Disorder‐induced Griffiths singularity of quantum phase transition (QPT) is a crucial issue in 2D superconductors (2DSC). In a superconducting system, the strength of disorder is found to be associated with the vortex pinning energy, which is closely related to the quantum Griffiths singularity; however, a direct study to elucidate the role of vortex pinning energy on the quantum Griffiths singularity in 2DSC remains to be undertaken. Here, an artificial 2DSC system is designed by randomly depositing superconducting nanoislands on 2Delectron gas (2DEG). Quantum Griffiths singularity is present in a graphene/Pb‐islands‐array hybrid, where the superconducting behavior transits to weakly localized metallic behavior induced by the vertical magnetic field and exhibits critical behavior with a diverging dynamical critical exponent approaching zero temperature. Compared to the study of graphene/Sn‐islands‐array hybrid where the sharp QPT is observed, the vortex pinning energy acquired from the Arrhenius plot analysis is greater in graphene/Pb‐islands‐array hybrid, which may contribute to the presence of the quantum Griffiths singularity. This work may provide a comprehensive interpretation of the QPT in 2DSC. The disorder‐induced Griffiths type quantum phase transition is observed in 2D graphene/Pb‐islands‐array hybrid at ultralow temperature. Compared to the similar graphene/Sn‐islands‐array hybrid with sharp quantum phase transition, the larger vortex pinning energy of graphene/Pb‐islands‐array hybrid is believed to be responsible for the observed quantum Griffiths singularity. The QPT can dominate the thermodynamics up to a relatively high temperature and in fact, the appearance of many unusual superconducting properties results from the proximity of quantum critical points (QCPs), which can be distinguished by a finite‐size scaling (FSS) behavior. Quenched disorder (static in time) has a profound influence on the QPT of 2DSC and high‐temperature cuprate superconductors that are intrinsically disordered.The thermodynamics of 2D superconductors (2DSC) is usually governed by quantum phase transition (QPT) because of the enhanced quantum fluctuation induced by finite‐size effects in a low‐dimensional electron system.10 Sup The conventional perpendicular magnetic field turned SIT/SMT is usually sharp with a fixed QPT at zero temperature, which has been previously observed in the amorphous and granular 2D superconductors, interface superconductor LaTiO3/SrTiO3, under‐doped La2−xSrxCuO4 and graphene/Sn‐islands‐array hybrids. While recent experiments instead show a smeared SMT with a divergent dynamical critical exponent (known as the quantum Griffiths singularity) as observed in crystalline superconducting Ga thin film, the LaAlO3/SrTiO3(110) interface, monolayer NbSe2, and ion‐gated ZrNCl film. The presence of quantum Griffiths singularity is believed to be caused by a disorder effect in inducing superconducting rare regions (puddles). In a superconducting system, the dynamics of vortices can determine the electromagnetic properties of superconductors where the quenched disorder strongly influences the dynamics of systems in pinning the vortex. Consequently, the strength of disorder is characterized by the vortex pinning energy that is obtained from analysis of the Arrhenius plot. However, previous observations of quantum Griffiths singularity were reported in quite different 2DSC systems, and the relevant vortex pinning energies cannot be compared in parallel between various 2DSC systems. Therefore, a systematic study to elucidate the role of vortex pinning energy on the quantum Griffiths singularity in 2DSC remains to be undertaken. According to our previous work, the superconducting puddles‐2DEG hybrid is an artificial 2D superconducting system, providing a general platform to explore 2D superconductivity with different vortex pinning energies.The disorder can suppress global superconductivity in 2DSC by either applying magnetic fields to generate vortices or degrading sample quality.19 The where a double quantum critical behavior with a sharp QPT can be realized. Compared to that in graphene/Sn‐islands‐array hybrids, the vortex pinning energy in the graphene/Pb‐islands‐array hybrid is greater, and is responsible for the quantum Griffiths singularity. These results may improve current understanding of the profound influence of the vortex pinning effect on the QPT in 2DSC.In the present study, we deposit Pb nanoislands on single‐crystalline graphene to form a 2D superconducting system consisting of graphene/Pb‐islands‐array hybrid. By applying a vertical magnetic field, the system shows a quantum Griffiths‐type superconductor to metal transition (SMT) in contrast with our previous observation in graphene/Sn‐islands‐array hybrids with different vortex pinning energy,8 wher2 Then, 20‐nm‐thick Pb was deposited on single‐crystalline graphene by electron beam evaporation . Owing to the poor wettability of graphene and the low melting point of Pb, the deposited Pb is prone to being randomly distributed into irregular disconnected nanoislands, as suggested by cross‐sectional transmission electron microscopy  substrate becomes totally insulating below 10 K , the top single‐crystalline graphene provides an ideal 2DEG platform that enables 2D coupling between the superconducting Pb nanoislands. Like the superconductor‐metal‐superconductor system acting as a basic Josephson junction, the Pb nanoislands and the adjacent single‐crystalline graphene constitute Josephson junction arrays.Single‐crystalline graphene was synthesized by chemical vapor deposition on an intrinsic Ge (110) substrate .28 TheRs(T) at zero magnetic field  curve exhibits semiconductor‐like behavior . Since the shunt effect from the intrinsic Ge (110) substrate is absent at temperatures below 10 K, the observed semiconductor‐like behavior is due to the weak localization behavior proposed in 2D metals. Then, the system undergoes a two‐step superconducting transition process. First, a small decrease in resistance is observed near the critical temperature of bulk Pb . As when cooling from TcPb, the second transition appears due to the Josephson coupling effect and the sheet resistance decreases rapidly in a slide‐like shape to the zero‐resistance transition temperature Tczero≈0.55K (Region III), where Rs(T) falls below the resolution limit of our instrument . Region IV corresponds to the true superconducting region with zero resistance. Compared to a graphene/Sn‐islands‐array hybrid, the superconducting transition temperature range of a graphene/Pb‐islands‐array hybrid is found to be relatively broad, which may be ascribed to the reduced Josephson coupling effect due to large average spacing of Pb‐islands. The Josephson coupling effect through the 2DEG provided by single‐crystalline graphene is confirmed by comparison experiment in that the graphene/Pb‐islands‐array hybrid becomes insulating when oxygen plasma is utilized to remove the graphene between adjacent Pb nanoislands . The observed insulating behavior also demonstrates that Pb nanoislands deposited on single‐crystalline graphene are completely disconnected from each other. For a 2D superconducting system, a Berezinskii–Kosterlitz–Thouless (BKT) type transition is expected, which interprets the process such that the bound vortex–antivortex pairing breaks into the unbound vortex–antivortex at elevated temperature. The BKT transition temperature (TBKT) is derived from the V–I measurements at V∝I3. In the log–log scale V–I plot in Figure V∝Iα behavior is observed, and TBKT is 5.3 K where α = 3, as indicated by the dash‐dot line in the inset to Figure The temperature‐dependent sheet resistance  The characteristic of SMT in graphene/Pb‐islands‐array hybrid can be revealed by detailed transport measurements near the QCP. Figure