intact L1 ectodomain that mediates cell-cell adhesion  and invoWe wished to determine the localization of biglycan in human CRC tissue. We used 38 paraffin-embedded human CRC tissue samples and immune-stained them with anti-biglycan antibodies. The results summarized in The studies described above demonstrated that we have identified biglycan among the proteins whose levels are highest in the secretome of L1-expressing CRC cells and that the induction of biglycan by L1 is required for CRC progression. We found that suppressing the increase in biglycan in L1-transfected CRC cells blocks the multiple pro-tumorigenic properties conferred by L1 overexpression in CRC cells, including increased proliferation under stress, cell motility, tumorigenesis and liver metastasis in mouse models. Biglycan is a small leucine-rich proteoglycan (SLRP) and is mainly known for its role in the ECM and infiltrating immune cells in the stroma ,19, whicA unique property of L1 expression in CRC cells is that L1 is induced only in invasive CRC cells at the tumor edge but not in the homeostatic colonic mucosa, or even in adenocarcinoma tissue of the colon . FurtherBy what mechanism/s is increased biglycan expression in L1-expressing CRC cells contributing to CRC progression? A wide variety of mechanisms have been implicated in biglycan-mediated tumor progression, including upregulation of VEGF ,28, the Taken together, the targeting of biglycan expression in L1-expressing CRC cells promises to be a useful strategy to detect novel therapies of CRC in invasive CRC cells that are positive for L1.The LS 174T cell line was cultured in RPMI-1640  supplemented with 10% FBS  and 1% penicillin/streptomycin solution . LS 174T-L1, LS 174T+biglycan, LS 174T-L1/D598N, and LS 174T-L1/H210Q cells were cultured in RPMI-1640 medium with neomycin (800 µg/mL) .Transfection of LS174T cells was performed using the Xfect™ transfection reagent , according to the manufacturer’s instructions. For cell proliferation assays, 2500 cells were seeded in 12-well plates containing RPMI-1640 with 0.1% FBS, and the proliferation rate was assessed by cell counting over a period of 5 days. Cell motility was determined by the artificial “scratch wound” closure assay as described [The biglycan cDNA expression vector was obtained from Dr. Liliana Schaefer  . pSUPER.The following antibodies were used for immunoblotting: rabbit anti-L1  at 1:2000 dilution, mouse anti-biglycan, SC-100857  at 1:1000 dilution, rabbit anti-phospho-IκBα #2859  at 1:1000 dilution, rabbit anti-NF-κB p65, sc-109  at 1:1000 dilution, mouse anti-β-tubulin  at 1:5000 dilution. RIPA lysis buffer supplemented with 1% complete protease inhibitor cocktail was used to prepare cell lysates as described [Immunofluorescence was performed on cells grown on glass coverslips. Cells were permeabilized with 0.5% Triton X-100, fixed with 4% paraformaldehyde , incubatTotal RNA was isolated from cells using the Bio-Tri reagent  according to the manufacturer’s protocol. Synthesis of first-strand cDNA was carried out using SuperScript™ II Reverse Transcriptase  according to the manufacturer’s protocols. The primers used for amplification are described in 6 cells in 100 μL PBS were injected at different sites in the flanks of male nude mice [6 cells in 20 μL PBS into the distal tip of the spleen of 4–5-week-old male nude mice as described [Subcutaneous tumor growth was induced as previously described ,30. Brieude mice . Mice weescribed . Mice weThe Weizmann Institutional Animal Care and Use (IACUC) ethics committee reviewed, approved, and supervised the animal studies.Immunohistochemistry was performed on 38 paraffin-embedded human colorectal adenocarcinomas using a rabbit polyclonal anti-biglycan antibody , at a dilution of 1:650, as previously described .t-test. A p-value of <0.05 was considered significant and marked by an asterisk.Statistical analysis was performed on SigmaPlot v11 software and the significance of results was calculated using the student’s non-paired


Hydrogel-based bio-inks have been extensively used for developing three-dimensional (3D) printed biomaterials for biomedical applications. However, poor mechanical performance and the inability to conduct electricity limit their application as wearable sensors. In this work, we formulate a novel, 3D printable electro-conductive hydrogel consisting of silicate nanosheets (Laponite), graphene oxide, and alginate. The result generated a stretchable, soft, but durable electro-conductive material suitable for utilization as a novel electro-conductive bio-ink for the extrusion printing of different biomedical platforms, including flexible electronics, tissue engineering, and drug delivery. A series of tensile tests were performed on the material, indicating excellent stability under significant stretching and bending without any conductive or mechanical failures. Rheological characterization revealed that the addition of Laponite enhanced the hydrogel’s mechanical properties, including stiffness, shear-thinning, and stretchability. We also illustrate the reproducibility and flexibility of our fabrication process by extrusion printing various patterns with different fiber diameters. Developing an electro-conductive bio-ink with favorable mechanical and electrical properties offers a new platform for advanced tissue engineering. Engineered materials that can imitate native tissue properties are promising tools for treating a wide variety of clinical problems in patients and for use in research labs. In particular, hydrogels engineered to be conductive can be used to produce flexible, biocompatible sensors for the in vivo recording of bio-signals and biomolecules, or in tissue engineering applications . HoweverHydrogel-based bio-inks should be flexible, physically robust, and capable of withstanding the host tissue’s physical activity and movement. Additionally, the hydrogel must have suitable electro-conductive properties for conducting currents generated by in vivo sensors or by the living tissue itself . Hydrogels with shear-thinning properties are good candidates for use as inks with applications in 3D printing of tissue and soft electronics . This isSome electro-conductive materials that have been used for engineering bio-inks include metals such as gold , copper operties . Graphenoperties .The use of hydrogel-based electroconductive bio-inks has the advantage of offering a soft substrate at the interface between the electronic circuit and the tissue, a feature that overcomes the issues associated with a mechanical mismatch between current flexible electronic systems and soft tissue. An ideal bio-ink needs to be printed on a substrate that is flexible, durable, and is not cytotoxic. However, providing a stretchable, durable, and cost-effective method remains a constant challenge . VariousIn the present work, we report a novel silicate-based conductive bio-ink composed of alginate, Laponite, and rGo. This material composition provides a printable and flexible hydrogel with low electrical resistance that can be embedded into a multilayered hydrogel bed using a multistep process. The properties of the novel bio-ink, including its structural morphology, rheological characteristics, and conductivity under different physical conditions, are analyzed. Employing rGo in the structure of the bio-ink resulted in the enhanced electro-conductivity of the final hydrogel. The shear-thinning properties, electro-conductivity, and biocompatibility of this hydrogel can be used for engineering a three-dimensional network that can mimic the extracellular matrix (ECM) structures by 3D printing a desired form . The othPartially exfoliated graphite crystals were used in this research. The exfoliation process involves expanding the graphite platelets up to hundreds of times in order to eliminate aggregation and improve the lubricity and flexibility of this material . Partialin water ,52. Thisin water .w/v) alginate and vortexing the solution to dissolve all of the particles, 6% (w/v) Laponite was added to the 4 °C solutions of alginate/graphene oxide and vortexed vigorously for 5 min to form a final gel, as shown in In this study, the aqueous suspension of graphene oxide was prepared by, first, dispersing 5 and 3 mg/mL graphene oxide in deionized water and then sonicating the dispersion for 5 min to form a uniform colloid, as shown in Zeta potential analysis of the prepared hydrogels provides insight when discussing the electrostatic interactions of the nanocomposite hydrogels. According to the literature, the zeta potential of the Laponite is consistently negative in both the acidic and the basic pH range . The zetw/v)% of gel) is a minor component of the current nanocomposite hydrogel, some of the alginate’s characteristic peaks overlap with the intense peaks of the Laponite. The characteristic peak of the Laponite is observed at 1005  spectra . As showectively . Additio spectra . Furthera [cm−1,  while th1, [cm−1 . Since atructure . MoreoveLaponite . SimilarOH bands . This peThe XRD analysis was carried out to prove the presence of graphene oxide nanosheets in the structure of the dried Laponite/alginate hydrogel. As depicted in The unique isomorphic substitution of Laponite can enhance the shear-thinning properties, plastic behaviors, and the high elastic response of the hydrogel composites . SpecifiThe electrostatic interactions between Laponite and graphene oxide lead to a stable colloid . LaponitLaponite has been reported to improve the shear-thinning properties of alginate . In ordeAs observed in The shear-thinning properties of the different formulations of the bio-ink can also be determined by measuring the viscosity under constant shear. The viscosity increased with the addition of 3 mg/mL graphene oxide to the alginate/Laponite bio-inks. This increase in viscosity was attributed to the electrostatic interactions between the negatively charged graphene oxide and the positively charged Laponite, as previously mentioned. As shown in In order to characterize the mechanical integrity of the bio-ink upon printing, the recovery of the nanocomposite hydrogel was measured from high (100% oscillatory strain) to low strain (1% oscillatory strain) conditions. Previously, Laponite and gelatin showed a rapid elastic recovery in less than 10 s . The