Arterial blood gases revealed metabolic acidosis. Definitive diagnosis was by a positive real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens, and high-resolution computed tomography (HRCT) finding of new-onset ground-glass opacities on the very first day of admission that was the presenting day. The patient became unresponsive and died overnight. As numbers of COVID-19 show an uprise, this case highlights that IPF patients with relatively advanced age need to exercise extra caution because they are at high risk for developing overwhelming COVID-19-linked sepsis, which may be fatal.The new disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was dubbed coronavirus disease 2019 (COVID-19) by the World Health Organization and declared a pandemic. Initially thought to be a pathogen that primarily attacks the lungs, SARS-CoV-2 has turned out to be a much more formidable foe impacting almost every organ and system aggressively. I report the case of a 60-year-old man who came to the ED due to symptoms of high fever, headache, mild confusion, dry cough and exacerbated dyspnea since the last 24 hours. He had a history of idiopathic pulmonary fibrosis (IPF) and was undergoing treatment with antifibrotic medication. Apart from IPF, he had no other comorbid. He acquired SARS-CoV-2 infection by close contact and infection deteriorated into pneumonia and septic shock. Complete blood count showed white blood cells at 3.3×10 Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease (ILD). The precise etiology of IPF is unclear although risk factors include old age and cigarette smoking, the onset is insidious and the prognosis is poor ,2.A new disease broke out in Wuhan, China in December 2019 as a cluster of pneumonia cases with etiology unknown . As moreHere I describe a case of an old man with preexisting IPF and laboratory-confirmed SARS-CoV-2 by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR), who presented acutely with rapid progression (within hours) to septic shock.A 60-year-old man was brought to the ED with a one-day history of high fever, headache, mild confusion, dry cough, and increasing shortness of breath.2) above 90% and pirfenidone therapy, and had adhered to his medical regime. Apart from that, he was taking no other medications. He had smoked one pack of cigarettes daily for 15 years and quit 20 years ago. The patient worked as an investment banker and did not use alcohol or illicit drugs. There was no exposure to an inciting agent . He had not traveled recently, but was caring for his wife since four days who had tested positive for COVID-19. His last high-resolution computed tomography (HRCT) done a week before presentation has been included for analysis; a definite usual interstitial pneumonia pattern on this HRCT affirmed IPF  was already negative. His C-reactive protein was 55.9 mg/L, ferritin was 1480 ng/mL , and lactate dehydrogenase was 443 U/L . Coagulation studies revealed a prothrombin time (PT) of 23 sec, activated partial thromboplastin time (aPTT) of 53 sec, and D-dimer level of 2.1 μg/dL . Blood count, serum chemistry and liver function study is given in Table Arterial blood gas status six hours into admission is given in Table 2 on pulse oximeter was 86%. The patient was put on high flow oxygen, and remained on double inotropic support and Inj dopamine at 3 µg/kg/min. But despite all efforts, he collapsed of overwhelming infection. The emergency medical team found the patient unresponsive with no pulse.On the night following admission, his hemodynamic status deteriorated rapidly. Blood pressure fell to 50/20 mmHg despite receiving IV fluids. The venous access sites were oozing blood. Urine drainage from the Foley catheter was <20 mL/hr. GCS fell to 4/15. SpOThis patient's high fever, lymphocytopenia are indicative of SARS-CoV-2 pneumonia complicated by septic shock , the result of an overwhelming inflammatory response to infection. Severe sepsis is marked by organ dysfunction due to poor blood flow . His laboratory studies showed a consumptive coagulopathy , which, along with bleeding from the IV catheter site and elevated D-dimer, was likely due to DIC .IPF patients have an inexorable decline in respiratory reserve and lung function. Cytokines are implicated in the pathogenesis of IPF including initiation of a process called epithelial-mesenchymal transition, and SARS-CoV-2 itself causes further cytokine activation and inflammation thereby also justifying the use of steroids as a therapeutic option in virally driven hyperinflammation, but precisely why COVID-19-linked sepsis may be fatal . HRCT isAnswers to the following questions are being sought: the impact of COVID-19 on the rate of preexisting ILD progression, the mortality rate and predictors of mortality in patients with preexisting ILD and COVID-19 [In an analysis issued by the Chinese Center for Disease Control and Prevention using a cross-sectional study design, among the 44,672 confirmed cases of COVID-19, the case fatality rate was found to be elevated in those aged >/60 years, in males and among those with preexisting comorbids-10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6% for hypertension, and 5.6% for cancer. All 1023 deaths that occurred were critical cases; critical cases were identified as those that exhibited respiratory failure, septic shock, and/or multiple organ dysfunction . There iIn a retrospective study to determine the clinical outcome in 38 patients with a mean age of 68.3+/-11.5 years with IPF admitted to the Intensive Care Unit between 1995 and 2000, of the 37 patients whose data was available, nine patients (24%) developed sepsis with one patient each developing severe sepsis and septic shock. Thirty-five patients (95%) developed one or more organ failure. IPF was associated with poor short and long term prognosis . AlthougSARS-CoV-2 has a propensity to affect older adults with underlying IPF. IPF patients are at high risk for invasive and potentially fatal SARS-CoV-2 pneumonia. Manifestations of sepsis are more acute and severe in IPF patients. IPF patients be alerted to their increased susceptibility to fulminant SARS-CoV-2 infection and therefore they must go an extra mile to reduce potential exposure to COVID-19. Research is needed to elucidate further the clinical course, diagnostic criteria and outcomes of patients with concurrent COVID-19 and IPF.


ALS patients could be discriminated from PD and Ctrl with a sensitivity/specificity of 89 %/77 % and 89 %/83 %, respectively. Our findings demonstrate that TDP‐43 misfolding measured by the immuno‐infrared sensor technology has the potential to serve as a biomarker candidate for ALS.Pathologic alterations of Transactivation response DNA‐binding protein 43 kilo Dalton (TDP‐43) are a major hallmark of amyotrophic lateral sclerosis (ALS). In this pilot study, we analyzed the secondary structure distribution of TDP‐43 in cerebrospinal fluid of ALS patients ( Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with rapid loss of motor function. It leads to necessity of artificial nutrition, ventilation or results in death within few years after diagnosis. To date, one of the key challenges in ALS diagnostics is to exclude other mimicking diseases, which are assessed based on clinical and electrophysiological parameters, while disease‐specific diagnostic and prognostic biomarkers are still lacking. Recently, neurofilament light chain and phosphorylated neurofilament heavy chain gained attention as potential diagnostic and prognostic biomarkers for ALS.48‐scoreatdateofsamplecollectionduration between symptom onset and date of sample collection were collected . It represents a mixture of monoclonal recombinant antibodies against different epitopes of TDP‐43 to facilitate the complete extraction of total TDP‐43 from CSF. The immunogen used for antibody production corresponds to human TARDBP (aa 130‐275). Specific binding of human TDP‐43 was further analyzed by siRNA mediated knockdown of TDP‐43 and antibody performance was evaluated by western blot using recombinant TDP‐43 as shown in the manufacturer´s description . Instrumentation and data preprocessing comprising elimination of spectral contributions of water vapor were described previously in great detail and applied in the present study.Briefly, highly specific and sensitive capture antibodies are covalently attached to the sensor surface, followed by surface inertization via casein blocking solution to avoid unspecific binding and to solely extract the all isoforms of the biomarker fraction from CSF. Unspecifically bound proteins are removed from the sensor surface by excessive rinsing with buffer. Thus, only the desired biomarker is detected by the immuno‐infrared sensor. For TDP‐43 extraction we used 10 µg/mL recombinant oligoclonal TDP‐43 antibody  dissolved in phosphate buffer (50 mmol/L Na−1), receiver operating characteristic (ROC) analyses including calculation of the area under curve (AUC) were performed 5 times with different subsets comprising five ALS cases versus five PD subjects and their corresponding amide I maximum values and the same procedure with ALS versus Ctrl. Analyses revealed a mean threshold at 1643 cm−1, whereas lower values were indicative for TDP‐43 misfolding, which resulted in best discrimination accuracy with highest sensitivity and specificity. This threshold was set as discriminating threshold for analyzing the whole study group. Data were analyzed using the software Origin2019 by OriginLab (Software version 9.60).A Grubbs test was carried out before the data analysis to exclude outliers, which, however, were not identified. A Shapiro–Wilk test was used as statistical significance test to evaluate the sensor read‐out values (distribution of the amide I maximum frequency) for normal distribution. Thus, nonparametric Mann–Whitney U‐tests were performed to calculate significant group differences between the three diagnostic groups. The chi‐squared test was used for a comparison of gender differences. Spearman rank correlation coefficient was used to examine correlations between clinical characteristics and TDP‐43 misfolding. To determine the decisive diagnostic threshold for group differentiation . The ALS female ratio (61%) versus PD (33%) was significantly different (P = 0.09), but there was no significant difference between ALS versus Ctrl . We identified a weak correlation of the CSF‐to‐serum albumin concentration quotients  with the amide I maximum positions in ALS  and Ctrl , but not within the PD group . The average disease duration of ALS patients was 1.5 years and mean ALSFRS‐R score was 38 points at the time point of examination. 