As pump intensity increased from 0 to 15 W/mm2, we observed a loss–gain–loss transition process, which was discussed in detail through coupled-mode theory. In addition, amplification at different frequencies was achieved by merely re-optimizing the geometric parameters of the dielectric resonators. This study offers an effective solution for enhancing terahertz radiation and developing terahertz lasers.Graphene under optical pump has been shown to be an attractive gain medium with negative dynamic conductivity at terahertz frequencies. However, the amplification over a monolayer graphene is very weak due to its one-atom thickness. In this paper, the proposed graphene-dielectric reflective metasurface effectively improved terahertz field localization and enhanced coherent amplification. The amplification coefficient of 35 was obtained at 3.38 THz at room temperature with an infrared pump intensity of 8 W/mm Terahertz (THz) radiation from 0.1 to 10 THz is the least studied subrange on the electromagnetic spectrum. Many efforts have been devoted to the generation and detection of THz waves, which promotes the rapid development of THz imaging, THz non-invasive detection, and next-generation wireless communication technology . Among ohν < 2EF), is slightly absorbed by graphene due to the intraband carrier transition. In contrast, graphene shows universal absorption of 2.3% from the interband carrier transition when hν > 2EF. Besides the absorption modulation in graphene, the study by Otsuji, T., et al. showed that a sufficiently strong optical pump [EF−ħω/2 through carrier–carrier scattering, after which they occupy the energy states closer to the Dirac point through the emission of a series of optical phonons [Graphene, composed of two-dimensional (2D) carbon atoms arranged in a hexagonal lattice, exhibits many fascinating properties ,8, inclucal pump ,13 or cucal pump  may inve phonons ,16,17. T phonons  and infr phonons , indicate2/2ħ. The one-atom thickness further limits the interaction of graphene with the THz waves, leading to a negligible amplification effect. The amplification can be enhanced by using multiple layers of graphene [However, the negative dynamic conductivity is one or two orders smaller than the characteristic conductivity graphene ,19,20, bgraphene , and by graphene ,23,24. Tgraphene . HoweverIn this paper, we studied the enhanced THz amplification when the optically pumped graphene was combined with dielectric metasurfaces. Without material loss, the high-Q resonance of the dielectric resonator together with the back mirror significantly enhanced the field intensity around and outside of the graphene, leading to power amplification coefficient of 35 at room temperature with monolayer graphene. The complex conductivity of graphene was always considered. The transition from absorption to gain, with different pump intensity, was studied in detail based on the coupled-mode theory. The gain frequency was changed by optimizing the geometry of the dielectric resonators.kB is the Boltzmann constant, ħ is the Planck’s constant, ω is the electromagnetic wave frequency, T is the temperature, and Fermi energy EF is related to the pump intensity byα is the fine-structure constant, νf is the Fermi velocity, and I is the pump intensity. Here, the relaxation time λ was 1.5 μm.The dynamic conductivity of graphene under optical pump can be described by : (1)σ=σiσintra is always positive. The real part of σinter in the Equation (3) assumes negative values when the photon energy is less than twice that of the Fermi energy (ħω < 2EF). The conductivity met this condition when graphene was pumped at high pump intensity I (see Equation (4)). When the negative σinter is large enough to cancel the positive σintra, the total conductivity becomes negative. However, with a further increase in pump intensity, σinter tended to saturation and σintra increased. The total conductivity became positive again. −5 S. At a fixed THz frequency, such as 4 THz  with the requirement of a slightly higher pump intensity.As one can see from Equation (2), the real part of the conductivity hd. The transmission line model of this structure is shown in hd (air was considered for simplicity) was set at 28 μm. The transmission line was shorted by the back mirror. The reflection coefficient of the normal excitation can be calculated by [We first considered a simple structure of optically pumped graphene sheet on top of a back mirror. The graphene and the mirror were separated by a distance of lated by :(5)r=1η0Bd = cos (khd)/((tan (khd/2) − 2η0 × sin (khd))) is the susceptance of the short-circuited transmission line, whose variation with frequency is shown in r1 from Equation (5) is shown in the dB = 0, i.e., the air thickness hd = λ/4. The peak reflection coefficient is a finite number instead of infinity due to the limited precision of the data points. However, the actual conductivity −5 S . The periodic boundary conditions were applied at the x and y boundaries and perfect electric conductor (PEC) at the −z boundary, while the Floquet port was adopted at the +z boundary for both incidence and detection of the electric field Ey. The simulation results perfectly agreed with the theoretical ones in Here,  −10−5 S , which ip = 51.5 μm. The dielectric resonator was a split-ring resonator (SRR) made of silicon, with inner radius rin = 6.8 μm, outer radius rout = 13.7 μm, thickness hSi = 28 μm, and opening angle θ = 14°. The opening was symmetric with respect to y = 0. The surrounding medium was air and would later be replaced with low-index dielectric toward the end of the study. This graphene-dielectric metasurface was illuminated by y-polarization  plane wave. The transmission responses of the pure SRR array without graphene and the back mirror is investigated in f1 = 3.36 THz and f2 = 3.5 THz. The corresponding near-field distributions at f1 and f2 were investigated. The electric fields at both frequencies were well confined in the opening gap of SRR as can be seen in f1 than at f2, as the Q factors of the two resonances were around 170 and 17, respectively. The high-Q resonance at f1 showed great potential to enhance the interaction of THz waves and graphene once the graphene was attached to the dielectric metasurface.In order to enhance the interaction between the gain medium and the THz waves, the monolayer graphene was attached to an array of dielectric resonators , and thef1. Graphene was lossy with positive f1. The corresponding field intensity at the top interface  as ,30,31: rin = 7.59 μm, rout = 12.36 μm (2), rin = 10.43 μm, rout = 15.96 μm (3), rin = 18.29 μm, and rout = 23.00 μm. All of them had the same opening angle of 14°. The reflection amplitude as a function of frequency is plotted in I = 0.35 W/mm2 and T = 77 K, an amplification coefficient of 55.6 was obtained at 1.75 THz; after, we re-optimized the lattice constant and radius . As the temperature moved away from 77 K, the gain effect gradually decreased, and the operating frequency also shifted slightly. As mentioned earlier, this is mainly due to the temperature dependence of both the real and imaginary parts of graphene conductivity.In the last step, we embedded the silicon SRRs into poly(methyl methacrylate) (refractive index of 1.48) in the reflective metasurface, and kept their top interfaces aligned so that the monolayer graphene could still touch the top interface of SRRs. We optimized the structure to maximize the reflection gain when the pumping intensity was 8 W/mm2. Within the coupled-mode theory, we analyzed the mechanism of loss and gain of the hybrid metasurface with different pump intensities. In addition, THz amplification frequency was widely designable by controlling the split-ring dimensions.In summary, we proposed and numerically investigated the amplification of terahertz (THz) radiation based on photo-pumped graphene-dielectric hybrid metasurface. The initial study showed that the monolayer graphene with back mirror was not enough to stimulate sufficient amplification no matter the pump intensity. Graphene was then attached to the high-Q silicon split-ring reflective metasurface, so that the strong field localization enhanced the interaction between terahertz wave and graphene. The amplification coefficient of 35 was obtained at the resonance frequency of 3.38 THz at room temperature with an infrared pump intensity of 8 W/mm


Sarcoidosis is a granulomatous disorder of unknown etiology characterized by noncaseating granulomas virtually in every organ and tissue. This finding represents the most important diagnostic clue to reach a correct definition of sarcoidosis, although the biopsy is invasive and has several risk procedures. Several efforts are made to suspect the diagnosis of sarcoidosis by combining noninvasive elements, in particular from imaging, though these findings are often nonspecific and reflect the wide multifactorial pathogenesis. Every effort should be made to obtain a detailed radiological picture that, if associated with a suggestive clinical picture, could avoid the need of biopsy in some specific cases. In this narrative review, we aim to describe main computed tomography (CT) features of pulmonary and abdominal sarcoidosis, by reporting strengths and limits of this technique, in particular for the identification of extrapulmonary, isolated disease. Sarcoidosis is a granulomatous disorder of unknown etiology where noncaseating and nonnecrotizing granulomas represent the histopathological key of the disease . Often, A literature search was performed on public databases . Search queries were the following: “sarcoidosis” AND imaging OR computed tomography; “sarcoid lesions” AND imaging OR computed tomography; “pulmonary” AND sarcoidosis OR sarcoid lesions; “lung” AND sarcoidosis OR sarcoid lesions; “abdominal” AND sarcoidosis OR sarcoid lesions. Duplicate papers were considered only once. Papers were excluded if the topic was not adherent to the theme of pulmonary, abdominal sarcoidosis and computed tomography. Papers with the main text not in English language were excluded as well.Sarcoidosis is a multifaceted disease where the clinical picture can be totally asymptomatic at the onset (in up to 50% of cases)  and clinThe nonspecific presentation of several cases of sarcoidosis, in particular when there is no lung disease and the abdominal involvement is isolate, has led to the definition of chameleon disorder ,5,6. LunAt present, there is no agreement on the real incidence of gastrointestinal sarcoidosis, that is reported to be very rare . However, the real epidemiology is unknown because most cases have an asymptomatic course, and it is supposed that the real incidence is larger than that actually described, as documented by postmortem studies ,9.Among all abdominal manifestations, the involvement of the liver and spleen is most frequent—reported to be around 10–25% of the cases. Various degrees of nonspecific liver test abnormalities can, however, be observed , with or without constitutional symptoms such as weight loss, anorexia, fever and