Rs(T) curves at different magnetic fields , showing SMT behavior. The Rs(T) curves at each field first behave as a weakly localized metal (dR/dT < 0) and then transit to a superconducting state (dR/dT > 0) at superconducting onset temperature Tconset(B) (indicated by black arrows) as the temperature decreases. And, the system exhibits a complete weak localization behavior once the applied magnetic field exceeds 3800 Oe. Tconset(B) shifts monotonically to lower temperatures with increasing magnetic field. To further investigate the SMT behavior near the QCP, magnetoresistances at temperatures from 50 mK to 4 K are measured, as shown in Figure  with two separated crossing points, the appearance of multiple crossing points in graphene/Pb‐islands‐array hybrids is reminiscent of the quantum Griffiths singularity of SMT in Ga film. Figure B–T phase diagram consisting of Bcross(T)  (blue dots). The tendency of Bcross(T) dots is in line with that of Tconset(B) dots and both yield the boundary between the superconducting state (dR/dT > 0) and the weakly localized metallic state (dR/dT < 0): however, the superconducting boundary exhibits an unusual upturn deviating from the Werthamer–Helfand–Hohenberg (WHH) theory (fitted by the blue dashed line), providing a prediction of mean‐field upper critical field (Bc2) in conventional type‐II superconductors under classical phase transition. At zero temperature, the WHH fitting gives a predicted Bc2 value of about 3300 Oe, which is far below the real critical field Bc∗ (by extrapolation) of about 3800 Oe. This special upturn is believed to be a consequence of the smeared quantum phase transition (QPT) corresponding to quantum Griffiths singularity.The magnetic‐field‐tuned SMT is essential for 2DSC, and SMT occurs at zero temperature but governs the thermodynamics up to finite temperatures.20 Thezv → ∞. To verify the nature of the multiple crossing points, FSS analysis is performed. In the FSS analysis, at least three curves are required. So, for the purpose of effective analysis, only the critical transition region formed by more than three adjacent Rs(B) curves can be approximated by one quantum “critical” point. Finally, a total of eleven respective “critical” points is obtained in the left‐hand panels of Figures S7–S9 (Supporting Information). According to the FSS law, the resistance near the critical point  takes the scaling form expressed thus: Rs = RcF(|B − Bc|Tzv−1/), where B is the magnetic field, Bc is the “critical” field, Rc is the “critical” resistance and F(x) represents an arbitrary function of B and T with F(0) = 1. The parameter v is the correlation length exponent, z represents the dynamical scaling exponent, and δ = |B − Bc| is the absolute value of distance from the transition. The FSS analysis for each “critical” point is shown in the right‐hand panels of Figures S7–S9 (Supporting Information). The derived zv values for each “critical” point are plotted as a function of magnetic field .Quantum Griffiths singularity is recognized for its multicrossing behavior and a divergent effective critical exponent zv → ∞.5, 6d Figure : it is s When approaching zero temperature, rare regions of inhomogeneous superconducting islands gradually emerge and interact via long‐range Josephson coupling to manifest global superconductivity. Recent studies show the quantum Griffiths singularity on highly‐crystalline superconductors with weak pinning and disorder. In principle, any static disorder will contribute to the increase of pinning in a superconducting system, therefore, the strength of disorder is characterized by the vortex pinning energy, which is obtained from analysis of the Arrhenius plot. The Arrhenius plot is often used to study the thermal activated flux flow (TAFF) behavior, where sheet resistance behaves in the form of R∝exp ( − U(B)/kBT), here, kB is the Boltzmann's constant and U(B) is the thermal activation energy, which is the slope of the linear fit in the Arrhenius plot.The quantum Griffiths singularity in 2D superconductors was first observed in Ga thin film, as a consequence of the formation of rare regions at ultralow temperature due to quenched disorder.1 WhenFigure U(B) = U0ln(B0/B), indicating the highly 2D nature of the long range vortex–vortex interaction in the graphene/superconductor‐islands‐array hybrid. The slope U0 of the U(log B) curve in Figure  For the graphene/Pb‐islands‐array hybrid analyzed in the present work, the vortex pinning energy is U0Pb=2.2kB: this is more than three times that of the graphene/Sn‐islands‐array hybrid . Note that the average vortex pinning energy is U02∝γξ2, where ξ is the superconducting coherence length and γ is the disorder parameter. Due to the fact that both graphene/Pb‐islands‐array hybrid and graphene/Sn‐islands‐array hybrid possess a similar superconducting coherence length , the greater pinning energy may mainly originate from a stronger quenched disorder, which indicates that strong disorder dominates the dynamic properties of the superconducting system, thus leading to the quantum Griffiths singularity in the graphene/Pb‐islands‐array hybrid. In fact, the assumed stronger disorder in the graphene/Pb‐islands‐array hybrid is verified by the comparison of the surface topographies of Pb and Sn nanoislands on graphene . According to SEM measurements, the spatial and size distributions of Pb nanoislands are more disordered in the graphene/Pb‐islands‐array hybrid, and there are considerable amounts of tiny scattering islands with only a few nanometers surrounding the core islands, which are rare in the graphene/Sn‐islands‐array hybrid. The presence of tiny scattered Pb islands will introduce additional disorder. Meanwhile, the mixed distribution of different sizes of Pb islands will yield inhomogeneous interisland Josephson coupling energy. Therefore, the vortex pinning energies together with the corresponding strength of disorder in the graphene/Pb‐islands‐array hybrid are much greater than that in the graphene/Sn‐islands‐array hybrid. It should be noted that, the strength of the disorder in 2DSC is very complicated, a direct comparison thereof between various 2DSC systems can only be achieved if a simple 2DSC system consisting of ordered superconducting metal nanoislands with variable spacing deposited on graphene can be constructed in the future.The magnetic field dependent activation energy  is plotted in B–T phase diagram for graphene/Pb‐islands‐array hybrid can be established  (blue dots) or Bcross(T) (pink dots). Most of the boundary can be described by WHH theory (blue dash‐dot line), as is often observed in conventional type‐II superconducting systems. Inside the WHH trace, the green dots TTAFF(B) defined as the detachment of the linear fit in the Arrhenius plot  shows the boundary of the thermally‐activated flux flow (TAFF) region below which quantum fluctuation overtakes thermal fluctuations. It is interesting to note that, in addition to the WHH trace, the boundary exhibits a special upturn, which is never observed in the similar system consisting of a graphene/Sn‐islands‐array hybrid . The special upturn region is found to emerge when the magnetic field exceeds Bc2, but disappears in a magnetic field above Bc∗. For the upturn region, the superconductivity is dominated by rare regions and the critical exponent zv diverging at zero temperature manifests the activated scaling behavior characteristic of the quantum Griffiths singularity. The obtained B–T phase diagram matches the proposed Griffiths systems, indicating that quantum Griffiths singularity truly occurs in graphene/Pb‐islands‐array hybrids as expected.With this summary of transport measurement results, a comprehensive d Figure 5. The b3B–T phase diagram shows that quantum Griffiths phase persists up to the infinite‐randomness QCP (Bc∗), which exceeds Bc2 from WHH