25 ALS patients had a spinal and 11 patients showed a bulbar disease onset  compared to PD subjects (1651 ± 7.7 cm−1 SD) and Ctrl (1646 ± 5.5 cm−1 SD), suggesting misfolding of TDP‐43 in ALS cases . To determine the diagnostic potential of TDP‐43 misfolding for differentiation of ALS versus PD and ALS versus Ctrl, we performed a ROC analysis on amide I maximum data resulting in an AUC of 0.85 (95%‐CL 0.75–0.95) for ALS versus PD and an AUC of 0.93 (95%‐CL 0.87–0.99) for ALS versus Ctrl. The threshold at 1643 cm−1 revealed a sensitivity of 89 % and a specificity of 77 % for the comparison of ALS versus PD and 89% Sensitivity and 83% Specificity for ALS versus Ctrl  with ALSFRS‐R slope ≥ 0.5 points/month showed significantly lower amide I maximum frequencies compared to slower progressive patients (n = 19) with ALSFRS‐R slope < 0.5 points/month (P < 0.05)   Fig. . Importa37) Fig. .In this pilot study, we investigated whether the secondary structure distribution of TDP‐43 is a potential biomarker candidate for ALS. The presence of TDP‐43 protein in human CSF measured by standard immunoassays was already shown in different studies.Our study revealed a significant increase of TDP‐43 protein conversion to β‐sheet enriched structures in CSF samples from ALS cases as compared to PD and Ctrl. Tests for diagnostic accuracy using a simple discriminative threshold resulted in a sensitivity of 89 % and a specificity of 77 % for TDP‐43 misfolding in case of ALS versus PD and 89% and 83% for ALS versus Others. Furthermore, ALS patients with clinically faster progression and patients in more progressed disease stages showed higher β‐sheet content of TDP‐43. We observed weak correlation of the Qalb and amide I maximum position for ALS and Ctrl, but not for PD. We suggest no direct effect of elevated albumin levels on our measurements, because unspecific binding of albumin would rather lead to higher amide I frequencies, since it consists primarily of helical structures and western blot analyses excluded unspecific binding of albumin. Therefore, a higher number of patient examinations should clarify this point.Moreover no specific binding of the antibody was achieved in CSF as evaluated by western blot. This was most likely due to the low levels of TDP‐43 in CSF, as shown in other studies.In conclusion, we present for the first time a TDP‐43 structure‐based biomarker for ALS, which should be validated in larger studies.L.T. and K.G. contributed to conceptualization and supervision. L.B., R.Gü., A.N., L.T., and K.G. contributed to methodology. L.B., R.Gü., A.N., L.T., and K.G. contributed to validation. L.B., R.Gü., and L.T. contributed to formal analysis. L.B., R.Gü., J.C.K., P.L., S.K., T.H., A.‐S.B., L.T., and K.G. contributed to investigation. L.B. and R.Gü. contributed to writing—original draft preparation. J.C.K., P.L., S.K., T.H., A.H., R. Go., A.N., L.T. and K.G. contributed to writing—review and editing. L. B. and L.T. contributed to project administration. All authors have read and agreed to the published version of the manuscript.P.L and L.T. are inventors on a patent for the use of Fasudil for the treatment of Amyotrophic lateral sclerosis . All other authors declare that there are no conflicts of interest.


Humidity detection range is an important indicator for measuring the performance of humidity sensors, but semiconductor humidity sensors often face the problems of narrow detection ranges and insufficient detection sensitivities. In this paper, a magnesium oxide (MgO) humidity sensor based on micro-arc oxidation (MAO) technology was designed to solve these problems by simultaneously using impedance and capacitance as the response signals, as well as by normalizing the output of the two signals. The experimental results showed that the average output of the micro-arc MgO ceramic film, with impedance as the response signal, could reach 150 in the low relative humidity(RH) range (11.3–67% RH), which was much higher than its sensitivity in the high humidity range (< 1), and the film showed fast response (13 s) and recovery (61 s). Under high humidity conditions (67–97.3% RH), with capacitance as the response signal, the output of the micro-arc MgO was as high as 120. Therefore, the micro-arc MgO humidity sensor with impedance, and the sensor with capacitance as the response signal, demonstrated good stability in low humidity and in high humidity environments, respectively, indicating that the method of selecting appropriate response signals for different humidity environments can be applied to extend the humidity detection range of sensing material, and to improve the humidity detection capability of a sensor. Humidity sensors have been widely used in various fields of human production and life, including weather forecasting, health care, and food processing ,3,4,5,6.Micro-arc oxidation (MAO) is a new technology to directly grow ceramic layers in situ on the surface of non-ferrous metals. This is done by placing a valve metal  in an aqueous electrolyte solution, and using electrochemical methods to generate spark discharge points in the surface micropores of the material, which is a method for generating oxides under the influence of thermochemistry, plasma chemistry, and electrochemistry. Technologies like this have the advantages of easy operation, environmental protection, and high efficiency ,17. MeanTo this end, this paper is devoted to the use of MAO to grow MgO film layers in situ on the surface of Mg plates to produce humidity sensing material. The microstructure and composition of the oxide layer were characterized by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). The phase composition of the oxide layer was analyzed by X-ray diffraction (XRD). At the same time, impedance and capacitance were selected as the response signals to detect the humidity sensing performance of the film layer. The experimental results showed that the micro-arc MgO film with a porous structure on the surface had a large specific surface area. In different humidity environments, the micro-arc MgO film layer with impedance and capacitance as the response signals showed a major difference in output, indicating that the method of selecting appropriate response signals for different humidity conditions could be used to extend the humidity detection range of sensing material.(a)First, a 20 × 20 × 5 mm magnesium plate sample was cut out (purity > 99.5%). Sandpaper (400 # → 600 # → 800 #) was used to grind and remove oil (10% NaOH solution), then the magnesium plate was rinsed with deionized water and air-dried for later use.(b)2SiO3 solution using deionized water was prepared, and then NaOH powder was added to adjust the pH of the electrolyte to 13.A 10 g/L Na(c)The sample was hung on the electrode and immersed into the electrolyte. The anode was a magnesium plate and the cathode was a stainless steel electrolytic cell.(d)The power supply parameters were adjusted. The average current density was 4A/cm2, the duty cycle was 35%, the frequency was 550 Hz, the temperature of the electrolyte was maintained at 10–40 °C, and the oxidation time was 20 min. A circulating cooling device was used to keep the temperature of the configured electrolyte at 10–40 °C.(e)After oxidation, the micro-arc MgO plate was rinsed thoroughly with deionized water and dried in hot air.(f)A 200 # interdigital electrode screen plate was designed and purchased. The test piece was placed under the mesh, and the prepared conductive silver paste was uniformly printed on the micro-arc oxidation plate through the screen hole by using a scraper.(g)After the printing was completed, the MAO plate was held at 80 °C for 1 h to ensure that the silver paste was completely cured to fabricate a micro-arc MgO humidity sensor.The specific manufacturing steps (as shown in As shown in Capacitance testing was performed using an LCR bridge tester (VC4090A)  at an operating frequency of 1 kHz. The entire device could continuously change the humidity in the test environment, which was mainly used to test the change in the two response signals (impedance and capacitance) of the sensor with humidity.3COOK (22.5% RH), MgCl2 (32.8% RH), K2CO3 (43.2% RH), NaBr (57.6% RH), NaCl (75.3% RH), KCl (84.2% RH), and K2SO4 (97.3% RH) of 25 °C saturated solution in order to obtain a stable humidity environment [In addition, this paper configured LiCl (11.3% RH), CHironment . This paThe surface morphology and microstructure of the micro-arc MgO film layer were characterized by SEM, as shown in The surface and cross section of the micro-arc MgO film layer were shown at different magnifications. The thickness of the micro-arc oxide film was about 32 μm, which had good continuity, while the surface had a large number of abnormal pores with a diameter of 4–8 μm. This microporous structure allowed the micro-arc MgO film layer to have a larger surface area, providing more adsorption sites and reaction channels for water molecules, which was helpful for enhancing the moisture-sensing properties of the material. The XRD measurement of the micro-arc MgO film layer was performed with an X-ray diffractometer. The XRD results  showed tR and SC:At the 1 kHz operating frequency, the impedance and capacitance of the film in different humidity environments were measured separately to investigate the effects of different response signals on the humidity sensing performance of micro-arc MgO. As shown in R and SC denote the output result of micro-arc MgO when impedance and capacitance are used as response signals. RRH and CRH are the impedance and capacitance of micro-arc MgO in various humidity environments, respectively. R97.3% and C11.3% represent the impedance and capacitance values of the micro-arc MgO at 97.3% RH and 11.3% RH, respectively.S2 is 0.9724 and 0.9977, respectively, indicating a good curve fitting. 2+) had greater electron affinity than the internal positive ions, the surface acceptor level occurred slightly below the conduction band bottom [2−) on the surface had greater electron repellency than the internal negative ion, so the surface donor level appeared slightly above the valence band. Before the adsorption of water molecules by micro-arc MgO, the density of surface states of donors was significantly higher than that of acceptor surface states, which led to the downward bending of the energy band at the surface, forming a hole depletion layer, and exhibiting high impedance [2− on the surface of the material, which caused the density of the surface donor state to decrease. The originally trapped holes were released, while the carrier concentration rose, showing a decrease in resistance [MgO is a p-type semiconductor, which has a larger band gap (7.8 eV) than other metal oxides. Since the surface positive ions  and hydrogen (H+) [As shown in gen (H+) :(3)H2O⇔H− was chemically adsorbed on the surface of the membrane and was connected to the metal cation (Mg2+) by hydrogen bonding, so that the chemically adsorbed aqueous layer was firmly bonded to the surface of the sensing membrane, which was difficult to remove. In a low humidity environment, discontinuous water molecules were mainly physically adsorbed above the chemisorbed layer to form a first physically adsorbed aqueous layer. However, because hydrogen bonding limited the free movement of water molecules, protons did not have a continuous jump path, thus at this stage, the capacitance increased slowly with increasing RH. As RH continued to increase to higher levels, multiple continuous water molecules appeared on the surface of the membrane layer, which made the transfer of hydronium ions (H3O+) easier than before. According to the Grotthuss chain reaction [OHreaction ,41, thisPhysically adsorbed water molecules would penetrate into the pores of the membrane layer, further improving the sensor response. All of these factors caused a sudden increase in capacitance, so there was a large slope in the relationship between capacitance and RH. Meanwhile, according to this mechanism, three adsorbing steps, including the generation of first chemisorbed layer, first physisorbed layer, and multi-physisorbed layer, exist in adsorption process. Each process will continuously increase the capacitance of the sensor. Compared to a resistive humidity sensor, the response time of a micro-arc MgO humidity sensor with a capacitance as a response signal is longer.For the first time, we used MAO to prepare a MgO ceramic moisture-sensitive film with a large number of micropores appearing on the surface, and we used impedance and capacitance as the response signals. The experimental results showed that in the low humidity range (11.3–67%RH) with impedance as the response signal, the average output was up to 150, with faster response (13 s) and recovery (61 s). Under the high humidity conditions (67–97.3%), with capacitance as the response signal, the average output of the micro-arc MgO humidity sensor was as high as 120. Based on the above experimental results, we can increase the humidity detection range of the sensing material by selecting an appropriate response signal for different humidity conditions, and then develop a humidity sensor with fast response and recovery, small hysteresis, and high response.