night sweats. Less frequently, symptoms of cholestasis such as pruritus and jaundice can be found .In the past, before the diffusion of high-resolution CT (HRCT), which allows a clearer definition of the interstitium impairment from sarcoidosis, lung involvement patterns were defined based on the Scadding classification at chest X-ray. This classification defines as stage I the presence of bilateral hilar adenopathy , panel AIn an appropriate clinical context, there are also radiological HRCT patterns of mediastinal and parenchymal involvement which are virtually diagnostic of sarcoidosis. This is the case in which the enlargement of lymph nodes is present at the subcarenal level and symmetrically at the hilar level , associaBecause of their typical lymphatic predilection, the nodules are mainly grouped along the bronchial vascular bundles, interlobular septa, interlobar fissures, and subpleural areas . The nodIn addition to presenting with typical radiological characteristics, sarcoidosis can manifest with a wide spectrum of atypical HRCT images such as unilateral and asymmetric hilar or mediastinal lymphadenopathy of the parenchyma that mimic a mass, ground-glass opacity, miliary distribution of opacities, thickening of the interlobar septa and fibrocystic changes ,14,17. FAtypical findings at HRCT raise several issues of differential diagnosis with other primitive or secondary lung disorders. Lymphangitic carcinomatosis (LC) differs from sarcoidosis because here the nodules are more distributed along the fissures and in the subpleural area compared to those of LC . FurtherWhen sarcoid nodules are isolated, more voluminous and confluent in the subpleural area, they can mimic the pseudo-plates of silicosis. Additionally, the presence of fibrotic lesions confluent in parailar conglomerates, and the distribution of lymph node calcifications with “eggshell” patterns are radiological findings that can mimic silicosis . The keyWhen lymph node involvement from sarcoidosis is more asymmetric and unilateral, especially if it is associated with less typical consolidative lung lesions, the suspicion is of a lymphoproliferative disorder, which in some forms can also be associated with peribroncovascular nodules; the predominant nodular and mid–upper craniocaudal perilymphatic distribution of the lesions can orient toward sarcoidosis, as stated before.A disorder that can be misdiagnosed as sarcoidosis and that manifests similarly to lymphoma is the multicentric Castleman disease (MCD). This rare disease affects lymph nodes and related tissues diffusely and causes fever, lymph node enlargement, dyspnea, hepato and splenomegaly, weight loss and loss of appetite. Typical findings are the lymph node enlargement found at CECT and, unlike sarcoidosis, the serum elevation of IL-6 levels. Biopsy is mandatory to reach the definitive diagnosis . SimilarSarcoidosis can sometimes affect the small airways and manifest with airflow obstruction, mimicking COPD. Additionally, lung carcinoma can be erroneously misdiagnosed as sarcoidosis, in particular when the irregular nodular lesions are single and located unilaterally .Tuberculosis (TB) should always enter into differential diagnosis with sarcoidosis, especially in the high-risk areas considered and in immunocompromised patients. More specific characteristics of TB reactivation are the HRCT presence of exudative lesions, acinar nodules and the tree-in-bud sign. Lymph node calcifications from TB can be recognized because they are denser than in sarcoidosis and tend to be more often unilateral, while in sarcoidosis, they are more often bilateral .The problems become more challenging when the two disorders coexist; in this case, the need for a biopsy is high to reach the correct diagnosis, in particular when sarcoidosis has an atypical clinical course ,22.In the case of a patient’s presentation in the full fibrotic phase, the diagnosis of sarcoidosis can be suggested by the characteristic centrifugal and dorsolateral distribution of fibrotic lesions with a prevalence in the upper lung fields. In advanced stages, the characteristics of fibrosis can include linear opacities, pulmonary arch distortion, traction bronchiectasis and honeycombing located mainly in the upper lung fields  23]..23].HRCT can be indirectly helpful to evaluate the prognosis of sarcoidosis patients by differentiating reversible from irreversible lesions. Lesions such as micronodules, nodules or peribroncovascular thickenings can undergo regression spontaneously or after treatment. Ground glass lesions have variable reversibility. Irreversible lesions include honeycombing, traction bronchiectasis and emphysematous bubbles . SeveralA recent HRCT score based on the presence of ground glass opacities, thickening of the interlobular septa and parenchymal consolidations can allow the quantification of the disease activity and predict the variation of forced vital capacity after a year of therapy ,26. Wals1) with characteristic images at HRCT . This score has demonstrated a high predictive value in terms of mortality [Another integrated clinical and radiological staging system combines a composite physiological index (derived from the diffusion capacity of carbohydrate monoxide (TLCO or DLCO), forced vital capacity and forced expiratory volume in the 1st second of expiration, FEVortality .HRCT can also be useful in sarcoidosis to reveal some complications such as mycetomas that occur in 2% of all patients with sarcoidosis and have a higher incidence in patients with pulmonary fibrosis, pre-existing lung cavities, cystic lung disease and bronchiectasis. Mycetomas are masses within a cavity in the fibrotic forms, that can be a potential source of fatal hemoptysis . Another18-FDG PET/CT has an important role in the evaluation of the inflammatory activity in several disorders, infectious, inflammatory and not. Recently, some studies have found that 18-FDG PET/CT (more than 67Ga scintigraphy) can also be accurate to reveal the presence of hyperactivity from sarcoid lesions in each involved organ, and can detect and quantify well the active inflammation of granulomatous lung lesions ,29. SomeIt should be considered that the positive scan should be interpreted with caution because the FDG uptake can also be present in other inflammatory processes and neoplastic diseases. We believe that the usefulness of 18-FDG-PET can be reserved mostly for the staging and follow-up of sarcoidosis, and also for evaluating the effect of the treatment, because most lesions can “turn off” at scans of follow-up after a successfully therapy ,33.Liver is the abdominal site most often affected with sarcoidosis, but its involvement is often underestimated, due to a pauci or asymptomatic course, while it can be found in up to 50–79% of patients at biopsy and 67–70% in autopsies ,35. BeyoLiver nodules appear usually as hypodense, nonenhancing lesions of variable size on CECT images  ,39. SingThe presence of focal calcifications is uncommon, and usually manifests as hyperdense, homogeneous areas, round or oval in shape on CECT . TypicalLiver is the organ that is less frequently involved alone in sarcoidosis; indeed, it is often associated with splenic disease . Folz etSplenic nodules can be observed in up to 15% of abdominal CECT, and are seen as single or multiple hypodense lesions larger than 1 cm, with an irregular shape and a confluence tendency. Punctate, hyperdense calcifications have been found in up to 16% of the patients, and also more clearly calcified lesions have been reported ,42.The differential diagnosis of isolated liver or splenic nodules includes tuberculosis, primitive benign and malignant tumors, lymphoma, metastasis, vascular lesions such as hemangioma and hematoma and infectious diseases, such as abscesses. A biopsy attempt should be considered for a definitive diagnosis in patients without typical clinical and radiological features of sarcoidosis .p < 0.01) and more often located in the retrocrural area [Abdominal lymph node enlargement is present in about 30% of patients and is mainly located in the hepatic hilum, para-aortic , celiac ral area .In recent years, contrast-enhanced ultrasound (CEUS) has demonstrated to be a novel and promising method in the imaging of liver and spleen sarcoidosis. Ultrasound contrast agents (UCAs) are safe and do not interfere with the kidney function. CEUS can reveal parenchymal inhomogeneity when baseline US is negative. Furthermore, hepatic lesions that are hypoechoic at baseline US, show, after UCA injection, a variable arterial enhancement and progressive hypoenhancement in the portal-venous and late phases. Additionally, hypoechoic splenic lesions appear as progressive hypoenhancing nodules compared to the adjacent splenic tissue, in both the arterial and parenchymal phases .The gastrointestinal (GI) tract is rarely affected with sarcoidosis, about 10% of all manifestations; every part of the GI tract can be involved. It is usually asymptomatic and often associated with lung disease .The gastric antrum is the most frequently affected area. The granulomatous infiltration of the antral mucosa can be localized with ulcer formation, gastritis or nodular irregularities that are similar to polyps or can be diffuse, producing a thickening of the mucosa and a reduction in the lumen. Radiological findings can range from a peptic ulcerlike appearance to a clear thickening of the mucosa that mimics the Menetrier’s precancerous disease or gastric cancer ,45,46.Colon sarcoidosis is even rarer, and can be asymptomatic or manifest less frequently with symptoms of intestinal obstruction such as constipation or abdominal pain . ImagingRare cases of appendicular sarcoid involvement have been described in the literature in association with the systemic disease. In granulomatous appendicitis, CECT shows an appendage of significantly increased dimensions and soft tissue density, absence of periappendiceal fluid and distinguishable walls, unlike acute appendicitis .The peritoneal involvement is extremely rare in sarcoidosis and can manifest as exudative ascites and single or multiple granulomatous nodules in the peritoneum. CT is an excellent method to evaluate the peritoneum and can allow the identification of peritoneal sarcoidosis, that is characterized by ascites and/or peritoneal thickening as well as hypoattenuating nodular infiltrates of the peritoneal ligaments and mesentery .The differential diagnosis of peritoneal sarcoidosis includes ovarian cancer, carcinomatosis, eosinophilic gastroenteritis, amyloidosis, typical infections such as tuberculosis, Whipple disease and fungal infections. Some small granulomatous nodules are not visible on the abdomen CT, and therefore, laparotomy and laparoscopy are indicated to evaluate the involvement of the parietal and visceral peritoneum ,50,51.Enlarged mesenteric and abdominal lymph nodes are the most common cause of intestinal obstruction due to extrinsic compression ,39. PancThe exact incidence of renal sarcoidosis remains unclear, because sometimes image findings are absent and