theory. From the comparative experiments undertaken between Pb and Sn nanoislands on graphene, the observed quantum Griffiths singularity may be attributed to the enhanced vortex pinning energy in graphene/Pb‐islands‐array hybrid. The proposed artificial 2DSC system consisting of single‐crystalline graphene/superconductor‐islands‐array hybrid provides an ideal platform to investigate the influence of disorder on the QPT in 2DSC.In conclusion, the Griffiths‐type QPT has been reproduced in the artificial 2D superconducting graphene/Pb‐islands‐array hybrid. The 42 to atmospheric pressure. Afterwards, the chamber was heated to 916 °C and kept at that temperature during the growth progress with a mixture gas of CH4, Ar, and H2 for 300 min. Finally, the chamber was quickly cooled to room temperature under the protection of H2 and Ar.Monolayer single‐crystalline graphene was synthesized on the hydrogen‐terminated intrinsic Ge (110) surfaces via an atmospheric pressure chemical vapor deposition technique. The chamber was first evacuated to high vacuum and then aerated by a mixture gas of Ar and HThe Hall bar device was fabricated as follows: first, a 10 nm Ti/100 nm Au electrode pattern was deposited utilizing a Hall bar stencil mask 1. Then, the graphene (except in the channel region) was etched by oxygen plasma aligned with the stencil mask 2. Finally, a 20‐nm‐thick Pb was deposited by electron beam evaporation on the channel region of the Hall bar device using the designed stencil mask 3.3–He4 dilution refrigerator (Quantum Design) equipped with a heat capacity cable/RF filter box to eliminate stray RF currents.The temperature and magnetic field dependent resistances were measured by a physical property measurement system . Ultralow temperature was reached in an HeThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Pulmonary granulomatous disease encompasses both infectious and non-infectious disease forms. Presently, the immunopathogenesis of granulomatous inflammation is incompletely understood. This issue of Frontiers in Immunology explores recent insights concerning the clinical and immunological aspects of pulmonary granulomatous disease.Judson summarizes current knowledge of the immunopathogenesis of sarcoidosis as well as the nature of varied environmental and occupational exposures, which could cause or affect the disease. Many infectious agents have been implicated in the disease, especially mycobacterium tuberculosis, and the review summarizes evidence for sarcoid patient immune responsiveness to such agents.Sarcoidosis is a complex multi-system disease of unknown cause which can be related to a diverse collection of environmental signals. The review by Muefong and Sutherland in their review of neutrophil activities in this deadliest of infectious diseases in humans. The authors raise the possibility that neutrophils may play a more central role in tuberculosis pathogenesis than previously thought. They propose that some neutrophil-related inflammatory mediators as potential targets for developing novel tuberculosis therapies.A different perspective on pulmonary tuberculosis, another granulomatous disease, is provided by Hena reviews the effects of race on sarcoidosis epidemiology. The author presents data that show that in the United States, black patients with sarcoidosis experience more severe pulmonary disease, more multiorgan involvement, and an overall worse prognosis. The author proposes that epidemiologic concepts can be used to modulate and even prevent sarcoidosis in black Americans at risk of life-threatening disease phenotypes.Kraaijvanger et al. address the problem of identifying useful biomarkers for sarcoidosis diagnosis and prognosis. As noted by the authors, sarcoidosis is a heterogeneous disease, making treatment decisions problematic. Exploration of signaling pathways in sarcoidosis such as JAK/STAT and mTOR may result in the discovery of more specific biomarkers that may be relevant to prognosis. The authors stress that there is an unmet need for more specific and more sensitive biomarkers in sarcoidosis care.Gerke focuses on the deficiencies of the current treatment options for sarcoidosis. Sarcoidosis treatment decisions are problematic because of the marked heterogeneity of the disease. Clinical evidence is sparse because the disease is relatively rare and few clinical trials have been performed. Goals of treatment are to protect organ function and to decrease symptoms, but most clinical sarcoidosis trials have not focused on the impact of the disease on function or quality of life. Gerke emphasizes the lack of knowledge concerning etiology and pathophysiology of the disease and the need to utilize more patient-centered approaches to treatment for exploration of immunosuppression, symptom control, and treatment of co-morbid conditions.Gerke study, Talreja et al. present original research on alveolar macrophage and blood monocyte gene profiles in response to in vitro dexamethasone treatment in sarcoidosis. Effects of glucocorticoids on alveolar macrophages or monocytes have not been well documented. These authors describe profound transcriptosomal changes in lung macrophages relative to cellular metabolism, lysosomal phagosomes and cytoskeleton function. Further studies are proposed to examine proteome profiles in additional cell types relevant to pulmonary sarcoidosis that can correlate with RNA seq data and give a more comprehensive picture of dexamethasone effects within the lung.Relevant to the Mohan et al.’s study using a multiwall carbon nanotube model of chronic granulomatous disease demonstrated many similarities to sarcoidosis including high expression levels of MMP12 . These investigators used MMP12 knock-out mice to investigate the role of MMP12 in granuloma formation and persistence and demonstrated similar acute responses (10 days); however; at day 60, there was a marked reduction in granuloma persistence suggesting that MMP12 is essential for the persistence of granulomas.Arger et al. observed that T-Bet expression on Th17.0 cells reflected the extent of clinical granuloma burden in sarcoidosis patients. These authors postulated that T-Bet Th17.0 cells represent a transition state leading to interferon-producing Th17.1 cells which are elevated in BAL fluid and mediastinal lymph nodes of sarcoidosis patients with granulomatous inflammation. These studies emphasize the importance of Th17 in sarcoidosis.Greaves et al. performed a comparative review of adaptive immunity in two pulmonary diseases: pulmonary sarcoidosis and chronic beryllium disease (CBD). The authors note that one of the defining features of both CBD and sarcoidosis is the pulmonary infiltration of activated CD4+ T lymphocytes. Interestingly, sarcoidosis lung also contains a significant population of Th17 cells which are absent in CBD. While beryllium is the antigen that can activate CBD lymphocytes, the antigenic specificity of sarcoidosis lymphocytes is not yet known.Locke et al. reviewed various in vitro and in vivo models of sarcoidosis. Each of the current model systems has strengths and weaknesses. The authors suggest that the integrated use of the various preclinical models will accelerate progress toward identifying targets and the testing of new drugs.We hope that the articles in this issue of Frontiers in Immunology will educate researchers and clinicians concerning the immunology of pulmonary granulomatous disease. Furthermore, we hope that these articles will serve as a stimulus to further exploration of the mechanisms of granuloma formation that will ultimately improve the lives of patients.All authors contributed equally. All authors contributed to the article and approved the submitted version.This study was funded by grants ES025191 to MT and CHHE P30 ES025128.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.


Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80–100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process. Long interspersed element-1 (LINE-1/L1) represents the only autonomous retrotransposon family in the human genome whose members are currently mobilised and it constitutes a significant source of endogenous mutagenesis , 3. A fuAPC gene initiated a case of colorectal cancer [L1 retrotransposition is repressed by multiple cellular mechanisms including the methylation of a CpG island located in the 5′UTR acting to reduce the levels of L1 mRNA expressed –21. Howel cancer –28. Somal cancer . It is hl cancer .C9orf72 gene but not in those who were negative for the expansion [Drosophila models of TDP-43 pathology, TDP-43 represses non-LTR and LTR retrotransposon transcripts [Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an uncertain aetiology involving the rapid and progressive degeneration of motor neurons of the brain and spinal cord. It is usually fatal within 3–5 years of disease onset and there are no current treatments to reverse or stop the course of the disease . ALS casxpansion , 40. In nscripts , 38. Mornscripts . In addinscripts .We hypothesise that either an increase in the genomic burden of RC-L1s could contribute to the genetic risk of an individual to ALS or epigenetic changes to these L1 loci altering their expression or both could play a role in disease development. To address these hypotheses, we generated a list of seven genomic RC-L1 loci (Table Genomic DNA (gDNA) samples for genotyping of the five specific polymorphic RC-L1 insertions were obtained from the MNDA UK DNA bank cohort (ref DNA0042). gDNA of 2 control, 2 familial ALS and 2 sporadic ALS cases was obtained from the cerebellum and motor cortex from the London Neurodegenerative Diseases Brain Bank. Of the two FALS cases one carried the SOD1 p.D101G variant and the other the TARDBP p.M337V variant. The 3 sporadic ALS gDNA samples from the blood and motor cortex were obtained from the Sheffield Brain Tissue bank. Sample details are summarised in Additional file The five selected polymorphic RC-L1 insertions were genotyped in gDNA samples from the MNDA UK DNA bank cohort, London Neurodegenerative Diseases Brain Bank and Sheffield Brain Tissue bank using GoTaq hot start polymerase (Promega) under standard conditions. PCR assays to test for presence/absence of each RC-L1 locus were designed with three primers each, two flanking the insertion and one located in the L1 5′ UTR  , enablinSNRPN, an imprinted locus, was used as positive control for the successful enrichment of gDNA in both methylated and unmethylated fractions and to determine if there was relative equal representation of methylated and unmethylated alleles in the respective fractions of gDNA. The volume of isolated gDNA from the methylated and unmethylated fractions that yielded equal signal intensities in the PCR for the SNRPN locus was used as input for the amplification of the 5′ junction of the RC-L1s and the empty sites.Genomic DNA (gDNA) from controls, familial and sporadic ALS patients was sheared using a S220 focused-ultrasonicator (Covaris) with the following parameters duty cycle 5%, intensity 3 and cycles per burst 200 for 40 s × 4 to obtain fragments of 500 bp. The sheared gDNA was then purified and concentrated using a 1:1.1 ratio of DNA to Agencourt AMPure XP Beads (Beckman Coulter). Methylated and unmethylated DNA was isolated from 300 ng of each gDNA sample using the CpG MethylQuest kit (Millipore) according to manufacturer’s instructions. The CpG island of SNRPN locus were amplified in the methylated and unmethylated fractions of gDNA using primers in Additional file The 5′ junctions of 6 RC-L1 loci from Table RP) as determined in L1 retrotransposition reporter assays in cell culture [RP)) in a cellular retrotransposition assay and L1_chrX_p22.2, L1_chr6_p22.3 and L1_chr8_q24.22 showed the three highest percentage activities of 82 elements tested [Seven genomic RC-L1 loci were selected from the literature due to their exceptionally high retrotransposition rate  and SALS individuals (minimum of 173) from the MNDA UK DNA bank cohort. Association analysis of each RC-L1 locus did not demonstrate any significant association with SALS  was amplified in each gDNA sample to ensure successful isolation of methylated and unmethylated DNA fractions as only one of the two SNRPN alleles is methylated. Amplifying this CpG island also demonstrated on average an equal representation of the methylated and unmethylated allele in the respective gDNA fractions. The average relative methylation of the CpG island of the SNRPN locus in cerebellum, motor cortex and blood comprised of 50%, 48% and 55%, respectively  were enriched for methylated gDNA fragments by pulling down methylated gDNA using MBD protein and thereby separating methylated from unmethylated gDNA fractions. The specific gDNA targets of interest were then amplified from both fractions by PCR in order to determine if the region of interest was enriched either in the methylated or unmethylated gDNA fraction. As an internal control, the CpG island of the imprinted locus small nuclear ribonucleoprotein polypeptide ely Fig. a–c.Fig. Six out of the seven RC-L1s shortlisted in Table To determine if the methylation state of the RC-L1s was tissue dependent, we compared the percentage of the RC-L1 5′ junction in the methylated fraction of gDNA from the cerebellum, motor cortex and blood of all individuals . While 5′ junctions of RC-L1 loci are on average methylated to the same degree in cerebellum and motor cortex, there is a significant difference in the methylation status between the highly methylated RC-L1 5′ junction in blood relative to the less efficiently methylated L1 promoter regions in neuronal tissues tested  Fig. a. When cThe human genome harbours two sets of RC-L1 loci. There is one set that all individual genomes have in common, and the other set whose members are polymorphic for their presence or absence. Therefore, numbers, genomic locations and mutagenic potential of RC-L1s differ between individuals. Our study focussed on seven highly active RC-L1 loci (including five polymorphic L1 elements and two L1 insertions fixed in the reference genome) of the 80 functional reference L1 insertions  and ~ 10Drosophila model of ALS demonstrated the de-repression of transposable elements (including members of the L1 superfamily) that were involved in DNA damage-induced cell death of neurons [An essential prerequisite for L1 mobilisation is the expression of functional L1 mRNA and the L1-encoded protein machinery including ORF1p and ORF2p from genomic RC-L1 elements. L1 expression is regulated by methylation of a CpG island located in the L1 5′UTR between pos. 30 and pos. 450 of an intact L1 element and this is mediated by a highly conserved Yin Yang 1 transcription factor binding site , 49, 50. neurons . It has  neurons . This co neurons , 57–60.  neurons . Other n neurons , 61.ALS is a complex disorder involving both genetic and environmental risk factors for developing the disease with multiple steps in the molecular processes that result in ALS . Our stuAdditional file 1. Details of samples used in methylation analysis of RC-L1s. Additional file 2. Primer sequences used to amplify empty site and 5′ junction of RC-L1 loci and SNRPN locus.Additional file 3. Example gel images of 5’ junction amplification of RC-L1s in unmethylated and methylated fraction of gDNA.