stoAs previously mentioned, printing is gaining popularity for fabricating biomimetic scaffolds for tissue engineering and drug screening; however, developing a biocompatible bio-ink remains a challenge . ParticuOnly a few existing bio-inks are electro-conductive, and even those are only slightly electro-conductive . Metalliw/v), 3% (w/v) Laponite, and 0, 3, and 5 mg/mL of graphene oxide, respectively. These bio-inks were unsuitable for extrusion printing due to the low mechanical integrity of the stacked layer, or their inability to form consistent and cylindrical filaments following extrusion.w/v) Laponite generated cylindrical filaments upon extrusion and provided the desired mechanical integrity for the stacked layer, which hinders the deformation of the pattern. w/v) Laponite disrupted extrusion, while employing 3% (w/v) Laponite resulted in droplet formation and the deformation of the stacked-layer after printing.In w/v) alginate, 6% (w/v) Laponite, and 0, 3, and 5 mg/mL graphene oxide, respectively, were chosen as the optimum formulations of the electro-conductive bio-ink. The feeding pressure and moving nozzle speed are determinative parameters for controlling the printability, filament formation consistency, and fiber diameter. w/v) alginate, 3% (w/v) Laponite, and 0, 3, and 5 mg/mL of graphene oxide, respectively. These formulations were unsuitable for extrusion printing due to their low mechanical integrity, the deformation of the stacked-layer, or the formation of a droplet instead of the desired cylindrical filaments following extrusion, as shown in w/v) w/v) alginate, 6 (w/v) Laponite and 0 (i), 3 (ii), and 5 (iii) mg/mL graphene oxide, respectively, show the printability of different formulations of the bio-ink  agarose solution was added to 4% (w/v) of w/v) alginate solution was added to the top of the agarose sheet, as shown in w/v) with 4% (w/v) of In order to fabricate the alginate substrate, 1.5% , graphene oxide, gelatin from porcine skin , agarose, and calcium chloride were all obtained from Sigma-Aldrich, St. Louis, Missouri. Laponite XLG, a synthetic nanosilicate, was acquired from BYK Additives, Germany.w/v) alginate, 6% (w/v) Laponite, and 5 mg/mL graphene oxide were prepared by, first, dispersing the graphene oxide in deionized water. The suspension was then sonicated for 5 min, alginate was dissolved in the graphene oxide suspension, and the solution was cooled to 5 ℃. Laponite was added to the solution and immediately vortexed for 5 min to ensure the homogenous distribution of Laponite nanoplatelet in the solution. In order to prepare different formulations of the bio-ink, different concentrations of the graphene oxide and Laponite were added to the solution, and the rest of the procedure was followed as explained above. A list of the different formulations of the bio-ink is given in Preparation of Bio-inks: A total of 0.5% (w/v) alginate, 6% (w/v) Laponite, and 0, 3, 6% (w/v) graphene oxide, respectively, were diluted to 0.2% (w/v) and sonicated for 5 min to ensure a uniform distribution of graphene oxide and Laponite. This test was conducted to study the effect of the introduction of different concentrations of graphene oxide on the zeta potential of the bio-ink.Zeta Potential: Zeta potential tests were conducted using a Brookhaven BI-ZR3 Zeta Potential Analyzer with a 600 nm wavelength laser at room temperature. Samples with 0.5% (Fourier Transform Infrared Spectroscopy (FTIR): The chemical structure of Laponite/alginate with various concentrations of graphene oxide was analyzed by a PerkinElmer Spectrum Two Fourier transform infrared spectrometer (USA) to obtain FTIR spectra by a potassium bromide (KBr) technique. Samples were firstly freeze-dried and then ground into powder and mixed with KBr to collect the spectra and determine the interactions between the components within the range of 400–4000 X-ray Diffraction (XRD): Firstly, samples were freeze-dried and ground into a powder. The crystal structure of the bio-ink with different concentrations of graphene oxide was analyzed using a PANalytical Empyrean X-ray Diffractometer at room temperature with a current of 40 mA and a voltage of 45 kV over the diffraction angle range of 10°–90° (2θ).w/v) alginate and 6% (w/v) Laponite.Scanning Electron Microscopy (SEM): SEM images were acquired using the Hitachi S-4800 FESEM microscope at an accelerating voltage of 1 kV. Samples were freeze-dried by storing them in a −80 °C freezer for 24 hr, lyophilized for 2 days, tapped to the SEM stubs, and then coated with gold–palladium. SEM images were employed to investigate the microstructural differences between bio-ink formulations with various concentrations of graphene oxide , with 0.5%  were measured using an Anton Paar MCR 502 rheometer  over shear rate sweeps of 0.001 to 10 Hz at room temperature. Viscosity was measured under a constant shear rate over 300 s, and stress recovery measurements were conducted at 1 Hz by alternating the application of 100% strain and 1% strain for 5-min intervals on the bulk bio-inks.w/v) Laponite, 5 mg/mL graphene oxide, and 0.5% (w/v) alginate. The electro-conductive bio-inks with alginate 0.5% (w/v), Laponite 6% (w/v), graphene oxide 5 mg/mL, and 2% (w/v) 3D printing Process: All 3D printing experiments for the present work were conducted employing a Cellink Inkredible+  microextrusion 3D printer with pneumatic pressure for extruding materials. Repetier and Slic3r software were used to manually generate codes for the 3D printing of rectangular patterns. In order to print serpentine and spiral patterns, AutoCAD was employed to develop the drawings and Cura was used to develop the final codes for 3D printing. Different formulations were used to study the printability of the bio-inks B. In ord5 mm see G. Besidew/v) alginate was chosen to develop a flexible substrate for printing an electrically conductive pattern. The first step to develop a flexible printed pattern was spreading the 4% (w/v) alginate solution in a 100 mm Petri dish and crosslinking it with 4% (w/v) w/v) agarose solution was prepared by suspending 1.5 g agarose powder in 100 mL deionized water and dissolving at 70 °C to form a clear solution. A 4% (w/v) w/v) alginate was spread to the same Petri dish at the top of the agarose sheet. The agarose sheet containing 4% (w/v) 3D Bioprinting on Alginate Substrate: A 4% (w/v) agarose sheet containing 4% (w/v) w/v) alginate solution to the agarose sheet for 20 min, 2 mm of the alginate solution was crosslinked to provide sufficient support and to maintain the printed pattern on the alginate sheet. Partially crosslinking the alginate solution is necessary for forming layers of alginate sheets from the bottom to the top of the solution. The layers of alginate sheets tolerate the weight of the bio-ink and prevent any deformations of the bio-ink after printing on alginate and eliminate sinking the pattern to unwanted levels of alginate substrate. After printing the pattern, the sample was crosslinked for 20 more minutes so to be fully crosslinked. During the next 20 min, the printed patterns and the alginate sheet were crosslinked in parallel.After preparing the alginate sheet, developing the printing codes, and choosing an optimum formulation of the bio-ink, different patterns were printed on the substrate. The most significant challenge in this process was trapping the printed pattern inside a half-crosslinked solution to provide a strong attachment between the printed patterns to the alginate sheet. Therefore, the prolonged crosslinking method played a significant role in providing control over the crosslinking procedure. The various volumes of alginate solution were prepared and crosslinked with a 1.5%  length and glued to sandpaper from two ends, and then the sandpapers were fixed inside two grips. This method successfully prevents any undesired ruptures in the prepared samples as a result of direct contact with the alginate sheets and the grips during the measurement. For the cyclic tensile test, the samples were stretched with a linear velocity of 1 mm/min and the test was repeated for 7 cycles with a maximum strain of 10%. The electrical conductivity of the printed pattern on the alginate sheets was measured after each cycle and during the first cycle using a multimeter.2 incubator at 37 °C. Dulbecco’s modified Eagle’s medium  supplemented with 10% FBS (Invitrogen 16000), 100 IU/mL of penicillin, and 100 mg/mL of streptomycin was used as the cell media and was changed every other day. Cells were cultured up to 90% confluency. Afterwards, the U251 cells were detached into a single cell suspension followed by centrifuging and diluting, and ready for counting using a hemocytometer to obtain a certain number of cells.Cell culture: U251 Glioblastoma cell lines were cultured in T-25 flasks in a 5% COv/v of fetal bovine serum at 37 °C, in 5% CO2 and fully humidified air for 1, 3, 7 days, respectively. The liquid extraction medium (500 µL each) was collected for the PB assay at each time interval and was substituted with the fresh DMEM + FBS solution. Then, 200 µL of each periodically collected liquid extract was added to each well and incubated for 24 h. Finally, the cell metabolic activity was determined using a PB cell viability reagent . PB reagent was added to each well at 10% concentration of the total well volume, and the plate was incubated for 15 min. Excitation and emission wavelengths of 560 and 590 nm were used to measure the fluorescent intensity of the incubated cells. Subsequently, the viability of the samples was calculated using the following equation:Cell viability assay: To measure the cell viability of the fabricated hydrogels with different GO concentrations, 96-well plates  were seeded with 10,000 cells per well and cultured in 0.2 mL of media for 24 h. Presto blue (PB) assay was used as a standard method for rapidly evaluating the viability and proliferation of a wide range of cell types by measuring the metabolic activity of the live cells. An indirect extraction method was used to assess the cell viability of the experimental samples. Equal weights (0.3 g) of GO-incorporated hydrogels in triplicate were incubated in 2 mL DMEM with 10% Cell Viability: (Average fluorescent density of the samples/Average fluorescent density of the control) ∗ 100.