General knowledge varies from one country to another; therefore, the mere translation of knowledge-based experimental tools from one language to another is usually not enough. This is one of the conclusions that can be extracted from the results of the Program for International Student Assessment (PISA), a measure of the knowledge achieved by 15-year-olds. This assessment provides each participating country 79 in 2018) with a comparative measure of the efficiency of their educational programs within an internationally agreed common framework and allows them to identify the most effective educational practices as well as gaps in curricula. Over the years, this periodic measure has reflected clear differences between countries in different areas of knowledge. The PISA program assesses mathematics, sciences, and reading, designed as an indicator of “how well the students master key subjects in order to be prepared for real-life situations in the adult world” . Russian is one of the most spoken languages in the world, the largest native language in Europe, one of the six official languages of the UN, and the second most used languages on the Internet globallyMetacognitive evaluations such as retrospective confidence judgments provide valuable information about the selection of a specific answer. Retrospective confidence is the subjective assessment of how correct the selected answer is  recruited on social media took part in the experiment for a small monetary compensation (250 rubles per hour of experiment ~ 3.5 USD).One hundred three native Russian speaking participants : most of them were completing their university studies , close to the 30% already had a university degree , and a very small amount only had completed high school . In Russia, it is compulsory to pass the Unified State Exam to get the diploma after finishing school; therefore, we can assure that all of our participants had a similar minimum of general knowledge.M = 7.76 (SD = 1.38), and none of them reported to be under medical treatment.We included two more additional questions about time of sleep last night and medication intake to assure the optimal state of participants to complete this long experiment. Five participants did not report the number of hours of sleep; for those who did, the mean average was https://iq2u.ru/, which is directly oriented to students and professors and contains exemplars of the questions used in the Unified State Exam. These exams are compulsory in Russia either to get the high-school diploma or access to university studies (https://en.wikipedia.org/wiki/Unified_State_Exam). We also selected some other questions from https://baza-otvetov.ru/, which is a website for people interested in solving quizzes. For each question, participants had to select one alternative and rate the confidence they had in its correctness on an 11-point confidence scale ranging in 10% steps from 0%  to 100% . Dependent variables were (1) accuracy and (2) confidence in the correctness of the selected answer.Five hundred two multiple-choice GKQs were used in the experiment see . Five huThe experiment was programmed using SR Research Experiment Builder . The experiment consisted of one training session with two questions, and 10 experimental blocks with 50 questions each. The order of appearance of the questions in the experimental blocks, the blocks, as well as the placement on the screen of the alternatives was fully counterbalanced for each participant. The training questions were the same for all participants and their answers were not included into the analysis.Participants were tested individually on a computer. First, participants read and signed the informed consent form and completed the demographic data along with questions about the number of hours of sleep they got the previous night, level of education, and medication intake. They were then given instructions explaining every phase of the experiment and presented with two training questions. Then, the main experimental part started. In each trial see , particiOut of the 500 multiple-choice GKQs, all participants consistently chose the correct answer for 8 of them. In addition, there were 7 questions more for the group of females  and 12 for the group of males  for which participants of each gender always selected the correct choice. There were 19 questions in the entire sample for which participants only selected one of two alternatives (the other two were never selected), and 66 questions for which one of the alternatives was never chosen. All of the questions for which one, two, or three alternatives were never selected are indicated in t test, and Cohen's d was used to estimate effect size. There were no differences between female and male participants considering all the questions or when splitting them by topic.Recognition tests are easier to solve than other memory tests such as cued recall or free recall because they are based on familiarity Tulving, . This fat test, Cohen's d for effect size, and Bonferroni correction for multiple comparisons when appropriate. We found that males assigned significantly higher confidence to the correctness of their answers to questions about History and Geography than females did. No other differences were found.x-axis represents confidence and the y-axis represents accuracy, is the diagonal and represents the point in which accuracy and confidence are perfectly matched . There is “overconfidence” when the confidence rating is higher than the accuracy obtained  and “underconfidence” when the pattern is reversed, that is, lower confidence rating than the accuracy obtained .Confidence–accuracy calibration curves show the correspondence between answer accuracy (objective measure) and confidence (subjective measure) with which answers are given in a test  and male , t(44) = 0.209, p = 0.835. Also, both Cs were significantly different from 0: for females t(44) = 10.156, p < 0.001, and for males, t(44) = 9.950, p < 0.001.We computed the Calibration index  disregards all cultural background, which has in fact been shown to affect problem solving (Chen et al., The multiple-choice format with four options made the present battery of questions suitable for a wide variety of experiments to be performed in Russian within a sample with similar characteristics. Moreover, the additional information obtained from the participants' subjective experience will enable experimenters to more carefully select questions to guide their experiments. All of our participants had a high-school diploma, which, for Russian citizens, means that they completed successfully the Unified State Exam, covering a range of subjects (Francesconi et al., Finally, in this study, we used new questions that were not previously used in other published studies. This somewhat complicated cross-cultural comparison of our results with other samples obtained in other languages and cultures. A follow-up step of this research line could be to improve this database incorporating questions used in other studies (e.g., Tauber et al., All datasets generated for this study are included in the article/The studies involving human participants were reviewed and approved by Ethics committee of National Research University-Higher School of Economics. The participants provided their written informed consent to participate in this study.BM-L, OZ, MA, and YS contributed in the design. MA collected the data. OZ and BM-L performed the data analysis. All authors contributed in writing of the manuscript.The materials of this experiment can be found in the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The effect of the parameters of this method on the structure of transferred graphene islands is investigated. The relevance of reducing the distance between irradiating and receiving substrates for the transfer of free-lying graphene is demonstrated. The reasons for the damage to the integrity of the carbon film observed in the experiments are discussed. The preservation of the original crystal structure of transferred graphene is confirmed by Raman spectroscopy.The patterning and transfer of a two-dimensional graphene film without damaging its original structure is an urgent and difficult task. For this purpose, we propose the use of the blister-based laser-induced forward transfer (BB-LIFT), which has proven itself in the transfer of such delicate materials. The ease of implementation of laser techniques reduces the number of intermediate manipulations with a graphene film, increasing its safety. The work demonstrates the promise of BB-LIFT of single-layer graphene from a metal surface to a SiO The use of graphene in optics and electronics requires transferring the monolayer carbon material to an arbitrary, usually dielectric, substrate and forming the necessary pattern from it; for example, the channel of the transistor ,2. The sHere, we report on the results of the BB-LIFT of the fragments of pure graphene film. The effect of the thickness of the absorbing metal layer and the gap between the donor and acceptor substrates on the quality of the transfer is analyzed. Possible changes in the internal structure and morphology are controlled by Raman spectroscopy and scanning electron microscopy (SEM), respectively.