Sarcoidosis is a multisystem disorder which, in rare cases, can affect the urogenital tract. The clinical presentation of this benign inflammatory disorder can easily mimic that of testicular malignancy. Therefore, it is crucial to differentiate between these two entities, as misdiagnosis may lead to unnecessary surgical interventions, which have important implications for future fertility. While testicular cancer must always be ruled out, sarcoidosis should be considered in all patients presenting with a testicular mass. Here, we present a case of sarcoidosis with bilateral epididymal and testicular involvement. The diagnosis was made by frozen section and the patient was treated with corticosteroids. Sarcoidosis is a systemic inflammatory disorder of unknown etiology, characterized histologically by the presence of noncaseating granulomas in affected tissues. It is predominantly a disorder of the lungs but can affect most of the body with ophthalmological, dermatological, endocrine and reproductive manifestations. Urogenital involvement with sarcoidosis is rare, with only 0.2% of patients diagnosed clinically and 5% post-mortem . The kidA 32-year-old black male was presented with a one-month history of painful swelling in the right hemiscrotum not responding to initial antibiotic therapy. Past medical history was unremarkable and there was no family history of testicular cancer or systemic disease. On examination, he had bilateral epididymal enlargement and tenderness of the right hemiscrotum. Scrotal ultrasound revealed bilateral hypoechogenic nodules of approximately 1 cm in both epididymal heads, with a right-sided testicular infiltration along the rete testis. Additionally, a small parenchymal lesion of approximately 3 mm was noted in the right testis  pointed towards a diagnosis of sarcoidosis. Lastly, a biopsy of skin lesions or endoscopic ultrasound biopsy of mediastinal lymph nodes can lead to a more definitive diagnosis and can be invaluable in differentiating pulmonary sarcoidosis from metastasized testicular carcinoma.The unclear relationship between malignancy and sarcoidosis has been a cause for much debate. A study by Rayson et al. among patients seen at the Mayo Clinic showed a 100-fold increased incidence of sarcoidosis after treatment for testicular cancer . HoweverConsidering the possible etiologic relationship between testicular cancer and sarcoidosis, all patients with a testicular lesion and sarcoidosis should be strongly encouraged to undergo an inguinal exploration with biopsy. Some authors advocate orchiectomy for all patients with unilateral masses, even if sarcoidosis is present in other organs . By contTreatment of sarcoidosis is generally expectant, as most patients will see spontaneous resolution within two years . HoweverWhen testicular masses are encountered in patients, the differential diagnosis must consider testicular sarcoidosis, particularly in patients with confirmed sarcoidosis or epididymal involvement. This case demonstrates the need for histological confirmation prior to orchiectomy as - in contrast to testicular cancer - testicular sarcoidosis may be managed conservatively in patients who wish to preserve their fertility. Lastly, health care providers should be aware of the possible association between testicular cancer and sarcoidosis; long-term follow-up of these patients may be necessary.


Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease. Sarcoidosis is a systemic inflammatory disorder of unknown cause which can lead to a variety of clinical symptoms. It commonly affects the lungs and intrathoracic lymph nodes, and is characterized by the formation of non-caseating epithelioid cell granulomas . In caseThe diagnostic trajectory of sarcoidosis is long and complicated; it requires invasive methods like bronchoalveolar lavage and evidence of granuloma in lung or other tissue through a biopsy , 7. The The discovery of a specific biomarker for this disease would help diagnose sarcoidosis. According to the National Institutes of Health Biomarker Definitions Working Group, a biomarker is “a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” . Such prThe ideal biomarker should not be related to other diseases and should be highly sensitive. Moreover, it should not be invasive, and should be reproducible. Also, the ideal biomarker should be inexpensive . A combi18F-FDG PET) and high-resolution computed tomography (HRCT) as diagnostic and prognostic tools in sarcoidosis.In this review, we address current and possible future biomarkers in sarcoidosis. Serum and bronchoalveolar lavage biomarkers are discussed in terms of antigen presentation, granuloma formation, and T-cell activation. As regards imaging, we focus on the value of chest X-ray, fluor-18-deoxyglucose positron emission tomography . sACE is an acid glycoprotein which converts angiotensin I into angiotensin II. It is mainly produced by activated alveolar macrophages and correlates with granuloma burden and radiological stages II and III . ElevateFurthermore, ACE levels in the normal range could in fact be elevated in specific patients. This is based on the influence of an insertion (I) or deletion (D) polymorphism in the ACE gene on sACE levels . In healACE could also have a role in predicting treatment outcome. High serum levels of ACE before treatment correlate significantly with lung function improvement after 6 months of methotrexate treatment . What haLysozyme is a bacteriolytic enzyme that hydrolyses glycosidic bonds in order to degrade peptidoglycans in bacterial cell walls. At the site of infection lysozyme activity limits the cause of inflammation by rapidly degrading peptidoglycans . In sarcNeopterin is a non-specific marker of inflammation produced by activated monocytes, macrophages, dendritic cells, and endothelial cells upon stimulation mainly by interferon gamma (IFN-γ) . NeopterThe human cartilage glycoprotein-39 or YKL-40 is a growth factor for fibroblasts and vascular endothelial cells and is secreted by macrophages and neutrophils. Increased serum YKL-40 levels have been found in patients with diseases characterized by inflammation, tissue remodeling and ongoing fibrosis . In sarcCD163 is a transmembrane hemoglobin-haptoglobin scavenger receptor expressed selectively on most macrophages in human tissues and on at least 10–30% of monocytes. Expression of CD163 is increased by IL-6, IL-10, glucocorticoids, and most immunomodulatory factors. Expression of CD163 decreases under the influence of tumor necrosis factor (TNF), interferon gamma (IFN-γ), and transforming growth factor beta (TGF-β). These are all cytokines involved in granuloma formation and disease activity. This may suggest a correlation between the expression of CD163 and inflammatory status in sarcoidosis patients. Shortly after activation of the toll-like receptors-2,4, and 5 (TLR), CD163 is shed into the environment as soluble CD163 (sCD163) . This quC-C motive chemokine ligand 18 (CCL18) is a CC chemokine produced primarily by antigen-presenting cells such as macrophages, dendritic cells, and peripheral blood monocytes. CCL18 is chemotactic for both naive and activated T-lymphocytes. Elevated levels of CCL18 have been detected in serum of patients with T-cell helper 2 (Th2) predominant diseases like idiopathic pulmonary fibrosis, bronchial asthma and scleroderma . CCL18 cSerum amyloid A (SAA) is produced by the liver during an acute phase reaction. In inflammatory conditions, macrophages produce high levels of SAA, which indicates that elevated levels of SAA are a clinical marker of inflammation. Elevated levels of SAA are found in several inflammatory diseases like RA and Crohn's disease . ElevateChitotriosidase (CTO) is an enzyme of the chitinase family. It degrades chitin, a polymer found in cell walls of fungi and the exoskeletons of insects and crustaceans. Pulmonary neutrophils and macrophages can secrete CTO upon stimulation of toll-like receptors (TLRs) by IFN-γ, TNF, and granulocyte/macrophage colony-stimulating factor (GM-CSF). CTO serum levels directly correlate with sACE levels . HighestAs mentioned