Sarcoidosis is a rare, chronic inflammatory disease with a characteristic non-caseating granuloma formation. It affects women more than men. The lung is the most commonly affected organ, however, extrapulmonary involvement is also seen. Sarcoidosis can affect any organ or tissue and can also involve multiple organs simultaneously. As a disease, it shares clinical symptoms with a variety of autoimmune, non-autoimmune disorders and malignancies. Not only it mimics clinically, but it also coexists with these diseases, posing a significant diagnostic challenge. During this literature review, we obtained data from the previously published PubMed articles within the last five years and reviewed the possible etiological association and clinical coexistence between sarcoidosis and other diseases/malignancies. We aimed to determine the common clinical manifestations, various complex presentations of sarcoidosis and pathophysiological considerations for the association, and to emphasize the link with other diseases, particularly thyroid disorders/malignancies. Physicians should be aware of these associated diseases and should always make a clinical suspicion when confronting a sarcoidosis patient. Thus, a comprehensive diagnostic evaluation for these associated conditions ought to be done in sarcoidosis patients to avoid any delay in the curative treatment for these coexisting diseases and to prevent substandard outcomes. Sarcoidosis is a chronic multisystem granulomatous inflammatory disease of unknown etiology. The prevalence of sarcoidosis ranges from 2.2 to 160 cases per 100,000 people , Asian pMost common clinical manifestations of sarcoidosis are non-specific generalized symptoms like fever, fatigue, myalgias, arthritis which is also seen in various autoimmune disease that need to be differentiated from sarcoidosis. It may manifest acutely as Lofgren syndrome . Pulmonary sarcoidosis usually presents nonspecifically as dry cough, dyspnea and it progresses over stages.· Stage 0: no pulmonary infiltrates or lymphadenopathy· Stage 1: hilar and mediastinal lymphadenopathy alone· Stage 2: lymphadenopathy and pulmonary infiltrates· Stage 3: pulmonary infiltrates alone· Stage 4: pulmonary fibrosisExtrapulmonary locations are skin, lymph nodes, eye, liver, spleen, heart, nervous system, kidney, parotid gland, nose, larynx, bones, skeletal muscles, genitourinary tract, gastrointestinal tract . AlthougOwing to its multiple organ involvement, its various presentation which could mimic other organ diseases and also its coexistence with several endocrine, non-endocrine autoimmune conditions and malignancies, the diagnosis could be challenging. Sarcoidosis of the thyroid gland was first reported in 1938 and the autopsy showing granuloma confirmed it in a 51-year-old male patient . SarcoidPathogenesis of sarcoidosis and pathophysiological considerations for multisystemic nature and coexistence with other conditions Pathogenesis of SarcoidosisEven though science is growing, the exact cause of sarcoidosis is still unclear. Environmental antigen, bacterial or other is assumed to be the potential triggers. In a genetically susceptible individual, the causing antigen is not successfully eliminated leading to a granulomatous inflammation . An airbPathogenesis of Sarcoidosis as a Multisystem DisorderStudies reported the importance of T helper 17 (Th17) cells in sarcoidosis pathogenesis . The intPathology of Sarcoidosis Association With Other Disorders/MalignancySarcoidosis doesn’t meet the criteria for autoimmune diseases; however, the co-relation between sarcoidosis and autoimmune diseases is reported frequently . An incrThe underlying mechanism between the coexisting of sarcoidosis and malignancy is still unclear . LongstaClinical features of sarcoidosisLofgren’s syndrome, a triad of bilateral hilar lymphadenopathy, arthritis, and erythema nodosum is an acute presentation of sarcoidosis. Constitutional symptoms like fever, malaise, fatigue, myalgias, weight loss are seen frequently . Lung inDiseases that mimic or coexist with sarcoidosisVarious case-control studies, cohort studies, case reports, and case series reported sarcoidosis with another coexisting autoimmune disease or as mimicking malignancy. Nevertheless, these reports are useful for physicians, to be aware that various systemic diseases may coexist with sarcoidosis . A TaiwaSarcoidosis and ThyroidVarious thyroid disorders like goiter, subacute thyroiditis, thyroid cancer, and sarcoid infiltration of the thyroid are seen in sarcoidosis patients. Several pieces of literature reported the co-occurrence of sarcoidosis and autoimmune thyroiditis (AT). Out of 348 sarcoidosis patients evaluated by Isern et al., 10 had AT, with nine cases having sarcoidosis precede AT . PapadopIn a national level questionnaire-based study conducted on 3835 self-reported sarcoidosis patients, they compared cases with and without self-reported hypothyroidism among sarcoidosis patients. They educated that hypothyroidism is a prevalent coexisting disease in sarcoidosis patients and sarcoidosis patients with hypothyroidism have more multiple organ presentations , such as skin, joints, eyes, liver, lacrimal glands showing sarcoid presentations than typical pulmonary sarcoidosis. Among various presentations, cutaneous sarcoidosis presenting as erythema nodosum, lupus pernio, papules, plaques, skin pigmentation, and subcutaneous nodules around scars and tattoos is most common in the hypothyroid group. Among these self-reporting hypothyroid groups, depression, fatigue, and physical impairment are reported significantly compared to the non-hypothyroid sarcoidosis group of patients . In concIn another retrospective study conducted on 317 patients in Japan, Kinoshita et al. reported dilated cardiomyopathy and cardiac sarcoidosis as risk factors for the development of amiodarone-induced hyperthyroidism . In brieIn a prospective study, conducted in an outpatient clinic for the prevalence of other autoimmune diseases in 3069 autoimmune thyroiditis patients (AT) versus two age and sex control groups , Fallahi et al. reported a very high prevalence of other autoimmune diseases in AT patients compared to controls. The most frequently observed combination of diseases was AT along with chronic atrophic gastritis (CAG) and vitiligo, and AT along with CAG and polymyalgia rheumatica. Sarcoidosis is seen in 19 patients of AT while only in two patients in the controls group (P = 0.0133) . In concNot only just the thyroid, diverse autoimmune and non-autoimmune endocrine disorders can be seen concurrently with sarcoidosis, although very few cases were reported making a diagnostic challenge to the physicians. Dayal et al. reported a case of a 9-year-old girl with probable sarcoidosis with autoimmune thyroiditis, diabetes mellitus, and hypercalcemic pancreatitis . AlsahwiSome variable presentations of sarcoidosisMiliary SarcoidosisAlthough very rare, miliary sarcoidosis is reported in the literature . So, in Neuro SarcoidosisNeuro sarcoidosis is seen in 5-26% of sarcoidosis patients . Even thOrbital Sarcoidosis Even though uveitis is the most common presentation of sarcoidosis we can also see orbital and adnexal  involvement with the extraocular muscles involvement most commonly. In a retrospective case study conducted on 59 patients with non-thyroid extraocular muscle enlargement by Savino et al., four were diagnosed with sarcoidosis involving the medial rectus and superior rectus presenting as a mass effect . Two casMulti-Organ Sarcoidosis Not only single organ involvement but complex presentations involving various organs simultaneously is also seen in sarcoidosis. Wadhwa et al. reported a case of splenic, hepatic, and thyroid sarcoidosis presenting as organomegaly diagnosed by autopsy along with autoimmune thyroiditis . AnotherMalignancies coexisting with sarcoidosisThe relationship between malignancy and sarcoidosis is not clear yet. In a prospective cohort study, Brincker and Wilbek reported malignancies more in the sarcoidosis patients compared to the general population  . A largeSarcoidosis With Papillary Thyroid CancerRiis et al. reported a case of sarcoidosis with coexisting PTC presenting with clinical symptoms of moderate hypercalcemia . PresentSarcoidosis With Other CancersNot only PTC, but sarcoidosis can also cause a diagnostic dilemma by resembling in presentation with various other cancers or coexisting with other cancers. Bala et al. reported a case of testicular sarcoidosis mimicking as testicular malignancy in a 49-year-old Indian male who also has coexisting PTC . AlthougCo-morbidities on mortality of sarcoidosisThe coexisting diseases have a strong influence on mortality in patients with sarcoidosis. In an observational prospective cohort study conducted by Nowinski et al. on 557 sarcoidosis patients and non-sarcoidosis patients as controls thyroid diseases are seen more frequently in the sarcoidosis group compared to controls. The study reported that the more the number of co-morbidities the less the survival probability .LimitationsWe faced few limitations while conducting this traditional review. Many studies used in this review had small sample sizes (case reports). Only articles published in the last five years in PubMed were included. Articles in languages other than English could not be included.We conducted this literature review to discover more about the complex nature of sarcoidosis disease. Here we elaborate on the pathogenesis underlying the sarcoidosis, its multisystemic nature and its association with various other disease conditions, its variable presentations and its coexistence with various autoimmune, non-autoimmune disease and malignancies. In this article, we tried to mention all the coexisting diseases and malignancies that we encountered in the last five years of PubMed articles.This literature review would be beneficial to the clinicians to have a better understanding of the sarcoidosis disease which will help them to diagnose the disease at an early stage, and to do evaluations systematically for other commonly associated diseases and to treat the patients thoroughly on time without any lacking, ultimately preventing the worst scenarios and the complications. As only a few papers that we used in our review article are of great sample size there is a need to study more about sarcoidosis complexity specifically in the larger group for better insight, especially in patients with various other associated diseases.