−5 mbar by the heating aluminum foil in a molybdenum boat to 900 °C with a current passing through it. Then, a polycrystalline graphene film grown on copper foil by chemical vapor deposition (CVD) was transferred to the surface of the aluminum film by a standard wet method using PMMA as a supporting polymer, which was chemically removed after the transfer [Experimental samples, the so-called donors, were prepared in two stages. First, to absorb the energy of the pulsed laser radiation, an aluminum film was deposited on the surface of a polished quartz plate. The metal film deposition was performed in a vacuum chamber at a pressure of 10transfer ,21,22. T2) to cut out the central homogeneous part of the laser beam. In such a projection scheme, the image of the mask was reduced 20 times into a 60 × 60 μm2 spot. In our experiments, the laser fluence in the irradiated spot was varied discretely from 1.2 to 3 J/cm2.The BB-LIFT procedure applied to the donor sample containing a graphene film is illustrated in 2) surface layer were chosen as receiving substrates, the so-called acceptor, which made it possible to control the transfer of the graphene film on the substrate surface by optical methods [Silicon substrates with a 90 nm-thick silicon dioxide  and SEM . The surface morphology was also analyzed using an Axiotech 25HD optical microscope .2. In this case, the graphene film starts to transfer after the irradiation with a laser fluence exceeding the value of 1.2 ± 0.1 J/cm2. Therefore, the working range of the laser fluence changes from 0.2 ÷ 0.8 to 1.2 ÷ 2.8 J/cm2. The distance between the donor and acceptor substrates remains the same as in previous experiments [2, a noticeable change in the amount of transferred material onto the acceptor surface is observed, which is associated with the beginning of the ablative metal transfer. It is indicated by the metal rupture that can be observed in In this work, we increase the thickness of absorbing aluminum film from 420 to 1900 nm, which leads to an increase in its ablation threshold from 0.8 ± 0.1 to 2.8 ± 0.2 J/cmeriments . When th2 hybridization) of single-layer graphene if the laser fluence exceeds the value of 1.2 ± 0.1 J/cm2. −1 (peak G) and 2670 cm−1 (peak 2D) are detected for the original film and transferred flakes. The width of the 2D peak is about 32 cm−1 in almost all regions, which indicates the transfer of single-layer graphene [−1 corresponds to the presence of defects in the carbon material. To analyze the defect formation in the transferred graphene material, we calculate the Id/Ig ratio of the intensities of the D and G peaks in the initial film and transferred graphene fragments. After the transfer, the Id/Ig ratio increases from 0.07 to a maximum of 0.18, which corresponds to a change in the distance between defects from 38 to 24 nm [The Raman spectroscopy analysis of islands of the transferred material shows that graphene is transferred by separate micron-sized flakes to the acceptor substrate with the preservation of the initial crystal structure (spgraphene . In the graphene . The incto 24 nm .2, which was not previously observed in experiments with a thin metal film at a fluence value reaching the threshold of metal ablation [The Raman spectroscopy analysis of the donor surface in the irradiated areas after the transfer shows a complete absence of graphene in them at a laser fluence higher than 1.6 ± 0.1 J/cmablation . Thus, a2, respectively. The increase in ratio corresponds to a decrease in the distance between defects from 38 to 32 and 26 nm, respectively.An analysis of the material transferred in the scheme without a gap between the substrates by Raman spectroscopy  shows th2, most promising for the imprint quality (2 [For a more detailed comparison and analysis of the morphology of the transferred graphene in the two considered configurations of the laser transfer scheme, we used SEM images.  quality . For com quality . In the ality (2  have shoality (2  or superality (2 .The BB-LIFT of the crumpled fragments of graphene film was demonstrated. The increase in the thickness of the absorbing metal layer allowed us to transfer the graphene material from all over the irradiated spot of the donor onto the acceptor substrate without signs of the metal. Reducing the gap between the substrates to a value of zero results in matching the patterns on the acceptor to the shape of the laser spot. Raman spectroscopy indicates the preservation of the initial structure of graphene after the LIFT, with a slight change in the distance between defects from 38 to 32 nm at the optimal conditions of the transfer. The SEM analysis shows the transfer of crumpling micrometer-scale islands of the graphene film. Therefore, the applied technique requires further optimization of the transfer conditions so as to print a continuous pixel from a graphene film.


Furthermore, the carrier mobility of the camphor-based CVD bilayer graphene at room temperature is 1.8 × 103 cm2/V·s. Due to the incorporation of camphor-based CVD graphene, the graphene/p-Si Schottky junctions show a good rectification property (rectification ratio of ~110 at ± 2 V) and good performance as a self-powered (under zero bias) photodetector from UV to LWNIR. The photocurrent to dark current ratio (PDCR) value is up to 230 at 0 V under white light illumination, and the detectivity (D*) is 8 × 1012 cmHz1/2/W at 560 nm. Furthermore, the photodetector (PD) response/decay time  is ~118/120 μs. These results support the camphor-based CVD bilayer graphene/Si Schottky PDs for use in self-powered and ultra-broadband light detection in the future.This work demonstrates a self-powered and broadband photodetector using a heterojunction formed by camphor-based chemical vaper deposition (CVD) bilayer graphene on p-Si substrates. Here, graphene/p-Si heterostructures and graphene layers serve as ultra-shallow junctions for UV absorption and zero bandgap junction materials (<Si bandgap (1.1 eV)) for long-wave near-infrared (LWNIR) absorption, respectively. According to the Raman spectra and large-area (16 × 16 μm Furtherformance . Under zf the PD ,51. CompHz1/2/W)  and the I-V characteristics of camphor-based CVD graphene/p-Si Schottky PDs [Fg) is lower than the Si Fermi energy (EFSi), leading to the SBH (qΦB) lowering, as shown in Fg is higher than EFSi , resulting in the increase in SBH. Moreover, the barrier height (qΦbi) of the hole from p-Si to graphene will be reduced gradually with an increasing forward bias, leading to a higher dark current. Therefore, the dark current under a low reverse bias (from 0 V to −2 V) is much lower than under a low forward bias (form 0 V to +2 V), as shown in As shown in ttky PDs ,55,56,57To highlight the stable and high-speed photoresponse properties of the camphor-based CVD bilayer graphene/p-Si Schottky PDs, the time-resolved measurements were performed under a 3 V bias, as shown in 2) Raman mapping images, and Hall measurements could reveal that our camphor-based CVD graphene has low defects, >95% coverage bilayer structures, a high-uniformity, and a high carrier mobility (1.8 × 103 cm2/V·s). By employing camphor-based CVD bilayer graphene/p-Si Schottky junctions, our PDs also show a high rectification ratio value (~110 at ±2 V) and high photo-sensing performances (such as an ultra-broadband (from UV to LWNIR) photoresponsivity (under zero bias), a high PDCR value (up to 230 at 0 V), and high detectivity (D*) (8 × 1012 cmHz1/2/W at 560 nm)). In addition, the operation speed of PD was revealed by the rise time and fall time as fast as 118 and 120 μs, respectively. This work demonstrates that the low-cost camphor-based CVD bilayer graphene incorporating p-Si holds promise for practical applications in the new generation of self-powered and ultra-broadband photon detection.In summary, a self-powered and broadband PD using a camphor-based CVD bilayer graphene/p-Si heterojunction was fabricated. Here, graphene layers could unite with p-Si to form ultra-shallow Schottky junctions for absorbing UV light effectively and, at the same time, graphene layers with zero bandgap could also provide a higher LWNIR absorption than Si. Raman spectra analyses, large-area (16 × 16 μm


P < 0.001). We concluded that IPF increases LC risk, and LC weakens survival outcomes in IPF. Close surveillance for LC development is mandatory for patients with IPF.Idiopathic pulmonary fibrosis (IPF) is an independent risk factor for lung cancer (LC) development; however, there are currently no clinical guidelines for LC surveillance in IPF. This study aimed to investigate the cumulative incidence and survival outcomes of LC in IPF. Using the National Health Insurance Service database, including medical information on people aged ≥ 40 years between 2011 and 2016, we identified IPF patients and confirmed the presence of comorbid LC. Patients diagnosed with IPF in 2011 were washed out, and mortality data were analyzed from 2012 to 2018. A total of 7277 newly diagnosed IPF patients were identified among Korean citizens aged ≥ 40 years (about 50 million people) between 2011 and 2016. Their average age was 71.5 years and 72.8% of them were male. The prevalence of LC in the IPF cases was 6.4%. The cumulative incidence rates of LC in IPF patients who did not have LC at the time of IPF diagnosis were 1.7%, 4.7%, and 7.0%, at 1, 3, and 5 years, respectively. The median time from IPF diagnosis to LC development was 16.3  months. The survival rate was significantly lower in the IPF with LC group than the IPF without LC group ( Epidemiological studies have revealed that IPF is an independent risk factor for lung cancer (LC) development after adjusting for shared risk factors. Hubbard et al. reported that the relative risk of developing LC in IPF is approximately eight times higher than in the general population, after adjusting for smoking history, based on United Kingdom healthcare databases3. The prevalence of LC in IPF was reported to be 4.4–13%, and up to 48.2% in an autopsy study of 83 usual interstitial pneumonia patients9. LC in IPF occurs more frequently in older male smokers and patients with combined emphysema10. Comorbid LC significantly affects survival in IPF. The mortality values are higher among IPF patients with LC than IPF patients without it13 and those with LC in the general population14. Additionally, the treatment of LC itself can cause acute IPF exacerbation, which is the most lethal life-threatening complication of IPF17.Idiopathic pulmonary fibrosis (IPF) is the most commonly occurring type of idiopathic interstitial pneumonia, characterized by chronic, progressive, fibrotic interstitial lung disease of an unknown cause and a histopathological pattern of usual interstitial pneumonia18. In the absence of an official recommendation for LC screening in IPF, a large number of IPF patients are diagnosed with advanced LC at the time of hospital visit due to symptom development over several years.Despite the presence of notable epidemiologic associations between LC and IPF, and poor survival outcomes, there are currently no clinical guidelines for the screening of LC in IPF; since the natural history of IPF is highly variable, some patients show a relatively stable disease course