patients can have only laboratory alterations of the calcium metabolism. However, it is hypothesized to be rare and, when present, renal sarcoidosis has various manifestations on imaging. The granulomatous glomerulonephritis from direct infiltration is uncommon and the renal function is usually preserved . The preSince the first joint statement by the American Thoracic Society (ATS), European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) in 1999, the diagnostic criteria of sarcoidosis have remained almost unchanged and are based on the finding of a suggestive clinical picture, evidence of non-necrotizing granulomas at biopsy and exclusion of alternative causes of granulomatous inflammation . This deIn the past, the Case Control Etiology of Sarcoidosis Study (ACCESS) Sarcoidosis Organ Assessment Instrument has been employed for more than ten years to evaluate the probability of organ involvement from sarcoidosis .However, the ACCESS instrument failed to identify all possible organs affected with sarcoidosis, becoming outdated over time. A new instrument has, therefore, been developed. In the WASOG Sarcoidosis Organ Assessment Instrument, clinical experts on Sarcoidosis were asked to define the probability of sarcoidosis organ involvement by using a Delphy study methodology, and an expert agreement of at least 70% was needed to obtain the consensus.Clinical manifestations were assessed as highly probable, when there was a likelihood of sarcoidosis causing the manifestation of at least 90%; probable, with a likelihood of sarcoidosis of between 50 and 90%; possible, with a likelihood of sarcoidosis of less than 50%; and indeterminate when there was no consensus . AlthougRecently, the diffusion of machine learning, a novel and promising technique that allows computers to learn and analyze imaging patterns like humans, is increasing the capacity of detection and interpretation of findings, quality of postprocessing and of reporting imaging features. This could translate into an improvement of diagnostic accuracy of traditional imaging techniques, and can result in an increase in operator performance . In sarcAn integrated clinical, laboratory and imaging investigation could provide a thorough approach to the patient with suspected sarcoidosis. In particular, clinical pictures that are highly suspicious, such as Lofgren’s, Heerfordt’s syndrome and Lupus pernio, are supportive of probable sarcoidosis. In the past, several efforts have been made to evaluate the usefulness of the Angiotensin Converting Enzyme (ACE) for the diagnosis of sarcoidosis, but several studies found a very low test accuracy and concluded that ACE levels are neither sensitive nor specific, as they can also be found to be elevated in other granulomatous disorders. Their elevation could not, therefore, be considered as diagnostic of sarcoidosis. . ACE levBronchoalveolar lavage (BAL) could reveal a significant lymphocytosis or an elevated CD4:CD8 ratio (>3.5), but is not sufficient, alone, to provide the specific diagnosis either of sarcoidosis or of any interstitial disease, though it can be helpful to reveal a suggestive pattern of eosinophilic or hypersensitivity pneumonitis and also to exclude tumors or infectious disorders ,67. SeveWhile it is easier to suspect the presence of extrapulmonary involvement in patients who have an established diagnosis of sarcoidosis , the proIn kidney disease, the renal impairment can be caused by three main mechanisms, namely the altered vitamin D metabolism, that can result from hypercalcemia and hypercalciuria mainly due to the overproduction of 1,25-dihydroxyvitamin by mononuclear cells trapped in pulmonary alveoli, and consequent nephrolithiasis and calcinosis; the granulomatous inflammation of the parenchyma, generally without progressive reduction in glomerular function up to renal failure; and acute interstitial nephritis with or without formation of granulomas . The altAlthough the diagnosis of pulmonary and abdominal sarcoidosis is often insidious, CT represents a valid diagnostic aid that can lead to the definitive diagnosis in many cases, especially in the presence of characteristic clinical pictures, such as Lofgren’s, Heerfordt’s syndrome and Lupus pernio. Here, the association with some findings such as bilateral hilar adenopathy is enough to achieve the diagnosis. Histological examination remains the gold standard to reach the definitive diagnosis, especially when radiological findings are atypical or found in isolation. In abdominal sarcoidosis, since the diagnosis is more challenging because baseline US could be falsely negative and CECT not indicated as a screening tool, it could be interesting to assess the diagnostic accuracy of novel methods such as CEUS as compared to CECT. The aim would be to evaluate which method reflects the best cost–benefit ratio to routinely detect nodules in sarcoidosis patients. New applications of machine learning could, in the future, increase the capacity of detection and imaging analysis in patients with sarcoidosis, but more studies are needed before their use in clinical practice.Finally, the promising role of PET/CT opens the way for future studies of the disease and for more applications in the follow-up, for both pulmonary and abdominal manifestations of sarcoidosis.


Interstitial lung diseases (ILD) are a heterogeneous group of illnesses of known and unknown aetiology. Differential diagnosis among the three disorders is often challenging. Specific biomarkers with good sensitivity and specificity are therefore needed to predict clinical outcome and guide clinical decisions. The aim of this study was to investigate inflammatory/fibrotic biomarkers, to determine whether single mediators or panels of mediators could be useful to stratify patients into three distinct domains: sarcoidosis, idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (cHP). A total of 163 ILD patients monitored at Siena Referral Centre for Sarcoidosis and other Interstitial Lung Diseases were enrolled in the study. Clinical data, pulmonary function tests and biochemical analytes were retrospectively collected. SAA levels were detected by ELISA kit and Krebs von den Lungen 6 (KL-6) were measured by CLEIA method, for sarcoidosis, cHP and IPF patients. Multiple comparison analysis showed significant differences in C reactive protein (CRP), white blood cell count (WBC) and creatinine levels between the three groups. In the logistic regression model, KL-6, CRP and WBC showed areas under curves (AUC) 0.86, for sarcoidosis diagnosis. The logistic regression model KL-6 and SAA showed the best performance with an AUC 0.81 for discriminating IPF than cHP and sarcoidosis. For differential diagnosis of IPF and cHP, KL-6 and SAA were considered in the logistic regression model, showed an AUC 0.79. The combination of serum biomarkers proposed here offers insights into the pathobiology of ILDs. These panels of bioindicators will improve diagnostic accuracy and will be useful in the clinical management of ILDs. Interstitial lung diseases (ILD) are a heterogeneous group of illnesses of known and unknown aetiology, characterized by progressive fibrotic involvement of the lungs , 2. TheyDifferential diagnosis between the three disorders is often challenging. Specific biomarkers with good sensitivity and specificity are therefore needed to predict clinical outcome and guide clinical decisions –17. KrebThe aim of this study was to investigate inflammatory/fibrotic biomarkers, including biochemical analytes, acute phase proteins and KL-6 to determine whether single mediator or panels of mediators could be useful to stratify patients into three distinct domains: sarcoidosis, IPF and cHP.A total of 163 ILD patients , 75 female (46%)) monitored at Siena Regional Centre for Sarcoidosis and other Interstitial Lung Diseases were enrolled in the study. Diagnosis of sarcoidosis, IPF and cHP was according to international criteria. The population included 97 patients with sarcoidosis; 24 of whom were selected for biomarker study. All patients underwent lung function tests, chest X-ray, high-resolution computed tomography of the chest (HRCT), immunological evaluation and blood sampling. Patients were not in therapy at the time of blood sampling. Serum samples were stored at − 80 °C until analysis. The sarcoidosis and cHP patients all had chronic persistent forms monitored at our referral centre; any patients with acute or subacute variants, including Lofgren syndrome and acute lymphocytic HP, were excluded. Biochemical data, including C reactive protein (CRP), red blood cell count (RBC), haemoglobin (Hb), white blood cell count (WBC), haematocrit (HCT), platelets (PLT), creatinine, urea, bilirubin, glutamic aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol concentrations, high- and low-density lipoprotein  and triglycerides, were also recorded. The data was entered in a specific database. Patients were all Caucasians and gave their written informed consent to participation in the study, which was approved by our Local Ethics Committee (CEAVSE code number 180712).CO). All parameters were expressed as percentages of predicted values.The following lung function measurements were recorded according to ATS/ERS standard parameters using a Jaeger body plethysmograph with corrections for temperature and barometric pressure: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide  following the manufacturer’s instructions. Concentrations were read at 450 nm with a Victor X4 fluorimeter . Concentrations of SAA were expressed in nanogram per millilitre.Krebs von den Lungen-6 was measured in serum by KL-6 reagent assay . The principle of the assay is agglutination of sialylated carbohydrate antigen in samples with KL-6 mAb by antigen–antibody reaction. The change in absorbance reflects KL-6 concentrations. KL-6 concentrations in samples were expressed in units per millilitre. The serum cut-off levels was 500 U/ml , 26, 27.J = max (sensitivity + specificity-1)) was used to establish the best cut-offs for diagnosis. A similar analysis was performed to test significant variables in the different diagnosis of sarcoidosis against the other ILDs and IPF against the other ILDs. A p < 0.05 was considered statistically significant. When performing several pairwise comparisons on the same variable, a Bonferroni correction for the p value was adopted. Spearman’s rank correlation was used to establish the relationship between analyte concentrations in each study group. Statistical analysis and graphic representation of the data was performed by GraphPad Prism 8.0 software.The results were presented as means and standard deviations (SD) or as medians and inter quartiles (25th and 75th percentiles) for continuous variables. Data distributions were non-normal. The one-way ANOVA non parametric test  and Dunn test were performed for multiple comparisons. The chi-squared test was used for categorical variables, as appropriate. We also performed a logistic regression to compare parameters between with sarcoidosis and other ILD patients and between