Melt-electrowriting (MEW) is an emerging method that combines electrospinning and extrusion printing, allowing the fabrication of micron-scale structures suitable for tissue engineering. Compared to other additive fabrication methods, melt-electro written structures can offer more appropriate substrates for cell culture due to filament size and mechanical characteristics of the fabricated scaffolds. In this study, polycaprolactone (PCL)/graphene composites were investigated for fabrication of micron-size scaffolds through MEW. It was demonstrated that the addition of graphene can considerably improve the processability of PCL to fabricate micron-scale scaffolds with enhanced resolution. The tensile strength of the scaffold prepared from PCL/graphene composite (with only 0.5 wt.% graphene) was proved significantly (by more than 270%), better than that of the pristine PCL scaffold. Furthermore, graphene was demonstrated to be a suitable material for tailoring the degradation process to avoid undesirable bulk degradation, rapid mass loss and damage to the internal matrix of the polymer. The findings of this study offer a promising route for the fabrication of high-resolution scaffolds with micron-scale resolution for tissue engineering. Tissue engineering is an evolving strategy for repairing damaged tissues or organs. This approach offers an efficient alternative for complicated treatments such as organ transplantation or implantation of artificial prostheses ,2. The mThe solution, therefore, lies in the development of biocomposites that are composed of a matrix infiltrated with a filler to compensate the deficiencies of the matrix. Among synthetic polymers, polycaprolactone (PCL) is a popular candidate for developing biocomposites. PCL is a Food and Drug Administration (FDA) approved bioresorbable polyester and has been used for medical devices since the 1980s . It is oProcessing materials into scaffolds with appropriate properties is the next challenge in the tissue engineering field. The emergence of 3D printing opened new avenues for the fabrication of complex structures for a variety of biomedical applications. Compared to conventional manufacturing methods, such as mould casting, 3D printing provides the advantage of fabricating structures with higher resolution and complexity at a faster speed. This technique can also be used to fabricate customised structures to accurately mimic the biomechanical properties of damaged organs and tissues ,13. In eAs an implantable synthetic polymer, PCL has been studied extensively to understand the degradation mechanism and excretion pathway . HoweverIn this study, we developed micron-scale scaffolds with tailorable mechanical and degradation properties using MEW of PCL/graphene composites. We examined the effect of graphene addition on processability and thermal properties of the polymer to develop a suitable substrate for in vitro tissue models. MEW of the PCL/graphene composites was optimised to fabricate scaffolds with the finest possible strut size. The mechanical properties and degradation profile of the scaffolds were also investigated.PCL (MW of 45 KDa) was obtained from Sigma Aldrich Pty Ltd . Lipase from Pseudomonas sp. Type VIII was purchased from Sigma Aldrich. Dimethyl formamide (DMF) was purchased from Chem-Supply .DMF-dispersed graphene dispersion and PCL/graphene composites were prepared according to a method described in our previous work . BrieflyPCL-CCG composites with different graphene content were prepared by mixing PCL in an appropriate amount of DMF-dispersed CCG at 75 °C for 3 h. The mixture was then cooled to room temperature, precipitated in cold methanol, filtered, washed with ethanol and dried in a vacuum oven at 50 °C. The composites were labelled according to the weight percentage of the graphene content per PCL, with PCL-CCG 0.1 and PCL-CCG 0.5 containing 0.1 and 0.5 wt.% graphene, respectively. Composites with up to 10 wt.% graphene content could be prepared without observable aggregation; however, they were not processable through MEW due to increased viscosity and melting point.Samples were printed using a Bioscaffolder 3.2  fitted with an MEW module. The system is equipped with a pneumatic extrusion print head capable of performing high-voltage induced fibre deposition operating at pressures of 0–600 kPa. The positive voltage is placed on the needle tip and a negative voltage of the collecting tray. This dual voltage power supply setup is similar to methods reported in literature that increases the maximum number of layers for each construct . For fabt-test to assess the mass loss at individual time points. Significant difference was indicated by p < 0.05.An enzymatic degradation assay was conducted using the method published previously . Lipase SEM images of printed samples were taken using a Low Vacuum Scanning Electron Microscope (LVSEM) JEOL JSM-6490LV  operating in high vacuum mode. The samples were coated with 15 nm of platinum (Pt) using a Dynavac SC100MS magnetron sputter coating system . Secondary electron imaging was performed at 15 kV accelerating voltage with a probe current setting of 45 and the specimen at 20 mm working distance. Images were taken at random cross sections of the scaffolds to better image layer resolution and filament shape. Magnifications of 250×, 1500× and 2500× were taken. For degradation samples, images were taken at random locations from a top-down view at 48 h and 96 h with magnifications of 100×. A high magnification of 0.5 wt.% graphene composite at 500× and 1000× was also imaged to determine the mode of degradation.n = 5 samples per group) were measured using a Shimadzu tensile tester . The scaffolds (20 × 5 × 40 mm) were subjected to tensile test with a constant rate to measure the maximum force (at their breakage point) and the strain, which is the percentage change in the length of the sample before it breaks. Raman spectra were recorded on a Horiba LabRam HR Evolution Raman Spectrometer using a 633 nm laser line with a 300-lines mm−1 grating through a 100× magnification wide angle objective. TGA was performed using a TG 209 F1 Libra  with a ramp rate of 5 °C/min up to 900 °C under a nitrogen atmosphere. Differential Scanning Calorimetry (DSC) analysis was performed by using a DSC 204 F1 Phoenix  in two cycles at 5 °C/min under a nitrogen atmosphere. The sample presealed in an aluminium pan was first heated to 110 °C (above the melting point of the polymer) and then cooled to −10 °C to record melting and crystallization peaks. Rheological properties were measured using an AR-G2 rheometer  with a 12-millimetre parallel plate geometry at 100 °C, which is the processing temperature of PCL and composites. Viscosity values were measured across a shear rate range of 0.1 to 1500 1/s. The mechanical properties of the scaffolds , and their recovery behaviour was investigated, as shown in −1. The Raman spectrum of PCL shows the characteristic peaks of the polymer at 1060 cm−1 and 1106 cm−1 , 1281–1305 cm−1 (CH2 groups) and 1726 cm−1 (ν C=O stretching mode). The other peaks at 1470–1418 cm−1 (δCH2) and 912 cm−1 (νC–COO) are attributed to crystalline domains [−1 are observed corresponding to D and G bands of graphene sheets. The peaks due to PCL are less visible in the Raman spectra of composites as the intensity of the characteristic D and G bands of graphene are greater than that of PCL. No significant change was observed in the position or ratio of D and G bands of graphene, indicating that the structure of graphene has barely been changed when mixed with PCL. Raman spectra A were co domains ,30. In sn = 5) of the composites is consistent with the percentage of graphene added to the reaction initially, indicating homogeneous dispersion of graphene sheets in the polymer matrix.TGA B curves DSC results C showed MEW is a solvent-free technique that combines the principles of melt extrusion printing and electrospinning to produce polymeric highly ordered porous structures . The intOnce MW and processing temperatures are established, instrument-based parameters such as voltage, distance, pressure and speed becomes important in controlling the fibre’s diameter. In this study, PCL and composites were printed at 100 °C (max. temperature), voltage of 5 kV and collector distance of 4.8 mm. The selection of a low voltage and low distance is consistent with the findings by Brown et al , demonstPCL was able to be extruded at 5 kPa, while composite materials require a minimum of 10 kPa due to the higher viscosity. The minimum pressure determined for all samples were then held constant against a range of printing speeds to determine the critical translation speed (CTS) necessary to print a continuous filament. Study conducted by Brown et al.  observedSEM was conducted on printed scaffolds . InteresPCL is a semi-crystalline, hydrophobic aliphatic polyester that is currently used for sutures, wound dressing and is a common scaffold material for bone-related applications. As a long term stable polymer, PCL subjected to hydrolytic degradation requires 2–4 years for complete degradation depending on molecular weight (MW) . In vivoIn the current study, MEW-fabricated scaffolds showed continued degradation beyond 24 h, as indicated in Hydrolytic degradation can proceed via surface or bulk-degradation with the former allowing predictability of the erosion process and the latter often resulting in instantaneous failure . TypicalIn this study, MEW of PCL graphene composites was investigated for the first time. The PCL-CCG composite was shown to be a better material for melt-electro writing of high resolution, multi-layer scaffolds, as shown by circular filaments and distinct layer separation. As confirmed by rheology and DSC results, the addition of graphene can increase the elasticity of the polymer and help it solidify faster, which will play an important role in the formation of multilayer structures with well-defined layers. Furthermore, the addition of as low as 0.5 wt.% graphene could significantly improve the strength of fabricated scaffolds by more than 270%. Bulk degradation and rapid mass loss in PCL can result in undesirable scaffold integrity and failure of implant. SEM and in vitro degradation results indicated that filaments have become thinner over time without formation of hollow filaments or holes in the internal matrix of the polymer. The degradation mechanism was evident to occur through surface erosion and uniformly through the interconnected networks and scaffold design. Degradation profiles can be altered through graphene concentration as PCL-CCG 0.5 significantly decreased the rate of degradation and extended the time. Due to increased viscosity and limitations of the instrument in extruding the composites, PCL-CCG with higher than 0.5 wt.% graphene content could not be processed, which will be the subject of future investigations.


In this paper, efficient analysis of the plane wave scattering by periodic arrays of magnetically-biased graphene strips (PAMGS) is performed using the semi-numerical, semi-analytical method of lines (MoL). In MoL, all but one independent variable is discretized to reduce a system of partial differential equations to a system of ordinary differential equations. Since the solution in one coordinate direction is obtained analytically, this method is time effective with a fast convergence rate. In the case of a multi-layered PAMGS, the governing equations of the problem are discretized concerning periodic boundary conditions (PBCs) in the transverse direction. The reflection coefficient transformation approach is then used to obtain an analytical solution in the longitudinal direction. Here, magnetically-biased graphene strips are modeled as conductive strips with a tensor surface conductivity which is electromagnetically characterized with tensor graphene boundary condition (TGBC). The reflectance and transmittance of different multi-layered PAMGS are carefully obtained and compared with those of other methods reported in the literature. Very good accordance between the results is observed which confirms the accuracy and efficiency of the proposed method. The tunability of its surface conductivity by an applying electric or magnetic field bias is the main advantage of graphene over metals, which leads to the design of tunable devices including tunable THz absorbers6, graphene frequency selective surface with tunable polarization rotation characteristics7, etc. Moreover, the magnetically-biased graphene has anisotropic surface conductivity and shows non-reciprocal gyrotropy at microwave and optical frequencies8, which makes it a good candidate for designing nonreciprocal components9 and achieving enhanced Faraday rotation10.Graphene, as a 2D material with hexagonal honeycomb lattice, has remarkable mechanical, electrical, and thermal properties such as astonishing strength and stiffness, optical transparency, high electronic mobility, and tunable surface conductivity11. The discontinuous Galerkin time domain (DGTD) method for the analysis of magnetically-biased graphene is reported by Li et al.12. The finite-difference time-domain (FDTD) method13 and the MoL14 are also reported for modelling magnetized graphene. Besides, magnetically biased graphene sheets are analyzed analytically by Heydari et al.15.To model the electromagnetic characteristics of graphene various methods have been implemented numerically. The graphene has been characterized using a circuit model through the partial element equivalent circuit (PEEC) method by Coa et al.17 take advantage of the unique electromagnetic properties of graphene. The GPSs with numerous applications including THz absorbers18, THz