without symptoms and, therefore, do not routinely visit hospitalsIn this study, we investigated the demographic characteristics, cumulative incidence, and mortality associated with LC in IPF patients using nationwide data to suggest the direction of LC surveillance.P < 0.001) and average age was higher  in the IPF without LC group than in the IPF with LC group. Similar proportions of urban and rural area-dwelling patients were observed in both the IPF without LC and IPF with LC groups. More than 40% of the patients in both groups were included in the fifth quintile of household income, the lowest socioeconomic status, and the distributions of household income were similar between the groups. Of the 464 patients in the IPF with LC group, 254 (54.7%) were diagnosed with IPF before LC, 127 (27.4%) had a simultaneous diagnosis of IPF and LC, and 83 (17.9%) were diagnosed with LC before IPF. Patients were classified as having a “simultaneous diagnosis” if LC was diagnosed within 3 months of IPF being diagnosed. Patients diagnosed with IPF more than three months in advance of the LC diagnosis were classified into the “IPF in advance” group, while those who were diagnosed with LC more than three months in advance of IPF were classified into the “LC in advance” group. The baseline demographics of the IPF with LC group, according to the order of diagnosis, are shown in Supplementary Table A total of 7277 newly diagnosed IPF patients were identified between 2012 and 2016. Their average age was 71.5 years and 72.8% of the study population was male. Of the IPF patients, 464 (6.4%) were diagnosed with LC during the study period. The baseline demographics of the IPF patients with and without LC (IPF with LC and IPF without LC groups) were compared  and age at the diagnosis of IPF  were independent risk factors for mortality in IPF patients  months, and 81.8% of the IPF patients with LC developed LC in 3 years from IPF diagnosis8. However, each of the three aforementioned studies was conducted at a single center. Yoon et al. conducted a study based on interstitial lung disease registry data in the United States, which included 1108 IPF patients, and reported that the median time from IPF diagnosis to LC development was 53.0  months, and the incidence of LC increased in the first two years after IPF diagnosis, which persisted until year four13. The present study is the largest nationwide cohort study to date based on the NIHS database of almost all South Korean citizens aged ≥ 40 years (about 50 million people) and included 7277 IPF patients from this population. In this study, the cumulative incidence rates of LC in IPF at 1, 3, and 5 years of 1.7%, 4.7%, and 7.0%, respectively, were lower than those observed in previous studies. IPF shows a varied natural course after diagnosis18; therefore, patients who visit hospitals routinely and are enrolled in study registries from previous studies may have a relatively severe and rapid progressive disease course. This may be the reason for the lower incidence observed in our population-based study, which is based on the NHIS database of almost all Korean citizens, and also a strength of this study compared to previous studies.Few studies have reported on the incidence of LC during the follow-up period for IPF. Ozawa et al. reported cumulative LC incidence rates of 3.3%, 15.4%, and 54.7% at 1, 5, and 10 years, respectively, in 103 IPF patients13. The median time from IPF diagnosis to LC development tended to be shorter in those aged ≥ 60 years, but there was no significant difference between the age groups.The cumulative incidence graph showed a constant incidence rate over the 5-year study period, while previous studies reported that the incidence rate increased until 3–4 years from IPF diagnosis and then decreased25. Lederer et al., in another review, proposed that annual low-dose CT should be performed according to the U.S. Preventive Services Task Force criteria for LC screening, and nodules should be managed according to risk group based on the established guidelines of the Fleischner Society1.Although there is no official guideline for LC surveillance till date, various suggestions have been proposed in previous reviews. Tzouvelekis suggested the performance of high-resolution computed tomography (HRCT) once a year in all IPF patients. For nodules with a diameter smaller than 8 mm, HRCT is suggested every 3–6 months. If HRCT shows progression of the nodule, and for nodules with a diameter of at least 8 mm, positron emission tomography-CT is recommended3, and the fact that the cumulative incidence rate was kept constant during the study period, it is suggested that all IPF patients undergo close HRCT screening.Considering previous reports, which state that the LC incidence in IPF patients is approximately eight times higher than in the general population after adjusting for smoking history26. A retrospective study reported that the incidence of LC was lower in IPF patients receiving pirfenidone27. Nintedanib was first approved in combination with docetaxel as a second line treatment for advanced non-small cell LC28. The anti-cancer effect of these two antifibrotic agents should be further investigated in both therapeutic and protective aspects.Another challenge associated with IPF in LC, in real clinical practice, is the identification of whether the antifibrotic agents that are used to reduce the degree of forced vital capacity decline in IPF patients have anti-cancer effects. Nintedanib and pirfenidone are two antifibrotic agents that have been approved for IPF treatment. A preclinical experimental study revealed that a combination of cisplatin and pirfenidone increases cell death rates and decreases cancer progression rates29. However, IPF is classified as a rare intractable disease in Korea and strictly controlled by the Korean NHIS for medical cost reductions. This may lead physicians to enter the diagnostic code with care. Second, data on confounding factors that may have affected the incidence and mortality of both IPF and LC, such as smoking, pulmonary function , and concomitant emphysema, were not available in the study. Further study is needed to confirm whether close HRCT surveillance for LC in IPF will help improve the mortality of IPF patients with LC.This study has several limitations. First, we defined IPF using the ICD-10 code assigned by healthcare providers; this may have reduced the diagnostic accuracy owing to inconsistencies with the diagnostic criteria defined by the International Consensus Statement of the American Thoracic Society and European Respiratory Society in 2011In conclusion, the present study revealed that the prevalence of LC in IPF patients was 6.4% and the cumulative incidence rates were 1.7%, 4.7%, and 7.0% at 1, 3, and 5 years, respectively, after IPF diagnosis. The 5-year survival rate was 15.6% in the IPF with LC group, which was significantly lower than that in the IPF without LC group. Our findings suggest the need for close HRCT surveillance for LC in all IPF patients.The National Health Insurance Service (NHIS) in Korea has provided health insurance services to all Korean citizens living in Korea since 2000. Consequently, a large amount of health-related data has accumulated in the NHIS database. To offer relevant and useful data for health researchers, the NHIS established a population database including data on socioeconomic status (household income), medical treatments, medical care institutions, and general health examinations since 2002. From the NHIS database, we identified IPF and LC based on International Classification of Disease, Tenth Revision (ICD-10) diagnostic codes. This study was approved by the Institutional Review Board and Ethics Committee of National Health Insurance Service of the Ilsan Hospital (IRB number: NHIMC 2019-1-291). All methods were performed in accordance with the Declaration of Helsinki.30. The ICD-10 code C34 was used for malignant neoplasms of the bronchus and lung. To estimate the cumulative incidence of LC in patients with newly diagnosed IPF and the time from IPF diagnosis to LC development, we excluded patients who were diagnosed with IPF in 2011 and analyzed those who were newly diagnosed with IPF after 2012. Mortality data were analyzed from 2012 to 2018.The NHIS database includes medical data on almost all South Korean citizens aged ≥ 40 years (about 50 million people) between 2011 and 2016. From this population, we identified patients visiting medical institutions with a diagnosis of IPF, coded as J84.18 according to the ICD-10. We excluded patients with ICD-10 codes for both IPF and connective tissue disease, owing to the possibility of interstitial lung disease being related to connective tissue disease. The ICD-10 codes for connective tissue disease were as follows: M05 for rheumatoid arthritis, M07 for psoriatic and enteropathic arthropathies, M30 for polyarteritis, M31 for other necrotizing vasculopathies, M32 for systemic lupus erythematosus, M33 for dermatopolymyositis, M34 for systemic sclerosis, M35 for other systemic involvement of connective tissue, and M45 for ankylosing spondylitis. The code J84.18 was classified as a rare intractable disease, and patients assigned to this code receive medical cost reductions from the NHIS by up to 10% of the total cost. Owing to the financial problems associated with rare intractable diseases, the ICD for these diseases has high sensitivity and specificityP values < 0.05 were considered statistically significant. All statistical analyses were performed using the SAS program, version 9.4 .Continuous variables were analyzed using the Student’s t-test, and categorical variables using Chi-squared distribution. Cumulative time-to-event distributions were estimated using the Kaplan–Meier method. Log-rank test was used to compare survival curves, and Cox proportional hazards regression analyses were conducted to assess the impact of LC on survival in IPF. In all cases, This study was approved by the Institutional Review Board and Ethics Committee of National Health Insurance Service of the Ilsan Hospital (IRB number: NHIMC 2019-1-291). Written informed consent was waived as the nature of retrospective study by IRB.Supplementary Table S1.