IPF and other ILD patients. We also performed a similar analysis with IPF as dependent variable against cHP. Associations are indicated as odds ratios (ORs) with 95% confidence intervals. We also assessed the validity of variables used to distinguish IPF and cHP by areas under curves (AUC) in the receiver operating characteristic (ROC). Sensitivity, specificity and positive and negative predictive values  were calculated for cut-offs of the different variables. The Youden index  is reported in Table p = 0.002; p < 0.001; p < 0.001, respectively).Lung function test parameters are reported in Table p < 0.001), whereas direct comparison of IPF and cHP parameters only showed a significant difference for DLCO (%) (p = 0.03).Direct comparisons between sarcoidosis and IPF and sarcoidosis and cHP parameters revealed differences in FEV1 (%), FVC (%) and DLCO (%) (p = 0.04), WBC (p = 0.004) and creatinine concentrations (p = 0.04). In particular, CRP values resulted decrease in Sarcoidosis patients than HP (p = 0.005) and IPF (p = 0.00007). Also, WBC resulted statistical decrease in Sarcoidosis patients than HP (p = 0.003) and IPF (p = 0.0007). Creatinine concentrations (p = 0.01) and HDL cholesterol (p = 0.04) were decrease in sarcoidosis patients than cHP and IPF patients. IPF and sarcoidosis patients showed differences in CRP (p = 0.01), Hb (p = 0.01), HCT (p = 0.02), WBC (p < 0.001), PLT (p = 0.02), creatinine (p = 0.02) and GPT (p = 0.03) values. IPF and cHP patients showed differences in urea concentrations and RBC count (p < 0.05). No other significant differences were found.Clinical biochemistry parameters are reported in Table p < 0.0001). Interestingly, KL-6 concentrations were significantly different between sarcoidosis and IPF (p < 0.0001), sarcoidosis and cHP (p = 0.02) and IPF and cHP patients (p < 0.0001). SAA concentrations were significantly different in IPF and sarcoidosis (p < 0.0001) and in IPF and cHP patients (p < 0.0001).Multiple comparison analysis showed differences in KL-6 and SAA concentrations (p < 0.001), CRP  and WBC    showed 70% sensitivity and 75% specificity in discriminating sarcoidosis patients from patients of other groups.ROC curves were plotted to assess the diagnostic value of the parameters and to determine cut-off values with sufficient sensitivity and specificity in the ILD groups. Sarcoidosis patients showed the best areas under the curve (AUC) than patients with other ILDs for KL-6  Fig. . In the 01) Fig. . KL-6 vap < 0.0001) and SAA   Fig. .Fig. 2a p < 0.0001) :74, PPP (%) 74.1; 01) Fig. . KL-6 vap < 0.0001) and SAA concentration    Fig. . The log01) Fig. . KL-6 var = 0.62, p = 0.004) in the sarcoidosis group. In the IPF group, SAA was correlated with creatinine  and CRP . In the cHP group, direct correlations were observed between KL-6 and HCT  and between KL-6 and RBC . CRP also showed a correlation with total cholesterol  and WBC count .Analysing each group separately, SAA and WBC were directly correlated (In this study, different combinations of biomarkers were analysed in an attempt to differentiate sarcoidosis, IPF and cHP patients. A diagnosis of sarcoidosis was associated with values of three different parameters: KL6, WBC and CRP, enabling this granulomatous inflammatory disorder to be distinguished from the fibrotic lung diseases IPF and cHP. The combination of these three biomarkers improved overall sensitivity and specificity with respect to the single parameters.The role of these analytes in sarcoidosis patients has been widely investigated , 28, 29,Concerning KL-6, this protein has already been reported as a potential biomarker of fibrotic lung involvement in sarcoidosis and shows an inverse correlation with DLco , 31. SinIn our population a reduction in WBC count was associated with sarcoidosis: lymphopenia is a common feature in sarcoidosis patients but not in other ILDs , 33. It In our study, the combined use of SAA and KL-6 was significantly associated with a diagnosis of IPF. The role of biomarkers in the diagnosis of ILDs is generally controversial, as no indicator has proved to be sufficiently accurate . In the On the basis of our results, we propose a combination of biomarkers for discriminating IPFs from other ILDs, especially cHP. The panel showed good accuracy, specificity and sensitivity.These results were quite unexpected: the role of SAA in fibrotic ILDs is largely unexplored as it has been considered a key molecule in granuloma formation and perpetuation –42. HoweIn conclusion, the combination of serum biomarkers proposed here offers insights into the pathobiology of ILDs and will improve diagnostic accuracy. Once validated in a larger cohort, the proposed panels of biomarkers will be useful in the clinical management of ILDs.


Since its discovery in 2004 by Novoselov et al., graphene has attracted increasing attention in the scientific community due to its excellent physical and chemical properties, such as thermal/mechanical resistance, electronic stability, high Young's modulus, and fast mobility of charged atoms. In addition, other remarkable characteristics support its use in analytical chemistry, especially as sorbent. For these reasons, graphene-based materials (GBMs) have been used as a promising material in sample preparation. Graphene and graphene oxide, owing to their excellent physical and chemical properties as a large surface area, good mechanical strength, thermal stability, and delocalized π-electrons, are ideal sorbents, especially for molecules containing aromatic rings. They have been used in several sample preparation techniques such as solid-phase extraction (SPE), stir bar sorptive extraction (SBSE), magnetic solid-phase extraction (MSPE), as well as in miniaturized modes as solid-phase microextraction (SPME) in their different configurations. However, the reduced size and weight of graphene sheets can limit their use since they commonly aggregate to each other, causing clogging in high-pressure extractive devices. One way to overcome it and other drawbacks consists of covalently attaching the graphene sheets to support materials . Also, graphene-based materials can be further chemically modified to favor some interactions with specific analytes, resulting in more efficient hybrid sorbents with higher selectivity for specific chemical classes. As a result of this wide variety of graphene-based sorbents, several studies have shown the current potential of applying GBMs in different fields such as food, biological, pharmaceutical, and environmental applications. Within such a context, this review will focus on the last five years of achievements in graphene-based materials for sample preparation techniques highlighting their synthesis, chemical structure, and potential application for the extraction of target analytes in different complex matrices. Over the last decades, nanotechnology has become a promising tool in relevant scientific fields, allowing humanity to reach top levels of quality in several areas such as engineering, chemistry, medicine, and sports, among others  distributed along with the thinnest structure of the negligible mass, but high Young's modulus, as already discovered , transparency, and impermeability to gases must be underscored  still represents a hurdle to its broad implementation. This occurs because the most utilized manufacturing approach is based on the graphite top-down mechanical exfoliation process by adhesive tape , only the external surface is available for such interaction, which potentially diminishes extraction performance due to this steric hindrance associated. Additionally, the delocalized π-electron system favors electrostatic interaction between the graphene and molecules that possess aromatic rings in its structure.For this reason, prevalent contaminants such as pesticides, preservatives, pharmaceuticals, and veterinary drugs can be remediated from the environment by using GBMs  is a 2D monolayer of carbon atoms covalently bonded in a honeycomb pattern, displaying a flat sheet conformation  can take off the graphene layers from the surface of a graphite piece. One of the advantages of mechanical exfoliation is the possibility of different pile-up layers of other 2D materials with several graphene heterostructures  is the most popular method to obtain graphene. As shown in Conversely, the bottom-up approaches are another alternative to synthesize high-quality graphene layers. The leading methods used include pyrolysis, chemical vapor deposition (CVD), plasma synthesis, and epitaxial growth  is like a graphene sheet functionalized on both sides with several oxygenated functions such as hydroxyl, carboxyl, and epoxy. These functions impose a hydrophilic character to GO; as a consequence, the interaction between layers is weaker compared to graphene, making GO an easily exfoliated material. GO structure depends principally on the purification methods . Thus, they can be currently used in several applications  yields a low substitution degree due to their stable carbon conjugation. However, covalent functionalization can be done by taking advantage of the oxygenated reactive groups of the graphene oxide (GO) sheets. Therefore, in the same way as the chemical reduction of graphene oxide, the hydroxyl, carboxyl, and epoxy groups can be covalently replaced by other functional groups. The GO surface modification with aliphatic amines to form an amide bond is one of the most common strategies  are by far the most commonly used sorbent in solid-phase extraction (SPE) and chromatographic separations. Apart from the conventional C8/C18 reversed phases, today mixed-mode polymeric sorbents are widely used in SPE because they present interactions with several compounds and better performance compared to the conventional ones, and they are also commercially available  for catechins being 11 times higher compared to GO sheets (18.7 mg g−1) and other rGO-amino groups . Hence, tributylamine-rGO was employed as a sorbent in a modified QuEChERS  method achieving a higher clean-up performance compared to traditional sorbents as PSA, C18, and graphitized carbon black (GCB), regularly used in QuERChERS , which allows the use of graphene sorbents in small quantities (<100 mg)  for the extraction of aflatoxins in corn samples. Calix[4]arene is a macrocyclic molecule of four phenol units bonded by methylene bridges, which can favor the extraction of aflatoxins by H-bonding, hydrophobic, and π-π interactions. The recoveries of aflatoxins (AFs) obtained employing cellulose acetate CFs (35–41%), polydopamine coated CFs (PDA-CFs) (45–55%), calix[4]arene-GO-CFs (60–72%), GO/PDA-CFs (63–82%), and calix[4]arene-GO/PDA-CFs (86–94%) as SPE sorbents showed that together calix[4]arene and GO increased the efficiency of the sorbent phase , which are cyclic oligosaccharides formed by starch enzymatic degradation, and are linked by several α-1,4-anhydroglucopyranose. In nature, they are made up of 6, 7, or 8 glucose units and categorized as α, β, and γ-CD, respectively. CDs have cone shapes with a hydrophobic cavity and a hydrophilic