filter19, and graphene-based frequency selective surfaces20, to name a few, have been reported in the literature. As a result, a fast and accurate method for the efficient analysis of GPSs is in need.Alternatively, graphene-based periodic structures (GPS) with fascinating properties like perfect absorption of light in a specific range of frequency21, finite-difference time-domain (FDTD)22, integral equations (IE)23, and Fourier modal method (FMM)26 have been reported for the diffraction analysis of GPSs in the absence of magnetic field bias while less effort has been made in case of magnetically-biased GPSs27.The study of electromagnetic waves interaction with periodic arrays of graphene has attracted great attention to the researchers recently. Different numerical methods, including the method of moments (MoM)et. al27.In this paper, the semi-numerical, semi-analytical MoL has been provided for the efficient analysis of the plane wave scattering by PAMGS. In this method, we use of PBCs to take the periodicity of the PAMGS into account. Hence, the fields and the derivatives are to be discretized with finite differences according to the PBCs. Besides, the constitutive parameters of the cross section as well as the surface conductivity of graphene strips are discretized. In those parts of the cross-section where there is no graphene, the conductivity value is zero. Hence, there is no need to introduce approximate boundary condition at the interface of two adjacent layers where graphene exists as done by Khoozani Moreover, unlike fully numerical methods, the solution of the problem in one coordinate direction is obtained analytically in MoL which means there is no need to use absorbing boundary condition (ABC) such as perfectly matched layers (PML) in this direction. Besides, the analytical nature of the method saves a lot of computing time compared to fully numerical methods. The reflection coefficient transformation approach is introduced to obtain an analytical solution in this direction. In this approach, the structure under the study is divided into homogeneous layers and the known reflection coefficient in the last layer is transformed through layers and interfaces to obtain the reflectance. Having known the reflection coefficient in each layer, the transmission coefficient is obtained by transforming the fields in the opposite direction.The rest of the paper is organized as follows: First, we present a brief description of the graphene properties. Then, we continue with the basic formulation of the problem. In this section, the MoL is introduced concisely. Afterwards, the plane wave incidence on a PAMGS for the two special cases of normal and oblique incidence is investigated. The reflection and transmission coefficients of a multi-layered PAMGS are obtained in the next subsection. Next, the numerical results of different PAMGSs obtained using the proposed method are presented.xy plane with a magnetic field bias 29 characterizing with an anisotropic surface conductivity to be obtained through a quantum mechanical analysis using Kubo formulation31. However, in the case of magnetic field bias, there exists an excitonic energy gap which is opened due to the interaction of electrons with the magnetic field that can be significant at low temperature. At high temperature, the carrier density increases and consequently the screening effect enhances. Hence, the gap disappears and the graphene sheet’s electronic band structure remains gapless32.Consider a graphene sheet in the mentclass2pt{minimxy plane under an electric field as shown in Fig. 8. For the case 827. Here, the optical properties of graphene are similar to those of Drude-type materials and as the result the quantum mechanical closed form expressions for 33e is the electron charge, T is the Kelvin temperature.The anisotropic nature of graphene’s conductivity can be interpreted by the electron motion in the surface conductivity, it can be electromagnetically treated as an special impedance boundary condition at the interface of adjacent layers called tensor graphene boundary condition (TGBC). The TGBCs are given byAlternatively, since the graphene sheet is modeled with a tensor These boundary conditions are then used in the next subsections to derive the reflection coefficient transformation formula through interfaces. Note that a time dependence of D as shown in Fig. y-direction.Consider a PAMGS with graphene strips of width entclass1pt{minima29. Besides, unlike infinite graphene sheets, graphene strips have non-uniform carrier density 33. For chemically doped graphene, the net charge is zero. Here, the edge effects are confined to a strip width in order of the dopant’s Wigner-Seitz radius. Hence, for wide enough strips these edge effects can be neglected and the graphene strips can be modeled with the same conductivity parameters as those of an infinite sheet33.Despite graphene sheets with gapless electronic band structures, one-dimensional graphene strips with finite width have been proposed to obtain tunable band gaps where the energy gap is controlled by the strip widthx-direction, we normalize the electromagnetic fields with respect to the phase as follows:x-direction and x-direction with period D.To start the analysis of a PAMGS and to consider its periodicity in Now we substitute Eq.  into Max34D and 34Next, we eliminate the longitudinal field components  in Eqs.  to obtaientclass1pt{minimas of Eq.  are discy-direction we put Besides, since there is no variation in the  in Eqs.  and 9)..y-directt refers to the matrix transpose, the solution to Eqs. (3434Using the definition  to Eqs.  and 14)\documentt refers to transverse components. In what follows, we investigate two special cases of normal and oblique incidence on a PAMGS using MoL.According to Maxwell’s curl equations 35 to obtain the field components in the correct position. Using the same definition for 8. Figure According to Fig.  in Eqs.  and 14)\documententclass1pt{minima of Eqs.  and 16)\documentg to Eq.  for the TE(H) and TM(E) polarized waves are investigated simultaneously. According to Fig. For the case of oblique incidence, the two particular cases of  in Eqs.  and 19)TE(H) andIn the analysis of a multilayer PAMGS as shown in Fig. i is the number of layer. On the other hand, By definitiontute Eq.  into Eq.To obtain the transmission coefficient of the structure we should transform the fields in the opposite direction from the input to the output as followsIn short, we considered graphene as an especial impedance boundary condition at the interface of two adjacent layers due to its 2D structure and computed the reflection coefficient transformation formula through the interfaces, accordingly. Other 2D materials including Group-IV monoelemental honeycomb materials and binary compounds of group III-V elements can be treated similarly provided that we can model them as an appropriate boundary condition.36. Then, a multilayer PAMGS as a tunable THz absorber shown in Fig. To validate the proposed method, the numerical results for two different PAMGSs are obtained and compared with those of other methods. As the first example, the Faraday rotation effect achieved by a PAMGS as shown in Fig. x-directed wave at normal incidence. In presence of a magnetic field bias, the direction of the transmitted electric field is deviated from that of the incident wave by angle 36y- and x-direction due to an x-directed incident wave, respectively.The PAMGS shown in Fig. 36On the other hand, the transmission efficiency is defined by36 and a commercial software as shown in Fig. Intel Core i7 8700K CPU, 32 GB RAM desktop computer while the MoL took less than 4 seconds on the same computer. As it is seen the three sets of results agree very well. According to Fig. The Faraday rotation angle and the transmission efficiency of the structure shown in Fig. Moreover, to investigate the effect of the chemical potential on reflectance and transmittance, the co- and cross-polarized reflectance and transmittance for different 6. This absorber is composed of a perfect electric conductor (PEC), a continuous graphene sheet (CGS), and the periodic array of graphene strips (PAGS). The PEC, CGS and PAGS are separated with an intermediate dielectric layer. The PEC is used to suppress the transmission and increase the absorption.The next example deals with a tunable THz absorber reported made of a multilayer PAMGS as shown in Fig.6 as shown in Fig. x-directed wave with normal incidence. As illustrated in Fig. To evaluate the efficiency and accuracy of the proposed MoL in analyzing this absorber with TE and TM polarizations is investigated. As shown in Fig. TE and TM polarizations are almost the same. As the result, this absorber can be referred to as a polarization independent absorber6.Next, the effect of incident angle on absorption for both TE and TM polarizations by multilayer periodic arrays of magnetically biased graphene strips (PAMGS). First, we discretized the governing equations in transverse directions concerning the periodic boundary condition using finite differences. Then, the reflection coefficient transformation approach was used to obtain the reflectance and transmittance of the multilayer structure analytically. Since the graphene parameters are discretized with finite differences in transverse directions, we set the surface conductivity to zero where graphene is absent. Hence, there is no need to introduce approximate boundary condition to model graphene. On the other hand, due to the semi-analytical nature of the method, there is no demand for the use of absorbing boundary conditions in the longitudinal direction unlike fully numerical methods. These advantages have made MoL a powerful computational tool for analyzing multi-layered graphene-based periodic structures. To validate the proposed method, numerical results for different PAMGSs are obtained using the proposed method and compared with those obtained by other methods reported in the literature. In all cases, the two sets of the results agree very well, which confirms the validity of the method. Analyzing 3D graphene-based periodic structures with 2D periodicity will be the subject of our future work.In summary, we used the semi-numerical, semi-analytical method of lines (MoL) for the efficient analysis of the plane wave scattering in the most general case of oblique incidence for both