Nintedanib has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In addition, in EU countries, nintedanib plus docetaxel is used for patients with advanced non‐small cell lung cancer (NSCLC) after first‐line chemotherapy. Here, we report a case of advanced NSCLC in a patient with IPF successfully treated with nintedanib monotherapy. A 69‐year‐old man was diagnosed with NSCLC complicated by IPF. After three lines of chemotherapy, he still had progressive disease. Because his IPF had also progressed, requiring supplemental oxygen, we decided to start best supportive care and introduced nintedanib to treat his IPF. One month later, we observed a partial remission of the primary tumor and pleural disseminations without severe adverse events. Nintedanib monotherapy might therefore be an effective therapeutic choice for NSCLC in patients with IPF who are unable to tolerate cytotoxic chemotherapy.Efficacy of nintedanib administered in a NSCLC patient with IPF.Nintedanib monotherapy might be a therapeutic option for NSCLC patients with IPF who are unable to tolerate chemotherapy. Idiopathic pulmonary fibrosis (IPF) is a risk factor for lung cancer development,A 69‐year‐old man was diagnosed as NSCLC  in March 2017. He had a smoking history and no special family history. Because high‐resolution computed tomography (HRCT) scan showed honeycombing in the lung bases, suggesting IPF, we chose carboplatin plus pemetrexed in combination with bevacizumab as the first‐line treatment. Thereafter, docetaxel plus ramucirumab were administered as the second‐line and carboplatin plus S‐1 as the third‐line treatments. After these chemotherapies, we observed progress of IPF and subsequently introduced supplemental oxygen therapy. Because of the progression of NSCLC and no more regimen with safety in a patient with IPF, we decided to start best supportive care and initiated treatment with nintedanib for IPF in May 2018.On the first day of nintedanib at 150 mg twice a day, his vital signs were normal except for tachypnea. Chest auscultation revealed fine crackles in both lower lung fields and clubbed fingers were also observed. A chest radiography showed reticular shadows in bilateral lung fields and a mass shadow in the left middle lung Fig a. Chest One month later, chest CT revealed regression of the primary tumor and pleural dissemination Fig e,f. The 2) significantly prolonged both PFS and OS, compared with placebo plus docetaxel.2) and pemetrexed alone in patients with advanced non‐squamous NSCLC.In the present case, we introduced nintedanib monotherapy in an IPF patient with NSCLC, and seven months of disease control was achieved with a modest adverse event, but no exacerbation of IPF. Nintedanib is an indolinone derivative that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor (VEGF) receptors 1–3, platelet‐derived growth factor (PDGF) receptors and fibroblast growth factor (FGF) receptors.All authors declare they have no competing interests.


Moreover, non-covalent functionalization proved to be impactful in imparting an overall enhancement of the nanocomposite mechanical properties due to good bonding between graphene and epoxy matrix, also showing a greater roughness which is decisive in influencing the interface adhesion efficiency.In this paper, a non-covalent π–π interaction between graphene nanoparticles (G) and a pyrene-based molecule (py) has been successfully accomplished to give the functionalized nanofillers (G-py). The proposed modification has proven to be a winning solution aimed at safeguarding the graphene’s notable electronic properties, while promoting a more effective nanofiller dispersion attributable to a decrease in viscosity with consequent improvement of the rheological properties of the formulated nanocomposites filled with G-py. The electrical current maps of the G-py based epoxy composites, loaded with filler weight percentages both above and below the electric percolation threshold (EPT), were obtained by tunneling atomic force microscopy (TUNA) technique. The possibility to detect low currents also for the sample at lower concentration (0.1 wt%) confirms the good electrical performance of the nanocomposites and, consequently, the successful performed functionalization. The non-covalent modification significantly improves the thermal stability of the unfunctionalized G of about 70 °C, thus causing an increase in the composite oxidative thermostability since the evolution of CO From a direct comparison between these conductivity values, it can be deduced that the non-covalent functionalization of G by pyrene derivative molecules to give G-py, not only preserves the electrical properties of the nanocomposites, but also leads to an increase in the value of the electrical conductivity of two orders of magnitude with respect to the resin loaded with the same 1 wt% of unfunctionalized G. The percentage of 1 wt%, calculated with respect to all the components of the epoxy matrix (R), has been chosen because it is above the electrical percolation threshold, which is in the range 0.025–0.1 wt% for the G based nanocomposites [−14 S/m. As main result of the morphological investigation, the chemical functionalization was found to be decisive in preventing the particle agglomeration during the dispersion phase, thus allowing optimization of the preparation process [Graphene is a two-dimensional spmaterial . Becausematerial , and higmaterial , graphenmaterial ,6,7,8,9.material . Howevermaterial . In thismaterial ,13. Covamaterial , substituctivity . Insteaductivity . In thismposites . The unf process ,19,20 of process  and also2 to shift to higher temperature values. Moreover, in this paper, non-covalent functionalization allows obtaining good mechanical properties as a result of an effective bond between the filler and the matrix, thus confirming its ability in acting as a strategic way to control the properties and improve the performance of graphene in various advanced applications [In addition, the rheological properties of the epoxy samples filled with unfunctionalized G and functionalized G-py nanoparticles are related to the material’s microstructure , the disications .2Cl2 dry. The functionalized G-py sample (1.080 g) was obtained after filtering, washing with 30 ml of the CH2Cl2, and drying throughout the night under vacuum the mixture which was kept under stirring for 2 h at room temperature.By exfoliating natural graphite characterized by a high surface area with an average diameter of 500 μm ), we obtained conductive graphene nanoparticles (G). In particular, the exfoliation procedure is based on intercalation of natural graphite in a solution of nitric and sulphuric acids, followed by an abrupt treatment at high temperature (900 °C) in a reactor to obtain the expansion of graphene layer spacing . The perBy mixing 80 wt% of the tetraglycidylmethylenedianiline (TGMDA) with 20 wt% of the reactive diluent 1-4 butanedioldiglycidyl ether (BDE) which is able to expedite the dispersion step of nanofiller , and, th−1. The Raman analysis was recorded at room temperature. An excitation wavelength of 514 nm and a laser power of 30 mW was used.A micro-Raman spectrometer Renishaw inVia  was used to perform a Raman spectral mapping of both the functionalized G-py and the pristine G in the range 100–3200 cmField emission scanning electron microscope (FESEM) pictures of the two nanofillers G and G-py and their corresponding nanocomposites were acquired using SEM . Before the examination by FESEM, thin slices of solid samples were cut and subjected to an etching procedure with an oxidizing solution ,10,17 toA Keithley 6517A multimeter and an ammeter HP34401A  were used to measure the direct current (DC) conductivity values reported in this paper for some of the graphene-based nanocomposites analyzed.−1 were used. TUNA control parameters such as DC sample bias between 1 and 3 V, 1pA/V current sensitivity, 0.500 Hz s−1 scan rate, 512 samples/line were set for image acquisition. It should be pointed out that the TUNA nanoelectrical characterization was realised without using conductive silver paste which guarantees suitable electrical contacts of the sample with the ground [TUNA exploration was accomplished in a contact mode on the graphene-based nanocomposites after the etching procedure. An electrically conductive tip of 20 nm and platinum-coated probes with nominal spring constants of 35 Nme ground ,21. BrukA Physica MCR 301 (Anton Paar) rotational rheometer  fitted with a parallel plate geometry  was used to carry out the rheological measurements on the liquid systems, before they undergo the curing process. In particular, in this work, we show the rheological results of the ternary TGMDA/BDE/DDS mixture (labelled R), of the RY%G dispersions, where the Y values are 0.5, 0.75 and 1 wt% of the unfunctionalized graphene content, G, and of the RY%G-py dispersion, where the Y values are 0.5, 0.75 and 1 wt% of G-py.The linear viscoelastic region was determined by strain sweep tests, at the frequency of 1 rad/s and at the temperatures of 25, 50, and 75 °C.The linear viscoelastic (LVE) limit for the uncured epoxy matrix R (TBD) is 40% at T = 25 °C, LVE limit = 30% at T = 50 °C, and LVE limit = 10% at T = 75 °C.The linear viscoelastic limit for R0.5%G based epoxy sample dispersions with unfunctionalized graphene G are: LVE limit for the R0.5%G = 1% at T = 25 °C, LVE limit for the R0.5%G = 2% at T = 50 °C, LVE limit for the R0.5%G = 10% at T = 75 °C.The linear viscoelastic limit for R0.75%G based epoxy sample dispersions with unfunctionalized graphene G are: LVE limit for the R0.75%G = 0.005% at T = 25 °C, LVE limit for the R0.75%G = 0.07% at T = 50 °C, LVE limit for the R0.75%G = 0.3% at T = 75 °C.The linear viscoelastic limit for R1%G based epoxy sample dispersions with unfunctionalized graphene G are:R1%G = 0.002% at T = 25 °C, LVE limit for the R1%G = 0.02% at T = 50 °C, LVE limit for the R1%G = 0.1% at T = 75 °C.Moreover, the linear viscoelastic limit the R0.5%G-py dispersion with pyrene-functionalized graphene G-py are: LVE limit for the R0.5%G-py = 5% at T = 25 °C, LVE limit for the R0.5%G-py = 5% at T = 50 °C, LVE limit for the R0.5%G-py = 30% at T = 75 °C.Then, the linear viscoelastic limit the R0.75%G-py dispersion with pyrene-functionalized graphene G-py are: LVE limit for the R0.75%G-py = 5% at T = 25 °C, LVE limit for the R0.75%G-py = 5% at T = 50 °C, LVE limit for the R0.75%G-py = 5% at T = 75 °C.Finally, the linear viscoelastic limit the R1%G-py dispersion with pyrene-functionalized graphene G-py are: LVE limit for the R1%G-py = 5% at T = 25 °C, LVE limit for the R1%G-py = 5% at T = 50 °C, LVE limit for the R1%G-py = 5% at T = 75 °C.