external surface. This specific structure allows them to form inclusion complexes with specific molecules such as polyphenolics compounds through hydrogen bonding, hydrophobic, and Van der Waals interactions  ranging from 0.9955 to 0.9998. The LODs and LOQs for the nine analytes ranged from 1.1–60.4 to 2.7–170.5 ng L−1, respectively; RSD was 2.2–9.6%, and enrichment factors obtained from 22.5 to 1307.5. This high enrichment factor is attributed to the combined advantages of β-CD and GO. When compared with the commercial fibers and some published methods, the GO/β-CD sol-gel coating fiber showed a higher extraction efficiency, except for those organophosphate flame retardants containing a benzene ring. Similarly, Cao et al. combined the advantages of graphene and cyclodextrins with ionic liquids and ILs , which was used as a sorbent to extract plant growth regulators from vegetable samples using magnetic solid-phase extraction (MSPE) followed by UHPLC-MS/MS analysis. This approach showed fast separation, high surface area, high adsorption capability, and environmental friendliness. The comparison between Fe3O4@SiO2/GO, Fe3O4@SiO2/GO/β-CD, and Fe3O4@SiO2/GO/IL showed that Fe3O4@SiO2/GO/β-CD/IL had higher extraction efficiency and selective adsorption capacity.The combination of graphene and cyclodextrins properties becomes the resulting material attractive to be employed in sample preparation techniques. An interesting application was carried out by Deng et al. The novel β-CD–GO-coated SPME fiber was prepared using a sol-gel technique and immobilizing onto a pre-functionalized stainless steel wire  below 8.1%.For food analysis, β-CD combined with GO were used in the sample preparation during the analysis of organochlorine pesticide residues in honey . This trend is justified by the presence of epoxy and -COOH groups on the GO surface, favoring the bonding with the CDs. Although some works reported the employment of graphene combined with cyclodextrins as sorbent, these materials were obtained by graphene oxide reduction  which is considered an efficient and environment-friendly sample preparation technique  and maghemite (γ-Fe2O3) as the magnetic nanoparticles (MNPs) more frequently used , cobalt, (Co), and nickel (Ni) oxides, highlighting the magnetite . As an example, Chandra et al. prepared an rGO/Fe3O4 for arsenic removal from surface water samples  the chemical co-precipitation and (ii) the hydrothermal synthesis. The chemical co-precipitation is based on the deposition of iron ions over the nanosheets by adding an alkaline solution to an aqueous dispersion of graphene Fesolution . As Fe3+3O4 particles on the nanosheets. Within such a context, hydrothermal synthesis has been proposed as an alternative to yield sorbents with better Fe3O4 particles distribution with more G exposed adsorption sites and then, improved adsorption capacity. This method is based on the reduction of Fe3+ and GO in sodium acetate and polyethyleneglycol in an autoclave at elevated temperature . In this case, before graphene anchoring, Fe3O4 particles are modified with a silane coupling agent, consisting of tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES) , deep eutectic solvents, boronate affinity materials (BAM), supramolecules , aptamers, polymers, and metal-organic frameworks (MOFs). For those magnetic GBMs, their preparation and applications were recently comprehensively reviewed by Li et al. They provided a summary of the state of the art of them, highlighting application as MSPE sorbents of organic compounds, biomolecules, and metal ions  combined with GBMs. In this context, MIPs are prepared from a template (mold) which behaves structurally similarly as the target analytes, to achieve a selective interaction through a template-complementary binding site . In this section, their application in the field of sample preparation combined with GBMs is covered, highlighting preparation strategies of aqueous-recognition MIPs cleverly to achieve such functionalization  on magnetic graphene oxide (GO-Fe3O4) surface to remove 17β-estradiol (17β-E2) from food samples. The resulting sorbent has shown a functional extraction recovery of 84.20% at a low concentration level of 0.5 μmol L−1. Furthermore, due to the magnetic properties of the GO-MIP-Fe3O4, a simple, fast, and efficient separation of 17β-E2 were achieved, suggesting the combination between these materials as an excellent way to obtain hybrid sorbents. Following the same trend, Barati et al. (3O4 particles (GO-MIP-Fe3O4). In this case, the author worked with natural samples, specifically alkaloids (evodiamine and rutaecarpine) extract from Evodiae Fructus, suggesting a great versatility of such magnetic GO-MIP sorbent. Also, its analytes' recovery achieves values over 82% considering as good values from our viewpoint.An attractive approach to obtain high performative material involves the use of the graphene-based MIP functionalized with a magnetic particle to favor the extraction and sorbent isolation. Within such a context, Ning et al.  proposedi et al.  synthesiMoreover, In 1914, a work with ionic liquids (ILs) was reported for the first time, although at that time, the author had no idea of the importance that these would take in the scientific area almost a century later Walden, . From thThe ILs are compounds with a dual nature acting as nonpolar for nonpolar analytes and, inversely, for those with a strong proton donor group, depending on the separation mechanism that it presents  of controlled size by a co-precipitation method to obtain the Fe3O4-SiO2-G-PIL hybrid sorbent; the obtained material was used to determine preservatives in vegetables by QuEChERS following GC-MS analysis. In this study, it was possible to take advantage of the functional properties related to magnetic nanoparticles and also by its coupling to the GO with the polymeric ILs . Moreover, the method's detection limits varied between 0.82 and 6.64 μg kg−1 for the 20 preservatives studied. Similarly, Tashakkori et al. (−1) and the lab-made SPME fibers being used more than 120 times, which is a useful feature when compared with the commercially available ones such as PA and CAR/PDMS. These results reinforce the great interest in developing hybrid GBMs combined with ILS.Other interesting applications based on IL-GBMs include work published by Chen Y. et al. . They syi et al.  synthesi+Br−)-GO-Sil] as a hybrid IL sorbent to extract flavonoids in urine samples. They synthesized the material by an interesting process consisting of an in situ radical chain-transfer polymerization and then in situ anion exchange. In this case, the procedure started with the silica coating by GO, using a manufacturing layer by layer fabrication method. Then, the poly (VHIm+Br−)-GO-Sil anion was transformed into hexafluorophosphate (PF6−) by in situ anion exchange. The method based on SPE-HPLC-UV showed acceptable extraction recoveries for four flavonoids, with limits of detection in the range of 0.1–0.5 μg L−1. The proposed material showed ecological and cost-effective advantages. It can be applied successfully to the extraction and enrichment of flavonoids in human samples, even allowing the study of metabolic kinetics.Additionally, biological samples were analyzed by Ding et al. . They fuFinally, considering other types of samples, an interesting study published by Zhou et al.  was carrApart from the interesting application herein discussed, other relevant studies based on hybrid sorbents combining IL and GBMs are shown in 30) between the graphene oxide (GO) nanosheets and further support this onto polycaprolactone nanofibers, aiming to enhance temperature, and pH resistance to the sorbent phase. This novel material was applied in SPE extraction of four statin drugs showing acceptable analytical performance. The author emphasized the excellent ability of this sorbent to interact with acidic polar species, possibly due to the resistance to pH variations. Another interesting application was performed by Li et al. , due to the hydroxy and amine groups to which the ions bind metallic. This result demonstrates the potential of this hybrid sorbent material in the cleaning processes of contaminating metal ions in complex matrices such as water. Additionally, the authors emphasize its low producing cost as a useful characteristic since commercially available sorbents often are expensive and non-reusable.This section aims to present some alternative graphene-based materials that could be an alternative for the sample preparation in the future. For this reason, there are not many publications apart from the materials already discussed in the previous sections. An original example recently published by Tahmasebi  consistei et al.  whose sy30 insertions, can enhance the interaction with the π-electron system onto the GO surface, resulting in enhanced extraction performance. Similarly, Amiri et al.  selectivity for specific analytes and thus present chemical inertia for matrix interferents; (ii) good recovery and enrichment factors; and (iii) simple and non-expensive production. Once fulfilling these requirements, graphene-based materials have increasingly seemed to be the right candidate since their first application in sample preparation around 2011. Its large surface area, together with the π-π delocalized electron system, aid in improving so much the extraction performance of target compounds possessing aromatic rings as several chemical classes  as herein discussed on section Graphene and Graphene Oxide.in silica reported this result.Although the successful application in its “bare” form (G and GO), sometimes the functionalization of them seems to enhance even more the performance of such sorbents. For this reason, in this work, we have shown several different applications based on the use of hybrid materials consisting of GBMs anchored to other extractive sorbents such as alkyl and aryl groups, cyclodextrins, magnetic particles, molecularly imprinted polymers, ionic liquids, and among others. The functionalization is often achieved by forming covalent or hydrogen bondings, using sol-gel or polymerization router, or even electrochemical deposition. This interesting approach is encouraged by the possibility to ally the advantages of each class in only one. Apart from this goal, the clogging and backpressure problems often related to G and GO when packed in sorbent-based sample preparation techniques are overcome by the addition of other compounds. For example, several works underscored in sections Alkyl and Aril Groups, Cyclodextrins, and Magnetic Materials based on magnetic particles, or anchoring Similarly, increasing on extraction selectivity and by consequence, performance is observed when GBMs were functionalized with both MIPS or the tunable-ILs, as can be seen in sections Molecularly-Imprinted Polymers and Ionic Liquids. This background explains the significant tendency to work with hybrid graphene-based materials instead of its bare form. GBMs are an excellent sorbent, often surpassing the commercially available phases such as C8 and