The interest in theresearch of the structural and electronic propertiesbetween graphene and lithium has bloomed since it has been proventhat the use of graphene as an anode material in lithium-ion batteriesameliorates their performance and stability. Here, we investigatean alternative route to intercalate lithium underneath epitaxiallygrown graphene on iridium by means of photon irradiation. We growthin films of LiCl on top of graphene on Ir(111) and irradiate thesystem with soft X-ray photons, which leads to a cascade of physicochemicalreactions. Upon LiCl photodissociation, we find fast chlorine desorptionand a complex sequence of lithium intercalation processes. First,it intercalates, forming a disordered structure between graphene andiridium. On increasing the irradiation time, an ordered Li(1 ×1) surface structure forms, which evolves upon extensive photon irradiation.For sufficiently long exposure times, lithium diffusion within themetal substrate is observed. Thermal annealing allows for efficientlithium desorption and full recovery of the pristine G/Ir(111) system.We follow in detail the photochemical processes using a multitechniqueapproach, which allows us to correlate the structural, chemical, andelectronic properties for every step of the intercalation processof lithium underneath graphene. Among alkalimetals, lithium is especially interesting since, in addition to itscapability to engineer graphene doping,10 it bears direct technologicalapplications for graphene-based lithium-ion batteries.14 In that context, several strategies have appeared focusing on obtaininglithium-intercalated graphene as an anode material by chemical methodologies.11 Nanomaterials, and particularly crystallinecarbon materials, such as graphite or graphene, play a critical rolesince they present high mechanical flexibility (volume expansion)and higher electrical conductivity 17 and enhance the reaction/protection of the activematerial in batteries.18 Moreover, thecore processes happening in a lithium-ion battery (charge and discharge)are based on the rocking-chair19 or intercalationchemistry. Therefore, alternative routes allowing the intercalationof lithium underneath graphene as well as a detailed description atthe atomic level of the structures formed during the intercalationprocesses may be of interest in the field.Graphene (Gr) has been extensively studied over the past decade,In this work, wepresent a combined synchrotron-based X-ray photoemissionelectron microscopy/low-energy electron microscopy (XPEEM/LEEM) studyof the Li/Gr system. The combined use of diffracted low-energy electronsand photoelectrons allows us to follow in real time the chemical,structural, and electronic processes occurring during lithium intercalationthrough graphene. We show that LiCl thin films on top of a singlelayer of graphene grown on an Ir(111) substrate photodissociate uponexposure to soft X-ray photons. We observe rapid chlorine-ion desorptionand a sequence of rapidly evolving lithium intercalation processes.In the first stage, Li intercalates, forming an amorphous two-dimensional(2D) structure that successfully decouples graphene from the Ir(111)substrate. For increasing irradiation time, Li reorganizes below graphene,forming an intercalated (1 × 1) structure. Upon further extensiveirradiation, lithium diffuses into subsurface positions in the metal.220 Since the sample surface is homogeneous, wegenerally used the largest available aperture size of 10 μmdiameter for microspot measurements, having only occasionally employedthe 5 μm diameter one. For repeated or different measurements,the sample was moved to obtain a fresh area for each exposure cycle.Samples were prepared in an ultrahigh vacuum (UHV) chamber with abase pressure of 1 × 10–10 mbar. LiCl  was sublimated from a homemade Ta crucible annealedat 720 K controlled by a type-K thermocouple spot-welded to it withthe sample kept at room temperature. Ir(111) surfaces were cleanedby repeated cycles of argon-ion sputtering and annealing in an oxygenatmosphere (T = 1373 K and Poxygen= 2 × 10–8 mbar). To avoid anyresidual oxygen on the surface, the last cleaning cycle was carriedout without oxygen. Graphene was grown on a single crystal of Ir(111),crystallographic plane (111), in a decomposition process of ethylene.In the first step, ethylene (P = 1 × 10–8 mbar during 30 s) is adsorbed on the sample at roomtemperature (RT), and then the sample is flashed up to 1373 K for30 s. In the second step, the sample is exposed to a higher ethylenepressure (P = 1 × 10–7 mbar),again followed by thermal decomposition at 1373 K for 7 min.21All of the experiments have been carried out in the LEEM/PEEM experimentalend station of the CIRCE beamline at the ALBA Synchrotron.3hν = 136 eV, photonflux about 2.5 × 109 photons/s·μm2) activates the Li photochemistry and triggers the subsequent Liintercalation stages. Immediately after starting the irradiation,the LiCl layers start to photodissociate. During this photo-inducedreaction, LiCl dissociates, lithium reduces and intercalates, andchlorine oxidizes, presumably desorbing as Cl2, althoughwe cannot rule out the possibility of chlorine-ion desorption withoutrecombination. This leads to stage 2, which is obtained during thefirst 10–20 s of photon exposure and consists of an amorphousLi layer intercalated between graphene and Ir(111): Gr/a-Li/Ir(111).Because LiCl films are several monolayers thick, there is a gradualprocess of continuous intercalation that lasts for the first 100 s.When the coverage of intercalated Li reaches the monolayer (ML), lithiumorders in a Li(1 × 1) superstructure, resulting in stage 3: Gr/Li(1× 1)/Ir(111). After long irradiation times, 500–600 s,the LiCl thin film is completely photodissociated, and the next stageof evolution is reached. In stage 4, Li atoms penetrate into Ir(111)first few layers and adopt subsurface positions: Gr/Ir-Li/Ir(111).Stage 4 is the final stable stage observed in our experimental sessionsfor sufficiently long photon exposure times. It is therefore presumablythe most energetically favorable configuration while irradiating.In addition, we note that the pristine G/Ir(111) (stage 0) can berecovered from stage 4 by annealing the sample up to 900 °C.20 Thestructure evolution was followed by low-energy electron diffraction(LEED), the chemical evolution was tracked by X-ray photoemissionspectroscopy (XPS), and the band structure was measured with microspotangle-resolved photoemission spectroscopy (μ-ARPES). Althoughwe have used an ideal substrate to depict the process, the resultscan be extrapolated to other sp2-based materials, likegraphite, graphene on SiC, or free-standing graphene flakes, and morelikely to any other 2D van der Waals system.The full sequence of processes has been studiedin real time bya multitechnique in situ characterization in the PEEM/LEEM experimentalstation at the Alba Synchrotron.3.1Supporting Information Movie 1). All of the diffractionpatterns were measured at the same electron energy (65 eV) in realtime on the same sample, allowing a direct comparison between thedifferent irradiation stages. The largest illumination aperture (10μm diameter) was used in all cases. Control experiments showthat the low-energy electrons of the LEED alone have a negligibleeffect on the chemistry of LiCl films.22 In this pattern, iridium (blue arrow), graphene(black arrows), and the moiré spots are well resolved. In stage1, a thin film of LiCl is grown on the sample at room temperature;as a result, a new feature appears in the LEED pattern in the formof a ring (The diffraction patternof stage 0 is a flower-pattern structurearising from the moiré pattern observed on the pristine Gr/Ir(111)(t) zero, we start photon irradiationat 16° grazing incidence on the LiCl/Gr/Ir(111) sample. In thefirst 10–20 s, a dramatic change is observed in the diffractionpattern . Indeed, we observed a similar effect during intercalationof NaCl.22 Comparison of the evolutionwith and without X-ray irradiation demonstrates that the primary causefor LiCl dissociation and thus Li intercalation is the illuminationfrom the synchrotron, although we cannot fully rule out a small effectof the electron gun used for LEED, probably in the form of desorptionof a small fraction of LiCl. The detection of an intense graphenediffraction pattern and the absence of any moiré spots areclear signs of intercalation-induced decoupling.24 It has been reported that submonolayer lithium intercalationcan efficiently decouple graphene from the metal substrate, ironingout its corrugation.25 At stage 2, neitherthe Ir(1 × 1) spots nor any other Li-related features are resolved,pointing out the lack of crystallinity in the Li-intercalated layer.9At time (9 When Gr/Li(1 × 1)/Ir(111) is reached, thegraphene layer remains structurally decoupled from the metal surfaceand there are no moiré spots in the diffraction pattern. Inour experimental sessions, stage 3 lasts over 600 s of photon irradiationtime. During this long irradiation time, the background intensityaround the  spot gradually increases and finally the moiréLEED spots start to become visible. A sudden change at around 700s leads to stage 4  (1 × 1) spots (purple arrow) inthe diffraction pattern and 400 eV (Cl 2p and C 1s core levels), respectively. The photonenergy used to measure C 1s and Cl 2p is not the same as the one usedfor the lithium core-level and for the LEED studies presented above.Control experiments show similar evolution dynamics for both energies,suggesting that the photophysically induced processes are analogousin the X-ray energy range inspected here. 7/2 spectra are shown in Figure S1). The Ir4f7/2 core-level appears ata binding energy (BE) of 60.8 eV.26 Weresolve three different components for the Li 1s (27 The L2 componentintensity increases and shifts toward a lower BE (up to 55.2 eV) asthe Li-intercalated coverage increases up to the monolayer saturationcoverage and the system reaches stage 3 (Gr/Li(1 × 1)/Ir(111)).8 The L3 component also appears in the first stagebut dramatically increases in stage 4. We assign this component toLi atoms intercalated below the first iridium layers. At the end ofstage 3, LiCl has completely disappeared and the intercalated Li coveragesaturates but irradiation continues. As a consequence, Li atoms areforced to intercalate in subsurface positions, and the system wouldeventually reach stage 4, Gr/Ir-Li/Ir(111).25 The presence of the L3 component demonstrates that lithium is presentin the sample even though the LEED pattern resembles that of a cleanGr/Ir(111) system. Only after the high-temperature annealing (grayspectrum), all Li 1s components disappear and the structure, chemistry,and energy bands of pristine Gr/Ir(111) are recovered.Li 1s and Ir 4f28  to C atoms in the sp2 configuration and notea small shift (0.7 eV) toward a higher BE with respect to pristineGr/Ir (284.1 eV),25 which points toward an effectiven-type doping of graphene.8 At this stage,there is also a broad component (C1) at a higher BE that we assignto a combination of charge effects as a consequence of the insulatingLiCl film and the LiCl/Gr interface (mostly Li atoms interacting withGr). Component C1 is reduced drastically upon irradiation, disappearingcompletely at the end of stage 3 where no traces of LiCl can be detected.A smaller component (C2) appearing as a shoulder at a higher BE ofthe sp2 one (0.8 eV w.r.t. sp2) remains almostunperturbed during the evolution of the system and is related to then-doping of graphene. Such a component has been observed in the literaturefor graphitic systems interacting with lithium and other alkali metals.8 After annealing (gray spectrum) and recoveringstage 0, the C 1s peak shifts toward a lower BE and narrows, and onlythe sp2 component of graphene on Ir(111) is resolved.25Finally, we focus on the C 1score-level 3c. In st3.3hν = 136 eV), we trackthe changes in the band structure and therefore in the doping of grapheneacross all of the stages of evolution . All of thestructural and chemical changes introduced above will necessarilyhave a direct impact on the electronic band structure of the system.Using μ-ARPES , possibly due to electrostatic effectscreated by the insulating LiCl film  bands are completely recovered after annealing.In stage 0, the μ-ARPES energy cuts reveal the p-dopednatureof the Gr/Ir(111) system.4In summary, we present a methodto intercalate lithium at the graphene/iridiuminterface by photodissociation of an adsorbed LiCl thin film. A combinedcharacterization with LEEM, XPS, and μ-ARPES allows us to followevery step of the intercalation process in real time. We show thatupon photon exposure, LiCl dissociates, chlorine atoms desorb, andlithium intercalates graphene. This is evidenced by the changes ofthe diffraction patterns, the fast decrease of Cl 2p core-level intensity,and the evolution of the Li 1s peak. When the intercalated lithiumamounts to one monolayer, a 1 × 1 structure appears in the LEEDpattern. Finally, the process reaches a final state with lithium remainingin a subsurface position in the iridium substrate, as evidenced bythe lithium core-level signal and the LEED pattern. μ-ARPESmeasurements show a high n-doped graphene behavior from the beginningof the Li intercalation processes. As the intercalation process takesover, graphene bands evolve to an effective p-doped behavior. Thephoto-induced sequence does not damage the graphene layer, as evidencedby the fact that the Gr/Ir(111) original stage can be recovered uponhigh-temperature annealing. Our fundamental study contributes to abetter understanding of the Li intercalation process in graphiticmaterials upon photophysical methods, which may lead to new pathwaysfor the improvement of next-generation graphene-based anodes for lithium-ionbatteries.