−2 to 102 rad/s.Frequency sweep tests at 25 °C, 50 °C, and 75 °C were performed, within the linear viscoelastic region, varying the angular frequency from 103. A variable flexural deformation in three points bending mode was applied. The mechanical tests were carried out in a temperature range between −150 °C to 350 °C at the scanning rate of 3 °C min−2, frequency of 1 Hz, and displacement amplitude of 0.03 mm.Dynamic mechanical properties were measured with a Tritec 2000 DMA . The sample dimensions were 2 × 10 × 35 mm−1. The Cure Degree (DC) of the samples was assessed using the calorimetric data [A Mettler DSC 822 differential scanning calorimeter  in a flowing nitrogen atmosphere was used to carry out thermal characterization between 0 and 300 °C with a scan rate of 10 °C minric data ,22,26.A Mettler TGA/SDTA 851 thermobalance  was used to carry out the thermogravimetric analysis (TGA). The temperature range between 0 °C and 1000 °C at a 10 °C/min heating rate under both nitrogen and air flows was used to heat the formulated samples.The functionalized G-py nanoparticles were characterized by Raman spectroscopy. The G-py spectra were compared with those of unfunctionalized G to obtain information on the degree of structural ordering and therefore the bonding states of carbons in the graphene structure. −1, distinguishable with different intensity for all the samples. In the case of less crystalline graphite, further bands at ~1350–1355 cm−1, 1500 cm−1, and 1622 cm−1 are detectable. The D band at ~1350 cm−1 is induced by the disordered structure of graphene sheets. The presence in the second-order region (2200–3300 wavenumbers) of the 2D or G’ band at ~2700 cm−1, due to overtones and combinations of the disorder-induced bands, is characteristic of graphite crystallinities. G-py sample exhibits a pattern similar to the G sample. For both nanofillers, the very small difference in the intensity of the bands relative to each sample is due to the local region where the spectrum was detected. This difference is due to the fact that on the edge of the nanoparticles a greater number of defects is present. A general conclusion of this investigation is that the non-covalent modification did not destroy the layered structure of pristine G nanofiller, thus proving that non-covalently functionalized G-py can be successfully employed to formulate the functional nanocomposites for structural applications.In the Raman spectrum first-order region (1100–1800 wavenumbers), we can observe the main graphite band, named the G band, at ~1580 cmFESEM pictures of the pristine G and functionalized G-py nanofillers are shown in We can clearly observe that for both G and G-py samples, the exfoliated graphite sheets exhibit a highly fluffy morphology representative of thermally treated graphite. Furthermore, FESEM images show the folds and wrinkles present on the surface of the relatively large  and uniform graphene platelets. This confirms, as the Raman analysis, that the graphene-layered structure is not destroyed by non-covalent functionalization.The dispersion of the nanofiller in the polymeric matrix was analysed by the FESEM technique on sample surfaces that have previously undergone the acid attack of an etching solution which, by consuming the resin, allowed to discover the nanocharge. From −3 S/m obtained for the G based epoxy nanocomposite R1%G, loaded at the same loading concentration of 1 wt%, which corresponds to the percentage above the electrical percolation threshold. The enhancement in the electrical conductivity is most likely due to a better dispersion of the filler and the nature of the functionalizing py compound.Surface texture knowledge is an important question when aiming to comprehend the nature of the material surface and it is of primary importance when there is interest in verifying the adhesion effectiveness at the interface between the matrix and the nanoparticles. The mechanical interaction associated with the surface roughness can be effectively evaluated by means of TUNA technique which allows deriving quantitative measurements of roughness using two of the most significant height parameters, namely the roughness average (Ra), which is the arithmetic mean of the absolute values of the height of the surface profile, and the root mean square roughness (Rq) which is analogous to the roughness average (Ra), with the only difference being the mean squared absolute values of surface roughness profile. The Rq is more sensitive to peaks and valleys than the average roughness due to the squaring of the amplitude in its calculation .−1. Regarding the nanocomposite R0.1%G-py, the roughness values assessed for the TUNA pictures shown in the In this work, nanoscale roughness Ra and Rq values of the prepared composites R0.1%G-py see  and R1%GRegarding the nanocomposite R1%G-py, the roughness values assessed for the TUNA pictures shown in the In order to fully understand the influence of the non-covalently functionalized carbon nanofiller G-py on the mechanical behavior of the resin R and G-based nanocomposites, DMA was performed. In a context in which the hydrophobic nature of graphene makes it incompatible with most organic polymers and tend to irreversibly agglomerate itself, the modification of graphene nanoparticles by non-covalent method is becoming increasingly significant for the solution of this problem. In this regard, particular importance is given to π−π interactions because of their strength, comparable to covalent bonding  but withg) which is around 264 °C for the R0.5%G-py nanocomposite  in air of the unfunctionalized G and non-covalently functionalized G-py nanofillers is shown in In order to better understand and interpret the thermogravimetric data for the different analyzed systems, the TGA trend . This increase is most likely due to strong adsorption of nitrogen molecules, which are geometrically linear and characterized by small dimensions, on and among thin functionalized graphene layers.From the TGA curves, it can be clearly seen that for the functionalized sample G-py (see the black curve) the beginning of the thermodegradation phenomenon moves to a higher temperature of about 70 °C compared to unfunctionalized G (see the blue curve). More precisely, the non-covalent functionalization of graphene with pyrene derivative significantly improves the thermal stability of the starting unfunctionalized nanocharge G, effectively increasing the oxidative thermostability of the composite because the evolution of COThe curing degree (DC) has been gained in the dynamic and isothermal regime. For all the analyzed formulations, the curing reactions are active in the range between 125 °C and 250 °C in the dynamic regime. DC values of the pristine G and functionalized G-py based nanocomposites cured under isothermal heating conditions, shown in d) (in air and nitrogen) for cured (200 °C) epoxy resin (R) filled with G and G-py nanoparticles at different percentages by weight. In particular, the thermodegradation temperature (Td) referred to a sample weight loss of 5% for all the samples containing both pristine G and functionalized G-py nanofillers.d at about 360 °C in both inert and oxidative environment, as it can be clearly seen by observing the graph relating to the zoom of the initial values of Td.Samples cured in the oven at 200 °C show similar values of TThe rheological results for the liquid dispersions containing 0.5 wt%, 0.75 wt% and 1 wt% of the unfunctionalized (G) graphene nanoparticles in the R uncured resin, at the temperature of 50 °C, are shown in In The rheological results can also be analysed in terms of complex viscosity (η*) vs shear stress (τ) and they are shown in From the graphs shown in Moreover, it is noteworthy that the presence of edge-carboxylation of the graphitic material decreases the rheological percolation threshold to values similar to those observed for the mono-dimensional MWCNTs fillers .Finally, the complex viscosity (η*) vs. frequency (ω) for the liquid dispersions containing an amount of 0.5 wt% of the unfunctionalized (G) and functionalized (G-py) graphene nanoparticles in the R uncured matrix, at the temperatures of 25 °C, 50 °C, and 75 °C, are compared in 3). TUNA analysis was carried out using G-py weight percentages both below and above the EPT in order to investigate the electrical behavior of the conductive nanodomains of the epoxy/graphene systems. In particular, for the lowest concentration equal to 0.1 wt% of G-py, in most of the sample domains, no electrically conductive paths are observed, while for the highest concentration equal to 1 wt% of G -py, the presence of a conductive network at the nanoscale level with efficient adhesion to the interface clearly indicates that it is above the EPT. It is important to emphasize that the possibility to detect low currents also for the sample at lower concentration (0.1 wt%) confirms the good electrical performance of the nanocomposites and, consequently, the successful performed functionalization. These excellent electrical results are in perfect agreement with the rheological results. In fact, the inclusion of a functionalized G-py nanofiller amount of 0.5 wt% caused the decrease in the complex viscosity of the unfilled epoxy resin R, while instead the same quantity of unfunctionalized nanofiller G resulted in an increase of its viscosity. This aspect is of crucial importance from the industrial point of view since the use of non-covalently functionalized G-py allows to considerably simplify the steps of the preparation process of the nanocharged epoxy samples, thus favoring also the impregnation of the plies of carbon fiber fabrics. This is a problem that is by no means insignificant if we consider that nanofilled aeronautical resins used to impregnate carbon fibers contain a percentage of nano-charges capable of producing samples in the nanofiller’s concentration range beyond the EPT. A significant improvement in the thermal stability of the unfunctionalized graphene G of about 70 °C was registered, thus determining an increase in the composite oxidative thermostability since the evolution of CO2 shifts to higher values. Moreover, non-covalent functionalization proved to be particularly effective in conferring outstanding mechanical properties on the nanocomposites thanks to the strong interfacial adhesion between graphene-matrix and satisfactory dispersion of graphene nanoparticles inside the epoxy matrix.In this work, we have demonstrated that the non-covalent functionalization including mainly π–π interactions and hydrogen bonding represents a tactical way to control the properties and ameliorate the fulfillment of graphene nanoparticles characterized by carboxylated groups at the edge of graphene layers or graphitic blocks in advanced applications. Understanding the rheological behavior is of great importance for optimizing the manufacturing process of the structural nanofilled epoxy resins, where the amount of graphene is over the electrical percolation threshold (EPT) and for obtaining information about whether the structure is percolated. From the direct comparison between the direct current electrical conductivity values, we have found that the non-covalent functionalization of graphene G by pyrene derivative molecule, giving G-py sample, not only preserves the electrical properties of the nanocomposites, but also leads to an increase in the electrical conductivity value of two orders of magnitude with respect to the resin loaded with the same percentage of 1% by wt of unfunctionalized G nanofiller. The enhancement in the electrical conductivity is most likely due both to a more effective dispersion of the nanofiller in the matrix and the nature of the py functionalizing compound. In fact, the py compound is characterized by a structural nature very similar to a small portion of graphene. This small part of py compound may locally compensate for the reduced attitude in the electron conduction of zones of nanofiller characterized by structural defects (with a higher percentage of carbon atoms hybridized sp