C18.After all, by assessing the recent literature and considering the vast number of applications involving graphene in the sample preparation arena, as herein discussed, an increasing tendency to expand the footprint of GBMs functionalized with several classes must continue in the years to come. This conclusion is mainly supported by the unique favorable GBMs physical-chemical properties, which—together with the advancements on the materials synthesis routes, extraction techniques, and related subjects—evidenced this field as one of the most critical developments in the sample preparation area nowadays. Also, an increasing number of papers reporting the employment of hybrid GBMs and miniaturized sample preparation techniques must be expected. This trend can be projected considering the high potential obtained by combining the well-established benefits of automation/miniaturization with the use of more selective and performative materials, possibly leading to greener sample preparation techniques by following the Green Chemistry concept.EM wrote sections Introduction, Miscellaneous, and Concluding Remarks, as well as edited the whole manuscript. KM-C wrote sections Graphene and Graphene Oxide and Alkyl and Aril Groups, built The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This paper describes a new automated disengagement tracking system (DTS) that detects learners’ maladaptive behaviors, e.g. mind-wandering and impetuous responding, in an intelligent tutoring system (ITS), called AutoTutor. AutoTutor is a conversation-based intelligent tutoring system designed to help adult literacy learners improve their reading comprehension skills. Learners interact with two computer agents in natural language in 30 lessons focusing on word knowledge, sentence processing, text comprehension, and digital literacy. Each lesson has one to three dozen questions to assess and enhance learning. DTS automatically retrieves and aggregates a learner's response accuracies and time on the first three to five questions in a lesson, as a baseline performance for the lesson when they are presumably engaged, and then detects disengagement by observing if the learner's following performance significantly deviates from the baseline. DTS is computed with an unsupervised learning method and thus does not rely on any self-reports of disengagement. We analyzed the response time and accuracy of 252 adult literacy learners who completed lessons in AutoTutor. Our results show that items that the detector identified as the learner being disengaged had a performance accuracy of 18.5%, in contrast to 71.8% for engaged items. Moreover, the three post-test reading comprehension scores from Woodcock Johnson III, RISE, and RAPID had a significant association with the accuracy of engaged items, but not disengaged items. Many intelligent tutoring systems (ITSs) implement natural language dialogue and provide one-on-one human-like tutoring in an automated fashion . A well-Regardless of whether students learn from an ITS, a human tutor, or a teacher in a classroom, students are likely to become disengaged due to various reasons, such as fatigue, environmental distractions, loss of interest, or the stress of falling behind in a course, as will be elaborated below. One strategy that ITS developers have taken has been to increase engagement through gamification , but stuDisengagement occurs in a number of situations, such as when the student is 1) mind wandering , 2) distDisengagement also presents a problem for researchers interested in evaluating learning and performance. Time on task alone  can be considered contaminated by disengagement in contrast to diligent efforts to complete the task. Disengaged students may take too long a time (thinking about something irrelevant to the reading task) or too short a time (quickly finishing the question or session without comprehension) on a given question, problem, text or session. That is, a disengaged reader can be extremely slow or fast in processing during a learning task with low performance. Data analyses that do not consider the abnormal reading time due to disengagement may lead to unreliable or even misleading results. Moreover, a simple unidimensional measure of time is not sufficiently diagnostic of disengagement because both very fast times and very slow times can be signals of disengagement.Existing disengagement/engagement detection methods that focus on mind wandering have applied supervised learning approaches to train models using self-reported mind-wandering  or use oN = 52) who completed up to 30 lessons in a computerized learning environment (AutoTutor) that was part of a 4-month intervention that trained them on comprehension strategies. Answer time alone was not sufficient to identify the incidence of disengagement because accuracy in answering the questions is obviously important. Therefore, questions outside of the zone of engagement, “disengaged question-answer observations” were defined as being answered incorrectly and too quickly or slowly. This approach to identifying disengaged observations was completed after the 4-month study was completed. Unfortunately, this method, however, is not suitable for monitoring concurrent disengagement since disengaged question-answer observations can only be detected at the end of a reasonably large sample of lessons. That does not allow an intelligent learning environment to give feedback and guidance to the learner when disengagement is detected. Moreover, if a question is incorrectly and slowly answered, it may not necessarily indicate disengagement. It is possible that a student is at the very early stage of learning new material and spending time in productive comprehension activities. Nevertheless, an approach to detecting disengagement based on the accuracy and time to answer questions during training is a reasonable approach to building a disengagement tracking system. It does not require special physiological or neuropsychological sensing devices, eye tracking, self-reports of engagement, or machine learning with supervised training that cannot scale up to real-world applications. The approach would be more useful to the extent it could detect disengagement in a smaller time span, such as a minute or two.Graesser, Geenberg, Frijters, and Talwar (submitted) identified questions that a student answers that are within the student's “zone of engagement”. These “engaged question-answer observations” included questions that were answered neither too slowly nor too quickly (within ± 0.5 standard deviation of mean log of response time), based on a student's personal average speed of answering questions in a lesson. The participants were struggling adult readers (AutoTutor for Adult Reading Comprehension (AutoTutor-ARC), a version of AutoTutor to teach adult learners reading comprehension strategies. In AutoTutor systems, a tutor agent and optionally a peer agent hold conversations with a human student. When the conversation has two agents (tutor and peer), the conversations are called trialogues, as opposed to tutor-student dialogues , or mind wandering. We implemented the proposed algorithm to predict/monitor disengagement in AutoTutor-ARC. Our results show that items that the detector identified as the learner being disengaged had a performance accuracy of 18.5%, in contrast to 71.8% for engaged items. Moreover, three post-test reading comprehension scores from Woodcock Johnson III, RISE, and RAPID had a significant association with the accuracy of engaged items, but not disengaged items. The development of DTS algorithm is motivated by response time and performance data generated by the users of AutoTutor-ARC system. DTS has not been used in any intelligent system yet. The validation analyses in the manuscript can be considered as a “low stakes” application of DTS. If successful at detecting disengagement, the proposed real-time disengagement tracking system could be of value in enhancing learning efficiency in future AutoTutor-ARC systems, if it can be coupled with interventions during a lesson that re-engage a disengaged student. The algorithm could also be applied to other computer-based learning or assessments that utilize a question-answer environment.http://csal.gsu.edu). AutoTutor-ARC is a web-based intelligent tutoring system with 30 lessons focusing on building reading comprehension strategies  later in the manuscript) on each question is recorded per lesson per student.The lessons typically start with a 2–3 min video that reviews the comprehension strategy that is the target of the lesson. After the review, the computer agents scaffold students through the learning by asking questions, providing short feedback, explaining how the answers are right or wrong, and filling in information gaps. Since adult learners in AutoTutor typically have substantial challenges in writing, AutoTutor tends to rely on point-and-click (or touch) interactions, multiple-choice questions, drag-and-drop functions, and other conventional input channels. The learner chooses the answer by selecting an answer, while the peer agent sometimes gives his answer by talking. Flow within each lesson is driven by either a fixed sequence or contingent branching. The first set of question-answer items within a particular lesson is the same for all students who take the lesson. Fixed sequence lessons deliver the same set of conversational questions to all students, independent of their performance throughout the entire lesson. Contingent branching lessons start out with questions and materials at a medium level of difficulty, but subsequently shift to harder or easier materials/questions depending on their performance on the medium difficulty material . For exaThe data sets used to test the proposed algorithm were taken from three waves of an intervention study in two medium sized cities. Participants were 252 adult learners who were offered approximately 100 h of instructional intervention designed to improve their reading skills. The intervention period lasted over 4 months and was implemented in hybrid classes, which consisted of teacher-led sessions and the computer-based AutoTutor-ARC sessions. Their ages ranged from 16 to 74 years  and 74.6% were female. The reading level of participants ranged from 3.0 to 7.9 grade equivalencies. On average, the 252 participants completed 30 lessons. The adult students were also assessed with three standardized tests of comprehension before and after the instruction.The AutoTutor-ARC content  were scaled according to An automated disengagement tracking system (DTS) is ideally personalized to the response times of individual students who work on a particular lesson. For any given student, a DTS should adapt to the learner's pattern of engaged performance, that is, the typical response time when engaged in attending to lesson content. Disengagement is detected when a student's performance (reading time or accuracy in answering questions) significantly deviates from this ‘typical’ pattern. In AutoTutor-ARC, a student is asked to read a text or sentence