Electronic medical records (EMRs) offer the promise of computationally identifying sarcoidosis cases. However, the accuracy of identifying these cases in the EMR is unknown.The aim of this study is to determine the statistical performance of using the International Classification of Diseases (ICD) diagnostic codes to identify patients with sarcoidosis in the EMR.index of suspicion to identify cases with a high index of suspicion for sarcoidosis (confirmed and probable) based on clinical and radiographic features alone using the American Thoracic Society practice guideline. Through medical record review, we determined the positive predictive value (PPV) of diagnosing sarcoidosis by two computational methods: using ICD codes alone and using ICD codes plus the high index of suspicion.We used the ICD diagnostic codes to identify sarcoidosis cases by searching the EMRs of the San Francisco and Palo Alto Veterans Affairs medical centers and randomly selecting 200 patients. To improve the diagnostic accuracy of the computational algorithm in cases where histopathological data are unavailable, we developed an high index of suspicion to identify confirmed sarcoidosis cases increased the PPV significantly to 100% (95% CI 96.5%-100%). Histopathology documentation alone was 90% sensitive compared with high index of suspicion.Among the 200 patients, 158 (79%) had a high index of suspicion for sarcoidosis. Of these 158 patients, 142 (89.9%) had documentation of nonnecrotizing granuloma, confirming biopsy-proven sarcoidosis. The PPV of using ICD codes alone was 79% (95% CI 78.6%-80.5%) for identifying sarcoidosis cases and 71% (95% CI 64.7%-77.3%) for identifying histopathologically confirmed sarcoidosis in the EMRs. The inclusion of the generated index of suspicion data elements could significantly improve the case-identification accuracy.ICD codes are reasonable classifiers for identifying sarcoidosis cases within EMRs with a PPV of 79%. Using a computational algorithm to capture  Sarcoidosis is a complex disease with an unknown etiology that can involve multiple organs, and no universal or standardized measures can fully secure its final diagnosis -3. In fastructured data, including billing codes such as the International Classification of Diseases (ICD) codes, laboratory test results, and procedural codes; and (2) narrative or unstructured data, including progress notes, pathology reports, and imaging reports. ICD codes cast a wider net to capture patients in the EMR because they include both inpatient and outpatient claims compared with other classifiers such as Diagnosis-Related Group that only capture inpatient claims [Data from electronic medical records (EMRs) are commonly used in research and by health care systems, including the United States Department of Veterans Affairs (VA), to predict outcomes or assess care quality . EMR datt claims . Unstruct claims ,7,8. A ft claims -13. Anott claims  but onlyt claims -17. Moret claims -24. For t claims , Bayesiat claims .As the first step in evaluating the knowledge gap in developing future sarcoidosis-specific “computationally identifying algorithms,” we designed this study (1) to estimate the statistical performance of using diagnostic codes (ICD-9 and ICD-10) alone compared with a new approach that uses additional information from radiology and clinical domains, but not histopathology, to inform the utility of these codes for performing clinical phenotyping of sarcoidosis cases in large EMR data sets of the VA and (2) to assess the computational challenges in querying sarcoidosis cases and extracting high-quality sarcoidosis-related research variables from the EMR accurately.This was an observational retrospective study of EMRs available through VA Informatics and Computing Infrastructure (VINCI). VINCI provides access to comprehensive and integrated veterans’ national deidentified data sets and offers the necessary computational and analytical tools in a secure, high-performance computing environment ,27. ThisWe searched the EMR data in VINCI from 1989 to 2019 and identified all patients coded as having sarcoidosis in the VA health care system, as defined by the documentation of the ICD-9 and ICD-10 codes of 135 and D86.x (including subcodes), respectively. Data were extracted through executing SQL queries in an SQL Server 2017 database. A total of 14,833 sarcoidosis cases were identified.lottery method to randomly select 100 patients from each site without a replacement [To determine the statistical performance of using diagnostic codes (ICD-9 and ICD-10) in identifying patients with sarcoidosis from the EMR, initially, we identified patients with at least one claim (inpatient or outpatient) of ICD diagnosis code for sarcoidosis. To ascertain the true diagnosis of sarcoidosis based on the ATS diagnostic criteria  , 2 clinilacement   based on clinical and radiographic information, regardless of the availability of biopsy data, and to assess whether this approach would improve the diagnostic accuracy. The index of suspicion was applied to the initial cohort of patients with ICD codes for sarcoidosis (n=200). The clinical and radiological features were extracted from the available structured and unstructured data without including the histopathology results. If the patients were documented to have one or more of these features, they were assigned to the high index of suspicion group Heerfordt syndrome Lupus pernio or erythema nodosumMaculopapular or erythematous skin lesions or nodulesFacial nerve palsySymmetrical parotid enlargementOptic neuritis, scleritis, uveitis, or retinitisLacrimal gland swellingEvidence of granulomatous disease on direct laryngoscopyHepatomegaly or splenomegalyShortness of breath, dyspnea on exertion, cough, dizziness, or chest painPulmonary function test with obstruction, restriction, or low diffusing capacity of the lungs for carbon monoxideCardiomyopathy, cardiac arrhythmia, or atrioventricular node blockHypercalcemia, hypercalciuria, nephrolithiasis, or abnormal vitamin D levelsElevated angiotensin-converting enzyme inhibitors or soluble interleukin-2 receptorsBronchoalveolar lavage lymphocytosisRadiologicalBilateral hilar lymphadenopathy Computed tomography chest with perilymphatic nodules tracking the peribronchovascular bundleDiffuse infiltrates  or computed tomography chest or chest radiograph with fibrosisCardiac magnetic resonance imaging or positron emission tomography–computed tomography consistent with sarcoidosisEnlargement or nodules in liver or spleen Magnetic resonance imaging brain with increased inflammationExtrathoracic enlarged lymph nodes sarcoidosis with confirmed biopsy. Patients with a high index of suspicion and either no documented biopsy in the EMR or a biopsy showing no histopathological evidence of nonnecrotizing granulomas were categorized into the group of sarcoidosis without confirmed biopsy (probable sarcoidosis). Finally, those with a low index of suspicion were categorized into the group of unlikely sarcoidosis  to determine whether the use of this index of suspicion could improve the PPV of identification of sarcoidosis cases in the EMR.Using the This approach provides more information than just relying on ICD codes alone to develop robust computational sarcoidosis-specific algorithms consistent with the recent ATS practice guideline recommendations.Organ involvement was assessed based on the clinical history obtained from physicians’ notes and imaging and biopsy reports available in the computerized patient record system. For this assessment, to adjust for the variability in providers’ documentation, we adapted a set of criteria previously introduced in the National Institutes of Health–sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study .We collected the following data from the chart review: clinical site, gender, race, ICD-9 and ICD-10 codes for sarcoidosis , the pathological diagnosis from any available biopsy, organ involvement as described in primary histopathological if the data were available in the pathology report domains and secondary if the data were available only in the clinical note domains because of either a remote history of biopsy or because the biopsy had been performed outside the VA. The PFT reports at the SFVA and PAVA used Crapo reference equations to calculate the lower limit of normal values for spirometry and lung volume measurements.Pathological diagnoses were categorized into multi-organ phenotype, which we defined as the involvement of ≥3 organs.Using the clinical data from chart abstraction, we classified the patients into the clinical phenotypes proposed by the GRADS study, with the exception of Organ and assessmentLungPositive lung biopsy and positive mediastinal or hilar lymph node biopsyChest x-ray, computed tomography (CT) chest, or positron emission tomography (PET) demonstrating bilateral hilar lymphadenopathy; CT chest with perilymphatic nodules tracking the peribronchovascular bundle; chest X-ray, CT chest, or PET with diffuse infiltrates; and CT chest or chest x-ray (CXR) with fibrosisPulmonary function test (PFT) with obstruction, restriction, or low diffusing capacity of the lungs for carbon monoxide (DLCO)SkinPositive skin biopsyLupus pernio and erythema nodosumEyePositive conjunctival or scleral biopsyOptic neuritis, scleritis, uveitis, or retinitisCardiacPositive heart or pericardium biopsyAtrioventricular node block (second or third degree)Cardiomyopathy responsive to treatmentCardiac arrhythmia Cardiac magnetic resonance imaging (MRI) or PET-CT consistent with sarcoidosisLiver or spleenPositive liver or spleen biopsyEnlargement or nodules in liver or spleen Abnormal liver enzymesNeurosarcoidosisPositive brain or dura or peripheral nerve biopsyClinical syndrome or symptoms consistent with central nervous system sarcoidosis along with a positive MRIEar, nose, and throatPositive biopsy from ear, nose, or throatDirect laryngoscopy consistent with granulomatous diseaseMulti-organ involvement≥3 organs involved based on other criteria in this tableindex of suspicion). We did not report the positive likelihood ratio, given that the specificity for using ICD codes alone could not be calculated because our study design did not include a review of noncases. The PPV for the criterion of using only the ICD code was calculated as the number of patients with an ICD code for sarcoidosis divided by the total number of patients verified to have sarcoidosis by chart review (gold standard). The PPV for the criterion of using the ICD codes and index of suspicion was calculated as the total number of patients with a high index of suspicion divided by the number of patients verified to have sarcoidosis by chart review (gold standard). The sensitivity of histopathology reports alone compared with chart review was calculated as the total number of patients with a high index of suspicion and confirmed biopsy divided by the number of patients verified to have sarcoidosis by chart review (gold standard). We computed 95% CIs using the exact binomial method. For our estimates, significance was defined as P<.05.All statistical analyses were performed with R software  using RStudio (version 1.2.5). Descriptive statistics were computed to summarize the data. Categorical variables were presented as the frequency in percentages, and continuous data were presented as means and SDs. We estimated the PPV of the two aforementioned computational diagnostic criteria for sarcoidosis  were identified with the ICD-9 code of 135 and 50 (31.6%) with the ICD-10 code of D86, and 142 (89.9%) had confirmed sarcoidosis based on histopathological evidence of nonnecrotizing granuloma and were classified as having sarcoidosis with confirmed biopsy; the remaining 16 (10.1%) patients with a high index of suspicion did not undergo a biopsy and were classified as having sarcoidosis without confirmed biopsy . Of the 200 patients, 158 (79%) had a P=.18). In terms of clinical phenotypes, 37.9% (60/158) had a multi-organ disease , followed by stage II or stage III treated . Our study cohort did not include any individuals with acute presentation . Some patients overlapped with multiple clinical groups.high index of suspicion to identify confirmed sarcoidosis cases increased the PPV significantly to 100% (95% CI 96.5%-100%) with 90% sensitivity of histopathology reports alone compared with chart review  for identifying sarcoidosis cases and 71% (95% CI 64.7%-77.3%) for identifying histopathologically confirmed sarcoidosis in the EMR. After chart review, the inclusion of the generated t review .index of suspicion to the initial cohort, we also demonstrated that including a high index of suspicion that incorporated information from radiology and clinical domains, but not histopathology, significantly increased the diagnostic accuracy to 100% (95% CI 96.5%-100%). The results of this study will help researchers and health care systems better understand the accuracy of using diagnostic codes alone versus using ICD codes with a high index of suspicion for sarcoidosis as classifiers in detecting a complex disease such as sarcoidosis in the EMR. Furthermore, the study highlighted other computational challenges in querying sarcoidosis cases and accurately extracting high-quality sarcoidosis-related research variables