Scaffold-based bone tissue engineering is the most relevant approach for critical-sized bone defects. It is based on the use of three-dimensional substrates to provide the appropriate biomechanical environment for bone regeneration. Despite some successful results previously reported, scaffolds were never designed for disease treatment applications. This article proposes a novel dual-functional scaffold for cancer applications, comprising both treatment and regeneration functions. These functions are achieved by combining a biocompatible and biodegradable polymer and graphene. Results indicate that high concentrations of graphene enhance the mechanical properties of the scaffolds, also increasing the inhibition on cancer cell viability and proliferation. To design effective PCL-based scaffolds, we investigated the degradation kinetics of such scaffolds as a function of scaffold topology,18 the effect of processing conditions on the morphological development/microstructure formation during the printing process,20 and surface modification strategies to improve cell attachment, proliferation, and differentiation.21 Due to the piezoelectric and reverse piezoelectric properties of bone, our group also developed strategies to induce electroconductive properties on PCL-based scaffolds by adding a low concentration of conductive materials such as graphene.16Novel dual-function scaffolds are mainly made with a biodegradable and biocompatible polymer. This polymer is poly, showing that toxic effects are concentration-, time- and shape-dependent.23 Graphene has been reported to induce oxidative stresses and cell function assays, and confocal microscopy images indicated that reactive oxygen species induced by the carbon atoms on the edge of graphene can damage DNA.24–26 Moreover, authors also reported that the few-layer graphene dispersions have a specific killing ability on monocytes.27 Graphene also showed an effective ability to inhibit the migration and invasion of human breast and prostate cancer cells, as well as mouse melanoma cells.28Previously reported studies demonstrated that graphene, 2D single-atom thick sheets of carbon atoms bound in hexagonal lattice structures, shows high affinity to glioblastoma cells leading to the adhesion of graphene to the cell's body and, consequently, cell membrane damage. Other studies also reported different levels of cytotoxicity both 14 will be gradually released, inducing the apoptosis of the remaining cancer cells. This effect can be controlled by the graphene content, and both crystallinity and crystal orientation of PCL in the printed fibers, which strongly depend on processing conditions. After the degradation of these initial layers that are responsible for the treatment function of the scaffold, PCL layers (core part of the scaffold) will be revealed. These layers must be able to provide the necessary biomechanical environmental conditions to sustain the recruitment of healthy cells (bone cells or stem cells) and cell attachment, proliferation, and differentiation (regeneration function).The potential cytotoxicity of high graphene contents on a PCL matrix are explored in this article to create the first layer of the novel dual-function scaffolds . Graphen9 The obtained graphene nanosheets were mixed with PCL pellets  through a melt-blending process by using different graphene concentrations . The PCL pellets and graphene nanosheets were heated to 150°C and mixed together in a crucible for 30 min. The material was stirred for 30 min to homogeneously disperse the graphene. After cooling down for 3 h, the mixed materials were then cut into pellets and prepared for printing.Graphene nanosheets were synthesized from graphite by water-assisted liquid-phase exfoliation, as reported earlier.14 The following design and processing parameters were considered:Design parameters:Laydown pattern: 0°/90°.Square pores.Pore size: 350 μm.Filament diameter: 330 μm.Slice thickness: 270 μm.Processing parameters:Melt temperature: 90°C.Screw rotation velocity: 8 rpm.Deposit velocity: 12 mm/s.Pressure: 6 bar.Scaffolds were produced by a screw-based additive manufacturing system 3DDiscovery™ Evolution Bench-top  , which allows to print fibers with a uniform dispersion of graphene as previously reported by micro-Raman spectroscopy.Thermogravimetric analysis (TGA) was used to determine the exact amount of graphene present in the scaffold. Tests were performed by using the Thermal Analysis Q500 analyzer (TA Instrument) with PCL scaffolds and graphene-loaded scaffolds. Scans were performed in an air atmosphere with an airflow of 60 mL/min and temperature ranging from 35°C to 560°C at a 10°C/min ranging rate. TGA tests were performed by using samples with around 1 g of weight placed in platinum pans. The weight change of the samples was monitored by using the TA Universal Analysis 2000 software (TA Instrument).Morphological characterization of the scaffolds was performed through scanning electron microscopy (SEM). The Hitachi S3000N system  was used to capture images of both the top surface and cross-section of the scaffolds, using an accelerating voltage of 10 kV. Before image capturing, the scaffolds were cut into 4 mm blocks and coated with a thin layer of metal (10 nm gold) by using the EMITECH K550X sputter coater . The obtained images were processed by ImageJ (NIH).F and corresponding displacement Δh were measured by sensors while the samples were compressed, and they were then transformed into stress σ and strain ɛ values. The compressive modulus and compressive strength of the scaffolds were calculated and plotted by Origin (OriginLab).Uni-axial compression tests were conducted on the INSTRON X testing system  with a 100 N load cell. The scaffolds were cut into blocks of 3 mm of width, 3 mm of length, and 4 mm of height. Compression tests were performed in dry state with the strain ranging from 0 to 0.3 mm/mm (30%) and a displacement rate of 0.5 mm/min. Force In vitro biological studies were conducted by using both human adipose-derived stem cells (hADSCs) (Invitrogen) and sarcoma osteogenic (Saos-2) cells (ATCC). Cells were cultured in the corresponding medium  in T75 cell culture flasks  at standard condition  in a New Brunswick® Galaxy 170 R incubator (Eppendorf). Cells were harvested at approximate 80% confluency with 0.05% trypsin-ethylenediaminetetraacetic acid (Invitrogen) before cell seeding. Cells ranging from passage 6 to 8 were considered for biological evaluation.Before cell seeding, scaffolds were sterilized in 80% ethanol (Thermo Fisher Scientific) for 4 h, transferred to a 24-well plate, and rinsed three times with Dulbecco's phosphate buffered saline (Thermo Fisher Scientific). Fifty-thousand cells (counted by Cellometer Auto 1000 Bright Field Cell Counter [Nexcelom Bioscience]) in 0.8 mL corresponding medium were seeded on each scaffold sample and empty well (control group).29 At each particular time point, 0.8 mL of medium containing 0.001% Alamar Blue  was added to each well and incubated for 4 h. Then, 150 μL fluid from each well was transferred into a 96-well plate and the fluorescence intensity was measured by a Multi-Detection Microplate Reader Synergy HT (BioTec) (excitation wavelength of 540 nm and emission wavelength of 590 nm).Cell viability was evaluated at 1, 3, and 7 days after cell seeding by using the Alamar Blue assay, which can quantitatively monitor the metabolism and cytotoxicity of the cells.The SEM images of both the top surface and cross-section of the scaffolds are presented in 30–33Biological evaluation results are presented in These results show that the addition of graphene fillers can reduce the survival rate of both hADSCs and Saos-2 cells, and the PCL/graphene scaffolds exhibit a greater inhibition ability on Saos-2 cells than on hADSCs. Besides, cells can grow and proliferate well on PCL scaffolds between days 1 and 7, showing no significant inhibition effect.in vitro studies and other assays  will be considered before the in vivo study. Further, long-term in vitro and in vivo degradation tests will also be performed. In general, results seem to indicate that the proposed dual-functional scaffold can be a valid solution for bone cancer applications, without the secondary effects of current clinical approaches focusing on treatment and not on both treatment and regeneration.This article proposes for the first time a novel dual-functional 3D scaffold for bone cancer treatment and regeneration post-treatment. These scaffolds comprise external layers made of PCL and high contents of graphene and internal PCL layers. Results show the inhibitory effect of graphene, particularly on Saos-2 cells, and the high load of cell attachment and proliferation on PCL. The addition of graphene also contributes to increasing the compressive modulus and compressive strength, thus making it possible to achieve values similar to the human trabecular bone. This is particularly relevant for the initial stages where the scaffold must be able to support the loads in the host environment. All scaffolds were produced by using the same processing conditions; the consequences of rheological changes due to modifications on the material composition, differences in terms of filament diameters and pore size between printed scaffolds and designed ones were observed. These will be solved in the future by adjusting the processing conditions depending on printability and rheological characterization of the material. Besides, a wider range of materials, including graphene oxide and selenium, will be further investigated. Surface modification will also be considered to allow the incorporation of biomolecules or targeted cancer treatment drugs into the scaffolds. In terms of biological performance, longer