and to answer questions that are woven into the conversation between the two agents and the student. The system records the time that this student spends on each question and whether a question is answered correctly . The amount of time a student takes to respond to a question, namely the response time (RT), is one behavior that can be used to determine whether a student is disengaged while working on this question. Performance suffers when the student is disengaged. One indication that students are disengaged is that they respond too fast or too slow  on a question. Too short or long RT does not necessarily mean “disengagement”, since other factors influence RT. However, the short and long times can often be signals that probabilistically predict disengagement. For example, a short RT could be impetuous responding or gaming the system, whereas a long RT may be a difficulty level shift in texts/questions, mind wandering, or a personal bio break. To supplement the validity of RT indicator, we can consider another indication of disengagement: a significant drop in the correctness rate of a student. Thus, the DTS detects questions that a student is disengaged using both indications together. A flow chart of the DTS algorithm is shown in The top half of In the first phase at the beginning of a lesson, the DTS obtains the distribution of a student's engaged RT on questions. Response time is usually right-skewed, as is the current data set, so a log transformation was applied to make the data resemble a normal distribution. We assume an engaged student's b correctly answered questions and start to get disengaged at the s should be greater than or equal to b for the system to learn a user's engaged response time in a specific lesson. If b correctly answered questions as engaged response time. If there are less than b correct question-answer observations up to the b's response time as engaged response time instead. We excluded question #1 since the users usually take extra time to read the text in the first question and spend much longer time than usual. Let I be the first b correctly answered questions, whereas μ and σ are estimated byb correctly answered questions if they believe that there are extreme outliers in the s if the standardized response time satisfiesWe will now turn to some of the mathematical specification of the DTS algorithm. Suppose that students are engaged on the first X, but may be too fast to be engaged for student Y on the same question. Learners usually get disengaged for a variety of reasons. They may even get disengaged at different questions in different trials of the same lesson. Furthermore, an individual's reading ability may vary depending on the characteristics of the texts  included in each lesson. Because of these sources of variation, the system is required to learn engaged RTs (or reference behaviors) for each learner within each lesson.To have an adaptive DTS, the mean and standard deviation of engaged RT should be personalized for different students in different lessons. This means that 20 s may be an engaged RT for student Disengagement detection that is only based on response time would lead to a large number of false positives. Some lessons have a small number of “confidence-boosting” questions, which means learners will respond more quickly with high accuracy to these questions than to others. Students may slow down in subsequent questions that are more challenging, which may be falsely detected as disengagement by an DTS that only relies on response time. Other than “abnormal” response time, another important signal of disengagement is that disengaged students usually perform poorly since they are not focusing on the question. If a good student  responds to a particular question too fast or slow and also answers this question as well as neighbor questions incorrectly in a sequence, there is a high chance that this student is disengaged while working on the particular question. However, if a student performs poorly throughout the entire lesson, DTS should not categorize the questions with abnormal response time and poor performance as disengagement since the student may be struggling with this lesson, but not just disengaged on a few questions. As noted, in this study, DTS only identifies disengaged question-answer observations when assuming that the texts and questions are within the zone of what the student can handle and the student is engaged at the beginning of each lesson. Our targeted disengaged question-answer observations are those with “abnormal” (too fast or too slow) response times, poor local performance, but adequate overall performance. Students with low performance and engagement throughout the entire lesson or study is important also. It is possible that the content of the texts or questions may be too difficult. It is important to note that these questions will not be treated as ‘disengaged’ by DTS in this study.s), defined as A more formal specification of the algorithm may lend clarity. Let It is important to reiterate that the proposed DTS algorithm will not handle occurrences when a student is disengaged from the very beginning. These occurrences would not be counted as disengagement (even though they should be) so our predictive algorithm is conservative rather than been generous at detecting disengagement and such observations will dilute the predictive power of the DTS algorithm. It is also important to acknowledge that the algorithm has not yet been validated by self-reports of disengagement, eye tracking, and neurophysiological measures so the precise psychological status of the disengaged observations await further research. That being said, D’Mello and has colleagues  have proThe proposed DTS is designed to be a real-time monitoring of disengagement in an intelligent system. Using the predicted engagement/disengagement status for individual questions, we explored the pattern of disengagement in the AutoTutor-ARC as an empirical evaluation of the algorithm (It is important to clarify that DTS was not used during the CSAL AutoTutor study. It was developed after the end of the study.). For each of 252 students, we calculated the proportions of disengaged items, including fast- and slow-disengaged question-answer observations. A k-mean clustering analysis was applied to develop student profiles on proportions of the two types of disengaged question-answer observations. K-means clustering assigns data points into groups by iteratively reassigning and re-averaging the cluster centers until the points have reached convergence . GroupinAs an independent evaluation, learning gains were analyzed on subsets of the 252 students who took three standardized tests of comprehension before and after the larger CSAL AutoTutor intervention that included AutoTutor-ARC lessons. Of the 252 participants, 205 took both pre- and post-test of the Woodcock Johnson III Passage Comprehension subtest ; 143 tooTo investigate whether the learning gain is affected (presumably reduced) by disengagement, we performed paired t-test on the pre- and post-test scores of the three standardized tests after contrasting groups of students with different disengagement patterns at a fine grain level . These groups were obtained from the clustering analysis of the 252 participants on proportions of disengaged question-answer observations. It should be noted that these DTS-based clusters are different from the aggregate-based clusters identified by Fang et al. (submitted). We compared the two different types of clusters in this paper. Moreover, we tested the association of learning gain measured by the three standardized tests with the AutoTutor accuracy (i.e. proportions of questions correctly answered by students) of 252 participants. We first separated engaged and disengaged question-answer observations detected by the proposed DTS. For engaged (or disengaged) questions, reading comprehension at post-test was regressed onto the accuracy of engaged (or disengaged) questions adjusted by reading comprehension at pre-test.p-value We applied the proposed DTS algorithm to the data extracted from AutoTutor . We identified 16,851 questions with “abnormal” response times, of which 3,082 were disengaged question-answer observations  among the 252 participants. After aggregating the total number of questions from the lessons, we obtained the frequencies and proportions of disengaged question-answer observations for each of the 252 participants. The total number of questions that a student answered varied from Some students tend to have a higher proportion of fast-disengaged question-answer observations, whereas others have more slow-disengaged question-answer observations and yet others are high in both. To address this, a k-mean clustering analysis was performed on groups of students with similar disengagement patterns according to the DTS algorithm. Since students answered a different number of questions, we focused on the proportion (rather than the count) of fast- and slow-disengaged question-answer observations for each participant. The k-mean clustering analysis was implemented in R (version 3.6.0) on the proportions of fast- and slow-disengaged question-answer observations. We clustered the 252 participants into four groups (k = 4) according to the “elbow” method by visualizing the plot of “number of clusters” vs. “within groups sum of squares”.HiFast/HiSlow for short) represents students with a relatively medium-to-high proportion of fast-disengaged question-answer observations (2%) and a comparatively high proportion of slow-disengaged question-answer observations (7%). The second cluster (deep blue dots in LowFast/HiSlow for short) includes students with a small proportion of fast-disengaged question-answer observations (1%) and a medium-to-high proportion of slow-disengaged question-answer observations (4%). The third cluster (aqua blue dots in HiFast/LowSlow for short) represents students with a high proportion of fast-disengaged question-answer observations (3%) and a small proportion of medium-to-high slow-disengaged question-answer observations (2%). The last cluster (green dots in Engaged for short) represents students with small proportion of fast-disengaged question-answer observations (1%) and small proportion of slow-disengaged question-answer observations (2%). p-valueEngaged students by DTS, which is higher than “conscientious” and “struggling readers” (42% = 13/31) and much higher than “under-engaged” reader (34% = 32/93). Furthermore, when considering the students with local disengagement , the conditionalized percentages on on the slow end rather than the fast end were : higher performers (41/47 = 87%), conscientious (7/18 = 39%), struggling (14/18 = 78%), under-engaged (49/61 = 80%); low relative percentages for the conscientious readers is unexpected, but perhaps can be attributed to the relatively small number of observations.The current classification based on local engagement  was compEngaged. In contrast, Fang et al. categorized readers with low global accuracy to “under-engaged.”The