from the EMR. This approach could be adapted to develop automated chart review algorithms using additional data elements from structured and unstructured domains by applying advanced computational methodologies such as natural language processing (NLP) and machine learning.In this observational retrospective study of VA EMRs, we reviewed the medical records of 200 randomly selected patients with ICD diagnostic codes for sarcoidosis from the SFVA and PAVA medical centers . In thisThe randomly selected cohort of veterans in this study with sarcoidosis (with and without confirmed biopsy) consisted of 89.9% 142/158) of men and 10.1% (16/158) of women. Although the gender distribution in our study was different from that in A Case Control Etiologic Study of Sarcoidosis , it is c2/158 of Using ICD codes alone to extract health information is far more convenient than the time-consuming process of manually reviewing narrative data sets in unstructured data. However, using ICD codes to identify sarcoidosis cases in large data sets with thousands of patients poses several practical challenges. First, given the heterogeneity of sarcoidosis, it is challenging to efficiently confirm the presence of the disease. The verification process requires careful analysis of the available narrative data such as progress notes, imaging reports, and pathology reports to establish the case definition based on the sarcoidosis diagnostic criteria . Second,Moreover, there are no specific ICD codes for classifying the involvement of some organs in sarcoidosis  . Third, The definition of clinical phenotypes has become an essential goal for the sarcoidosis scientific community because genetic studies have identified different patterns of gene expression associated with disease severity and disease course ,41. In 2high-throughput phenotype algorithm using only structured data  and (2) a low-throughput phenotype algorithm that accesses structured and unstructured data to develop a sequential flowchart that should end with a case definition. Such a low-throughput approach uses high-performance computational tools such as NLP to process text and extract information using linguistic rules, thereby eliminating the need for a labor-intensive manual review by researchers [The two most applied approaches to defining computational phenotypes are (1) a earchers . Accordiearchers . Our stusecondary histopathological reports documented in the providers’ narrative within the clinical notes. This approach made the diagnosis of sarcoidosis less robust because the confirmatory biopsy reports in these patients could not be directly verified. However, we used the index of suspicion approach to define probable sarcoidosis cases regardless of whether a confirmatory biopsy report was available, which is consistent with the diagnostic algorithm recommended by the ATS practice guideline [multi-organ phenotype involved ≥3 organs, instead of ≥5 organs as proposed by the GRADS study [multi-organ phenotype. Lack of patients with involvement of ≥5 organs could be due to EMR-related limitations such as missing data and variability in documentation among providers or simply because these patients were cared for at non-VA tertiary medical centers. Third, the generalizability of our findings obtained from VA EMRs to other populations could be limited because the veterans form a special population with a different demographic distribution and exposure from the general population. However, the EMR data of the VA health care system cover >22 million veterans across the United States and >14,000 patients with sarcoidosis ICD diagnosis codes, providing an enormous number of patients to study a rare disease. Moreover, the number of patients whose records were examined in this study was 200, which could be considered a small sample size. However, we analyzed data from nearly two-third of all patients with diagnostic codes for sarcoidosis in the VA health care system across northern California.Our study includes several limitations. First, primary histopathological reports were not available for all the patients. In the cases where the biopsy report was unavailable (either because of a remote history of the biopsy or because the biopsy had been performed outside the VA), we relied on the uideline . Second,DS study . We chosindex of suspicion) from unstructured data could significantly improve the accuracy of case identification. Furthermore, to increase the efficiency of identifying sarcoidosis cases from large health care databases, more studies are required to develop a novel sarcoidosis-specific computational phenotype algorithm using automated emerging methods (such as machine learning and NLP). Moreover, our study sets the stage for promoting research on developing other such algorithms aiming to generate high-quality sarcoidosis-related research variables, such as determining the date of the diagnosis, organ involvements, Scadding stages, and the clinical status .Although ICD codes can be used as reasonable classifiers to identify sarcoidosis cases within EMRs with a PPV of 79%, using computational algorithms to extract clinical and radiographic information (


The effect of the size of nickel nanoparticles on the fabrication of a Ni–graphene composite by hydrostatic pressure at 0 K followed by annealing at 1000 and 2000 K is studied by molecular dynamics simulation. Crumpled graphene, consisting of crumpled graphene flakes interconnected by van der Waals forces is chosen as the matrix for the composite and filled with nickel nanoparticles composed of 21 and 47 atoms. It is found that the main factors that affect composite fabrication are nanoparticle size, the orientation of the structural units, and temperature of the fabrication process. The best stress–strain behavior is achieved for the Ni/graphene composite with Ni Graphene is a new two-dimensional 2D) structure  that is D structuperature ,5, to naperature ,7,8,9,10perature . Even a perature .The review by  containsLayered metal/carbon composites were also widely studied. In , it was The mechanical properties of layered graphene metal composites are strongly influenced by the graphene/metal interface. On the one hand, it can prevent the dislocations gliding, which reduces the strength properties of the composite. On the other hand, such interfaces can be a dislocation source in the metal matrix, leading to a degradation in mechanical properties or even failure ,27,28,29d strain ,36,37,38d strain ,40.Experimental production of carbon metal/graphene composites is a rather expensive and energy-consuming process. Since the structure peculiarities considerably depend on the experimental technique applied to obtain metal/graphene composite ,42,43, dIn most theoretical ,49,50,51In rly work . Taking z-axis to obtain a small flake. Graphene flakes filled with Ni nanoparticle were randomly rotated and translated x-, y-, and z-axes correspondingly to obtain 3D initial structure shown in The graphene flakes (GFs) initially were armchair carbon nanotubes , cut along the  results ,40.Periodic boundary conditions were applied in all directions. All of the simulations were conducted using the LAMMPS package with the AIREBO  interatoEquations of motion for the atoms were integrated numerically using the fourth-order Verlet method with the time step of 0.1 fs. A Nose-Hoover thermostat was used to control the system temperature under the NVT and NPT canonical ensembles (the substance amount (N), volume (V) or pressure (P) and temperature (T) are constant) when simulating the compression/tension of the structure and the annealing process, respectively.It was shown earlier by the authors of ,40 that x-, y-, and z-axes. The tension strain rate for each loading type was p= rotated so that the zigzag edges of the graphene flake extends along the I).In particle  and not I, II, III, and IV points in Annealing at 2000 K does not lead to a significant difference in the stress–strain state of the CG21 and CG47 composites: The process of fracturing the Ni/graphene composite after the ultimate tensile strength is achieved is shown on the example of GF filled with Nit 2000 K a–d. CarbFrom x-, y- and z-axes correspondingly after annealing at 1000 K (solid lines) and 2000 K (dashed lines) are presented together with the characteristic snapshots of the structure under tension. Only the main stress component . However, tensile stresses for CG47 after annealing at both temperatures have grown to the value of 120 GPa (points III and IV on the red curves).For the same reason, a difference of about 18% is observed in tensile stresses upon deformation of the CG47 composite after annealing at 1000 K and 2000 K at points x-axis, a gradual rearrangement of the graphene structure occurs due to the breaking of old bonds and the formation of new bonds between carbon atoms. As a result, the volume fraction of pores and voids remaining in the Ni/graphene composite CG47 after annealing at 1000 K significantly decreased and the structure of this composite under tension became almost identical to the structure obtained after annealing at 2000 K (see III and IV). This can explain the equality of stresses at points III and IV on the red curves. In this case, Ni atoms are evenly distributed throughout the CG47 composite. Comparatively, for the CG21 composite, Ni atoms are distributed inhomogeneously over the graphene surface during tension (see A and B), which inhibits the decrease in the volume fraction of pores due to the transformation of the graphene structure.Structural analysis showed that, during uniaxial tension along the sion see b A and Bx-axis. Atoms in blue show carbon atoms located along the zigzag direction of GF. Other graphene flakes after hydrostatic compression and annealing are oriented along the x-axis in almost the same way as in x-axis of the entire composite corresponds to the zigzag direction of graphene flake edge, which can lead to significant elongation of the obtained Ni/graphene structures to a strain of 3.5. As can be seen, bonds are straightened along x-axis before rved see d–f. In te formed f and amoy-axis and the corresponding snapshots of the structure at critical points. As for hydrostatic tension, an increase in the annealing temperature to 2000 K leads to an increase in the ultimate tensile strength for CG21 and CG47 by 15% and 23%, respectively , the stress/strain curves show a slow stress decrease.vely see a. A greavely see b; this cA, B, C, and D in y-axis . Tension of the composite results in a break in the carbon interatomic bonds . However, an increase in the annealing temperature to 2000 K leads to a significant increase in the ultimate tensile strength. The tensile strength for the CG21 (CG47) composite annealed at 2000 K is 72% (54%) more than that of the composite annealed at 1000 K. Such a large difference in tensile stress is associated with a decrease in the bulk porosity of composites with an increase of the annealing temperature.y axis, at ound see a–f.For correlation analysis, In x axis, and this direction coincides with the zigzag edge of the GF. It is known that the graphene strength along the zigzag direction is higher than that along armchair direction. Thus, the stress–strain curve for tension along the y-axis is lower for both composites. In the case of tension along the z-direction, a single flake is oriented by its open side. During compression, two edges of the initial flake can interconnect between each other and form something similar to a small nanotube. The fracture takes place along the armchair-type edge of this new structural element. However, it is the weakest direction since the edges around open side are not connected by covalent bonds and can be easily opened.The highest tensile stress value is achieved during uniaxial tension along the Composite CG21 exhibits better compression since the NiIn the structure with Nipression ,40,61. MFor all of the cases of uniaxial tension, structural amorphization occurred at The observed difference in the stress–strain curves in x-, y-, and z-axes.Molecular dynamic simulation is used to fabricate Ni/graphene composites with Nix, y, and z directions are very different. The most homogeneous structure is obtained for the CG47 composite after hydrostatic compression followed by annealing at 2000 K.It is found that all investigated composites have anisotropic strength properties. This is due to the fact that the volume fraction of pores and voids in the x-axis of composites annealed at 2000 K. In the process of uniaxial tension, the breaking of old and the formation of new covalent bonds took place, which led to the transformation of the graphene structure into an amorphous one. Thus, a high strain is achieved before the failure of the composites. At large strain, long mono-atomic carbon chains are formed with alternating double and triple bonds between carbon atoms.The best stress–strain behavior is observed under uniaxial tension along the It is found that, using hydrostatic compression followed by annealing at 2000 K, it is possible to fabricate a Ni/graphene composite; however, it is necessary to achieve a more homogeneous structure with a smaller volume fraction of pores and voids, which will lead to a decrease or complete disappearance in strength property anisotropy.