major discrepancy between the two clustering approaches can be attributed to the fact that DTS was developed to detect disengaged question-answer observations, rather than disengaged students. Thus, DTS only checks the accuracy of answers to a question locally (i.e. accuracy of neighbored questions), not globally (e.g. accuracy within lessons that accumulated over the 4-month intervention). In our study, a student is considered to be disengaged while working on a question if his/her performance on this (and neighbored) questions is lower than their global performance. If a student has a low accuracy throughout the entire lesson, DTS will count these question-answer observations as The next analysis computed the proportion of fast- and slow-disengaged question-answer observations among the 252 participants within each of the 30 lessons separately. A subset of the lessons have one or two texts with conversation-based questions woven into the lessons. Eleven of the lessons have multi-sentence texts that branched during the course of the lessons. For each of these lessons with branching texts, the AutoTutor system starts with a medium difficulty text with 8–12 questions and then branches to an easy or hard text, depending on the student's performance on the questions in the medium difficulty texts. A second set of nine lessons provide one medium level text with 10–20 questions woven into the conversation about the text. A third set of 10 lessons focused on single words or sentences rather than multi-sentence texts. These lessons had 10–30 questions that were scaled on easy, medium or difficult levels. When considering all 30 lessons, the questions at the medium difficulty level constituted the majority of questions. Since some lessons contain questions of different difficulty levels, we evaluated the proportion of fast- and slow-disengaged items stratified by difficulty levels of questions for 252 participants in the 30 lessons. Disengaged Question-Answer Observations. For each person and lesson, we calculated the proportion of disengaged question-answer observations. To test whether the disengagement rate of lessons from one theoretical level is different from another, a linear mixed model was conducted while adjusting the correlated observations due to the same student. The results revealed that lessons in the Word (W) theoretical level had the highest disengagement rate , textbase (TB), Referential Situation Model (RSM), and Rhetorical Structure (RS), based on p-valueComprehension was evaluated by three standardized tests . There was a pretest before the 4-month intervention and a posttest at the end of it. Learning gain is calculated by the difference between pre- and post-test. To assess whether disengagement has an effect on learning gains in AutoTutor, we separated disengaged question-answer observations from the engaged ones and tested the association between learning gains from three standardized tests of comprehension and the accuracy rate  in AutoTutor on disengaged and engaged observations respectively. Regression analyses were conducted on the learning gains in the comprehension tests as a function of the AutoTutor intervention with engaged vs. disengaged question-answer observations. These results are presented in This paper provides a disengagement tracking system (DTS) with an intelligent algorithm to monitor students’ disengagement based on their response time and performance on each question during their learning process in AutoTutor. A variety of approaches have been applied to predict and track disengagement in intelligent tutoring systems . Existinin vivo as a performance monitoring algorithm within an intelligent tutoring system.The proposed DTS consists of two steps. In the first step, the algorithm learns a student's baseline response time from his/her first 3Our study of disengaged question-answer observations in AutoTutor that were identified by DTS is consistent with the claim that disengaged observations have substantially lower accuracy on AutoTutor items whereas engaged observations high performance. This is a confirmation of the internal validity of the algorithm. Evidence of external validity was also confirmed in analyses of learning gains on comprehension skills that were measured by independent psychometric tests . LearninDisengagement detection and monitoring is of course important for improving learning in conventional learning contexts as well as intelligent tutoring systems . A few IThere are a number of limitations in this study that call for follow-up research. First, we assumed that the log-transformed response time follows a normal distribution, and hence an “abnormal” response time can be identified if a log-transformed response time falls outside of ested by . Thus, aSecond, the DTS algorithm assumes that questions in a lesson are similar/interchangeable in terms of the lesson content and difficulty. Third, the algorithm does not detect situations when the student is disengaged from the material at the beginning of the lesson. For the DTS to be meaningfully applied to AutoTutor, we assume that texts/questions given to students are suitable for them and have some modicum of value and/or interest. This is a plausible initial assumption because the lessons focus on subject matters that have value for struggling adult readers  or are interesting to adults. Hence, students presumably start out engaged in most of the questions and may be disengaged on a number of questions some time later. If a student is disengaged in the beginning of a lesson or disengaged from most of the questions, DTS would need to be adjusted with a different algorithm to improve its predictions.Fourth, there are a number of other situations that the DTS algorithm would need to be modified to handle. The proposed algorithm does not consider any intervention to re-engage the students. DTS needs to be adjusted if any intervention action is taken after a disengaged question is detected. If users encounter frequent technical issues in the early/testing stage of a new ITS system, the data should take that into consideration. DTS run the risk if identifying “false alarms in disengagement” or “misses in disengagement observations” if the questions at the early phase of a lesson are unusual and fail to calibrate their performance when engaged.In summary, DTS provides an algorithm that can automatically predict/monitor disengaged behaviors in other learning environments that collect self-paced responses to question-answer items during training. It was designed for, but not limited to, the AutoTutor-ARC system. It can be tailored to fit any ITSs. In the proposed algorithm, only the response time and accuracy of each question are utilized to predict disengagement since they are the only relevant items that are recorded by AutoTutor. If other predictors or measurements, such as item difficulty, self-reported engagement or student's gaze patterns captured by a commercial eye tracker are available in different intelligent tutoring systems, they can be incorporated into the proposed DTS with appropriate modifications to the proposed algorithm. These other sources of data can also be used to validate the DTS algorithm. Of course, these other measures may be difficult or impossible to collect when scaling up a learning system in the real world.


Our devices show an enhanced photoresponsivity (~ 800 AW−1) while the response speed is still fast (up to 10 μs). This photoresponsivity is about two orders of magnitude higher compared to that of a previous graphene-based photodetector. The photodetector exhibits a wide-range tunability via source-drain bias and back gate voltage. Our work addresses key challenges for the photodetectors and potentially provides the desired pathway toward practical application of graphene photodetectors that can be externally manipulated by an electric field with fast response speed and high sensitivity.Graphene has been demonstrated to be a promising material for optoelectronics and photodetection devices because of its ultra-broadband optical absorption and high carrier mobility. However, its integration with optoelectronic systems has been limited by the zero-bandgap and the lack of a gain mechanism. Herein, we demonstrate a novel photodetector based on the graphene nanoribbons (GRNs) with a sizable bandgap. Utilizing trapping charge at the interface between SiO Graphene, a two-dimensional 2D) layered material, plays an important role in many fields including electrodialysis , batteriD layered2 ]2)] and τ is excess hole lifetime (trapped hole lifetime), and τT = l2/(μVS − D) is the transit time of the carrier, while l is the length of the channel and μ is the carrier mobility, whereas VS − D is the source-drain bias. Hence, the gain and source-drain voltage exhibit a positive correlation. Apparently, G is linearly dependent on the source-drain bias. As a result, the maximum photoresponsivity of R = 170 AW−1 and the maximum gain of G = 14,500 were achieved at room temperature at VS − D = 0.5 V, which was a 100-fold improvement over previous graphene-nanostructure-based photodetectors [where etectors , 35, 36.R = 800 AW−1 and the maximum gain of G = 22400 were obtained at VG = - 4 V. This maximum value of photoresponsivity was five orders of magnitude higher than that of pure graphene photodetectors (~ 10 mAW−1) [RC) between the Au electrodes and the GNRs which was inseparably related to the Schottky barrier height at the interface [VG, the Schottky barrier height was reduced due to the lower Fermi level. In contrast, when the VG was increased to a positive value, the Schottky barrier height was enhanced, and the current in the channel was greatly suppressed.Figure 0 mAW−1) . Furthernterface . As the Iph = Pα, α = 0.85). Under lower light power, the contribution of the photogate current was dominant, and the photoconductive effect could be ignored due to a decrease in the number of photogenerated carriers [Finally, we turn to the time-dependence investigation of photocurrent under incident light of power. Figure carriers . Upon hi2 interface. The device exhibited a high photoresponsivity of 800 AW−1 at VG = − 4 V, which was two orders of magnitude higher than those in the previous research. Furthermore, the structure of our device is much simpler compared to the previous graphene-based optoelectronic device with the potential broad applications. The performance of the graphene nanoribbon device can be further improved by h-BN encapsulation, surface plasmons, ferroelectric field, and hybrid structures. The proposed graphene nanoribbons photodetector opens up exciting opportunities for ultrafast and high sensitivity for future graphene-based safety monitoring, photo-communication, and aviation applications.In summary, we have demonstrated a high-performance graphene nanoribbon photodetector modulated in a wide range through the external electrical field at room temperature. Meanwhile, without the external electric field, the performance of the device could be enhanced by the localized field at the Si/SiO