above, macrophages are key players in granuloma formation. However, macrophages are difficult to study or use as diagnostic/prognostic biomarkers, since they are predominantly found in tissue and granuloma. Monocytes are precursors of macrophages and are found in the bloodstream, making them accessible and interesting as biomarkers in sarcoidosis. There are three subtypes of monocytes, classical monocytes (CD14++/CD16–), intermediate monocytes (CD14+/CD16+) and non-classical monocytes (CD14–/CD16++). Intermediate and non-classical monocytes are more inflammatory type monocytes, and have been found to be elevated in sarcoidosis . In addiT-cells play an important role in the development of granulomas. Antigen presenting cells like macrophages present peptides to T-helper (Th) cells via MHC class II molecules. This activates T-cells and leads to greater proliferation and recruitment of neutrophils and monocytes . Based oSerum soluble interleukin 2 receptor (sIL-2R) is the circulating form of the membrane IL-2R, a proposed marker of disease activity in sarcoidosis. Upon activation, Th1 cells upregulate the expression of IL-2R on the cell surface, and are able to shed sIL-2R into circulation . IncreassIL-2R seems to correlate with active disease and multiple organ involvement, and can possibly predict progression and relapse after discontinuation of therapy –61 FurthIt is important to state that patients with impaired renal function have elevated sIL-2R. This can result in high sIL-2R levels in the absence of active disease. Since renal impairment can occur in sarcoidosis patients, this effect has to be kept in mind when sIL-2R is used as a marker to monitor disease activity .Although the innate immune system and T-cell immunity are known to be involved in the pathogenesis of sarcoidosis, it is becoming increasingly evident that B-cells are involved in granuloma formation as well. B-cell accumulation has been shown in granuloma and pulmonary lesions, and a positive effect of B-cell depletion has been reported , 63.In vivo and in vitro studies have shown that blocking of BAFF results in reduced follicular and marginal zone B-cell numbers, while overexpression of BAFF in mice resulted in an increase in activated B-cells, activated T-cells, autoantibody production, and hypergammaglobulinemia. In sarcoidosis patients, higher levels of BAFF have been found in serum in comparison to healthy controls (B-cell activating factor (BAFF) is a cytokine of the TNF family with a critical role in B-cell development and function. controls –66. Howecontrols . In addicontrols . In a diThe B-cell ablative rituximab targets CD20, a marker expressed on the surface of naïve and memory B-cells, and has been shown to yield clinical improvement in some sarcoidosis patients , 68. ThiNot only are numbers of naïve and memory B-cells altered, but sarcoid B-cells were found to be anergic in chronic sarcoidosis. This anergy could be partly due to the reduced levels of NF-κB/p65 found in sarcoid B-cells. B-cells with reduced NF-κB have an impaired response to antigens , 71. FurRegulatory B-cells (Bregs) are IL-10 producing B-cells. This type of B-cell has been found to reduce inflammation through cytoplasmic IL-10 expression . PhenotyThis observation does appear to be in line with findings in other inflammatory diseases like SLE, RA, and multiple sclerosis. Furthermore, since IL-10 is important in the development of fibrosis, this association could justify further research into this population of B-cells , 65.In conclusion, B-cells are relatively new and somewhat unknown cells in sarcoidosis. However, since B-cells seem to be involved in several processes in sarcoidosis pathogenesis, the expectation would be that BAFF levels and memory, naïve, and regulatory B-cell counts could be used to assess disease activity and could possibly be used in the diagnosis of sarcoidosis. However, further research is required before B-cell counts and BAFF levels can be used as biomarkers in sarcoidosis.All biomarkers mentioned above as serum biomarkers appear to have the same limitations, namely, insufficient sensitivity and specificity. Since many biomarkers have shown a mutual positive correlation , 28, 73,The diagnosis of sarcoidosis is often confirmed by analyzing bronchoalveolar lavage fluid (BALF) . Various*03 genotype, which is usually found in patients with Löfgren's syndrome (LS). This biomarker therefore proved to be more useful for the diagnosis of LS, while the CD4/CD8 ratio is useful for the diagnosis of any type of sarcoidosis. On the other hand, specificity proved to be higher for CD4+ Va2.3+ T-cells compared to the CD4/CD8 ratio in BALF (97 vs. 92%), which will help with the diagnosis of sarcoidosis  has been related to the retention of intraepithelial lymphocytes (IEL) in mucosal tissue of the lung. CD103 is expressed by lymphocytes within the bronchial epithelium, some alveolar wall lymphocytes and CD4+ T-cells in the BAL. Expression of CD103 on CD4+ T-cells in BAL fluid is found to be different in ILD patients, depending on the type of disease . In patiWhile the CD103+CD4+/CD4+ appears to be a useful diagnostic tool in sarcoidosis caution should be taken with the interpretation of this ratio. Therefore, a CD103+CD4+/CD4+ ratio 0.2 can be seen as additional evidence pointing towards a diagnosis of sarcoidosis.For a long time, sarcoidosis was seen as a Th1-driven disease, because of the variety of type 1 specific cytokines present in BALF and serum of sarcoidosis patients, including IFN-γ, IL-12, and IL-18. However, nowadays it is accepted that sarcoidosis is driven by a combination of Th1- and Th17-associated factors . Th17 ceRegulatory T-cells or Treg cells may also play an important role in the development of sarcoidosis. Treg cells normally suppress immune responses by the host immune system against self and foreign antigens. In the case of sarcoidosis, it is hypothesized that Tregs are functionally defective or exhausted, making them unable to fully suppress the immune responses . The dysAlthough there are thus conflicting results on the presence and effect of Tregs in active sarcoidosis, what is clear is that an imbalance exists between Th17 and Tregs. Th17 cells are elevated in the blood of sarcoidosis patients, while the number of Tregs is decreased . The TreNeutrophils are important players in the innate immune system, but their role in sarcoidosis is still little understood. Neutrophils are attracted by chemokines, such as IL-8, which are released by monocytes and macrophages . PatientOther immune cells in BALF which are associated with poor outcome and an advanced radiological stage are natural killer (NK) cells . NK cellNatural killer T (NKT) cells (CD3+CD16/56+) are a regulatory T cell lineage which both express T cell (CD3) and NK (CD16/56+) receptors on their surface membranes, thereby influencing both Th1 and Th2 cytokine systems and stimulating cell-mediated immunity or suppressing autoimmune responses , 97. NK The monocyte-macrophage cell lineage is the origin of the expression of a variety of cytokines and chemokines that play many different roles in the inflammatory phenotype of sarcoidosis, including T-cell attraction and promotion of Th1/Th17 differentiation . Some inIn the case of sarcoidosis, a recent study by Arger et al.  showed tKrebs von den Lungen-6 (KL6) is a human high molecular weight MUC1 mucin protein derived from type II pneumocytes and respiratory bronchiolar epithelial cells . An incrElevated levels of KL-6 have been found in BALF and serum in patients with idiopathic pulmonary fibrosis, sarcoidosis, and other ILDs –112.The fact that it is not a disease specific marker indicates that it has no major role in diagnosing sarcoidosis. However, in sarcoidosis patients both serum and BALF levels of KL-6 correlate with higher serum ACE levels and CD4+/CD8+ ratio , 112. SuThe biomarkers mentioned above give limited information about pulmonary sarcoidosis as individual biomarkers. However, combining some of these biomarkers may be helpful in the diagnosis and prognosis of pulmonary sarcoidosis. CD4/CD8 ratio and CD103+CD4+/CD4+ ratio appear to be useful diagnostic biomarkers to support the diagnosis of sarcoidosis, while disease severity can be predicted and monitored by a correlation between KL-6 and CD4+/CD8+ ratio. Furthermore, disease progression can be monitored trough the percentage of neutrophils, NK cells, and NKT cells in BALF. In addition, Th17.1 cells and Treg cells are promising prognostic biomarkers, however, further research is required to determine the diagnostic value. The BALF chemokines CXCL9-11 in their turn may be useful biomarkers for treatment decisions.18F-FDG PET) scanning are increasingly recognized as essential imaging techniques for adequately identifying sarcoidosis localization and determining disease management  are frequently used. However, in sarcoidosis patients with extrapulmonary manifestations, such as cardiac sarcoidosis or neurosarcoidosis, other imaging modalities are warranted. For these patients, magnetic resonance imaging (MRI) and fluor-18-deoxyglucose positron emission tomography , which consists of CT extent scores for nodularity, ground-glass opacification, interlobular septal thickening and consolidation. The total CTAS was found to predict response to treatment in FVC after 1 year in their cohort of 100 patients. Furthermore, CTAS had a high degree of interobserver agreement .r = 0.543, P < 0.001). Furthermore, higher CTAS scores were seen in patients with high sACE levels  scintigraphy was the most frequently used form of nuclear imaging in sarcoidosis, but 18F-FDG PET has replaced it, as it was shown to be more accurate in depicting extrathoracic lesions . Furthermore, 18F-FDG PET was far more sensitive than ACE and sIL2R in this study  at baseline was able to predict lung function improvement after 6 months of treatment     . As anti18F-FDG PET. Furthermore, 38 patients (51%) with positive 18F-FDG PET results had normal ACE levels, suggesting an added value of 18F-FDG PET as an adjunct to serum biomarkers  of mediastinal lymphnodes on 18F-FDG PET is a predictor of relapse after discontinuation of infliximab therapy, with a hazard ratio of 4.33 (p < 0.001). This suggests that high activity on 18F-FDG PET reflects the burden of inflammation and therefore the need for prolonged therapy. A small retrospective study of 23 newly diagnosed sarcoidosis patients showed that persistent disease activity on 18F-FDG PET during the first months of corticosteroid treatment is a predictor of relapse  to quantify disease activity. Recently, a new tool for the quantification of disease activity of the pulmonary parenchyma was proposed. Volumetric 18F-FDG PET analysis of global lung inflammation was proposed by Adams et al.  measures the total activity of the pulmonary parenchyma, and although this derivative from the total lesion glycolysis in oncology studies looks promising, it was not superior to SUVmax in predicting lung function change during infliximab therapy  and extracellular water/edema (T2 mapping) . T1/T2 mP < 0.004). Moreover, a large meta-analysis including 10 studies and a total of 760 patients concluded that patients with LGE on CMR were at increased risk of events, compared to patients without LGE , even if they had preserved left ventricle systolic function  . The authors suggest that future events may be driven by the presence of myocardial fibrosis instead of inflammation  . A studyammation .18F-FDG PET has an important role as a diagnostic marker for cardiac involvement and is included in the Hearth Rhythm Society Guideline for diagnosis of cardiac sarcoidosis. “Patchy uptake on dedicated cardiac PET (in a pattern consistent with Cardiac Sarcoidosis)” in the right context can point towards the diagnosis   .18F-FDG PET in combination with CMR in the diagnostic process was studied in a cohort of 107 patients suspected of cardiac sarcoidosis. Added value was found in 45% of patients, as they were reclassified as likely to have cardiac sarcoidosis, most of them (80%) being correctly reclassified when compared with the final diagnosis  (Combining cardiac  < 0.01) .18F-FDG PET and CMR together, depicting both the pattern of injury and disease activity in a single scan   .Neurosarcoidosis (NS) refers to the involvement of the central nervous system (CNS) and is seen in approximately 5% of all sarcoidosis patients. It is a serious and devastating complication which is difficult to diagnose because of the many different ways in which this disease can present itself , 153.18F-FDG PET, and HRCT are used in different steps of the diagnostic process  pathway . This paRecently, various case reports have been published in which JAK/STAT inhibitors like tofacitinib and ruxolitinib were successfully used to treat patients with therapy-refractory sarcoidosis , 166.It may be useful in the future to further unravel this pathway and focus on which specific patients may benefit from this therapy and whether JAK/STAT activation markers can act as biomarkers.The mechanistic target of rapamycin (mTOR) signaling pathway is involved in cellular metabolism as well as proliferation and has been implicated in an increasing number of pathological conditions .It has been demonstrated in a mouse model that granuloma can be formed spontaneously when the mTORC1-inhibitor TSC2 is depleted. It was also found that sarcoid granulomas from patients with active and progressive disease showed active mTORC1 signaling . A decreIn sarcoidosis, 50–70% of the patients experience fatigue, some even experience chronic fatigue. Fatigue can still be present when sarcoidosis has clinically resolved, causing an impaired quality of life . One of The average scalp hair grows by 1 cm/month, so this method can retrospectively measure the production of these hormones over months , 172. ThHair cortisol levels could be a future long-term biomarker for the measurement of chronic stress in sarcoidosis. A great advantage of this biomarker is that it is non-invasive and easily available, and can be used in a retrospective way. Using only one or a few hair strings, it may be possible to screen for fatigue and physical distress as well as to measure it in follow-up measurements. This can be used as an alternative to the currently used questionnaires, preventing variations in scores as to when patients fill in multiple questionnaires over time .18F-FDG has been shown to be a useful PET-tracer in severe sarcoidosis. Other tracers, such as somatostatin receptors (SSTRs) like 68Ga-DOTA-NaI-octreotide (DOTANOC) or 68GA-DOTA-D-Phe-Tyr-octreotide (DOTATOC), would appear to be reliable alternatives to 18F-FDG. Multiple inflammatory cells that are found in granulomas, including epithelioid cells and macrophages, have SSTRs on their surface, while normal monocytes have not. In the case of cardiac sarcoidosis, DOTANOC is taken up by sarcoid lesions but not by normal myocardium  allows responders to infliximab therapy to be distinguished from non-responders. This imaging method is already being used in several TNF-α mediated diseases, such as RA, inflammatory bowel disease (IBD) and spondyloarthropathy . In sarcreatment . 99mTC-iSarcoidosis is a complex systemic disease reflecting immunological responses to different antigens in patients with certain genetic susceptibility , 175. OmIn sarcoidosis, multiple diagnostic and prognostic biomarkers are already being identified by using single nucleotide polymorphism (SNP) technology, RNA sequencing and pathway analysis . Strong Although numerous biomarkers have been evaluated for patients with sarcoidosis in recent decades, no gold standard has been set for their use in diagnosis or predicting disease course. Combinations of several serum biomarkers have been explored, with promising results, but the Holy Grail remains to be discovered. Future research should focus on combining serum or BALF biomarkers and further refined imaging techniques such as CT, MRI, and PET. Data on successful treatment of sarcoidosis patients with JAK/STAT and mTORC1 inhibitors suggests that these new immunological pathways should also be explored for new prognostic biomarkers in the near future.RK, MJ, and AV wrote the manuscript, contributed to the concept, and designing of the work. AV and MV revised the work critically for important intellectual content. RK and MJ set up the reference database. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We theoretically investigate the crossed spin conductance (CSC) of a graphene-based heterostructure consists of ferromagnet, Rashba spin-orbit and superconductor regions. Using Dirac Bogoliubov-de Gennes formalism in the ballistic regime, we show that in the presence of Rashba spin-orbit coupling there are an anomalous crossed Andreev reection and spin-ipped co-tunneling in the process of quantum transport. We demonstrate that the CSC can be reversed with respect to charge conductance by tuning the Rashba spin-orbit coupling which experimentally can be adjusted by the applied perpendicular electric field on the graphene sheet. This feature in addition to a long spin relaxation time of Dirac fermions in graphene proposes designing a device with a non-local spin switch which is crucial for spintronics circuits. A wide variety of interesting phenomena such as topological superconductivity2 Majorana fermions5, topological quantum computation6 require superconductivity. Also, a major part of growing field of spintronics needs superconductivity7. More than 15 years, scientist have been tried to find a way for combining superconductivity and spintronics to make a long-range spin-polarized super-currents. Long spin relaxation time of Dirac fermions in graphene made it an important candidate for using in such a device9. Graphene not only has a simple structure, but also can be easily prepared in experiments with different properties. Superconductivity (S) and ferromagnetism (F) can be induced into graphene by means of proximity effect14. Designing hybrid structures involving S and F regions make graphene a very good host to explore the fascinating phenomena such as Klein tunneling16, supercurrent π-junction17 and spin-triplet correlation18. In contrast ot ordinary superconductors, the superconducting junction of graphene has the capability of reflecting an incident electron as a hole with a specular path. This process is known as Andreev reflection and the missing charge of 2e enters the superconductor as a Cooper pair20. The low-energy excitations of graphene near the K and K′ points of the Brillouin zone are governed by a 2D massless Dirac Hamiltonian22. The linear conduction and valence bands cross the Fermi level at these points. Because of these unique properties, graphene attracts huge attentions of scientists from fundamental to the technical point of view23. The Fermi level in graphene in contrast to ordinary conductors or semiconductors, can be also tuned by a gate voltage24.Hybrid structures of superconductivity have a suitable potential to use in the future technology28. The first one which is known as Dresselhaus spin-orbit (DSO) interaction29 comes from the spin dependent second neighbor hopping. The last one which is known as Rashba spin-orbit (RSO) interaction30, arises from a perpendicular electric field or interactions with substrate31. The RSO interaction which is induced by proximity to a tungsten disulphide substrate28 confirmed experimentally to be ~17 meV. The DSO interaction which is responsible to create a small gap in the band structure, predicted to be quite small in comparison with the larger effects like RSO interaction32. So, in this paper we ignore the DSO interaction and just focus on the RSO interaction.Spin-Orbit interaction has intrinsic or extrinsic origin in the graphene33, maximum spin Seebeck effect34, and tunable magneto-resistance35. In our previous work36, we show that the RSO interaction in the interfaces of F-S-F graphene junction generates the anomalous CAR and spin-flipped CT. These effects are the direct signature of breaking translational symmetry at the interfaces due to the RSO interaction and penetrating equal-spin triplet correlation into ferromagnetic region. Using gate voltage and tuning Fermi level, the sign of charge conductance in the ferromagnetic drain lead (F2) can be negative  competes with elastic co-tunneling (CT). The graphene-based junctions contain RSO interaction in their interfaces predicted to show odd-frequency triplet correlations37 and Blonder-Tinkham-Klapwijk38 formalism to derive two formulas for the CCC and CSC in the drain lead. We also show that the sign of the spin conductance can be switch from positive to negative by changing RSO interaction which is experimentally possible by tuning perpendicular electric field. This property in addition to the long spin relaxation time of Dirac fermions makes this set up very suitable for spintronics circuits. It is known that the typically p-wave superconductors are rare in nature. Normal impurities can easily break the Cooper pairs in p–wave and d–wave superconductors. But, the s-wave superconductors are robust against impurities and much more common in nature. So we consider an s-wave superconductor in the junction.In this letter, we proposed an experimental accessible device to generate negative crossed spin conductance (CSC) and tunable crossed charge conductance (CCC). We extend the Landauerx − y plane. We suppose that ferromagnetism, singlet superconductivity and RSO interaction are applied on the graphene by proximity. As shown in Fig. 36 because in a typical experimental situation, ballistic propagations can be spoiled by edge disorders.We consider a sheet of graphene in the The low-energy of quasi-particles of such a device describes by Dirac Bogoliubov-de Gennes DBdG equation19, and μi. Also, 0 is the superconducting gap in zero temperature and 39 in which The original DBdG Hamiltonian is a 16 × 16 matrix in the presence of an arbitrary direction of magnetization and spin-orbit interaction. However, graphene has another degrees of freedom, valley degeneracy which is responsible to electron-hole conversion. Due to the valley degeneracy in graphene, the Hamiltonian reduces to a 8 × 8 matrix. Nonetheless, one can use different basis sets that consequently change the form of Hamiltonian without affecting final physical results and conclusions. In our representation, the hole part is time-reversed of the electron part which denoted it by l and Fr) represents by hl and hr, respectively. Their directions fixed along the z axis without loss of generality. This choice makes the spin-dependent analyses of scattering process clear. λ is the strength of RSO interaction32. U0 is an electrostatic potential which is necessary to prepare enough density of states for induced superconductivity. So we assume heavily doped approximation, 39. The length of RSO and S regions are LRSO and LS, respectively. The eigenvalues of each region are obtained by diagonalizing Eq.  process or as a hole which is called crossed Andreev reflection (CAR). So, in the scattering process into drain lead we have four probabilities: spin-preserved CT 33. In the RSO region, the wave function is split into electron and hole sector, and these two are not coupled. When an incoming electron is entering the RSO region and reaching the RSO/S interface, it is converted into a hole that travels back into the ferromagnetic contact. All of the possibilities and scattering processes are explained in previous works in details33. All wave functions should satisfy the boundary conditions as follow, to calculate the probability amplitudes.Furthermore, the total wave function in RSO . At the point where these two types convert to each other, the mentioned discontinuity would happen.The application of RSO interaction can completely suppress the values of junction’s conductance, leading to negative CSC and positive CCC simultaneously. When the current approaches the right ferromagnetic lead in the junction, it passes through with no reflection. This is a manifestation of the CCC. The passed carriers have a down-spin or up-spin direction. Negative CSC means that all carriers have similar spin directions. As the Interestingly, changing the value of RSO term alters the sign of CSC from positive to negative values and vice versa, as shown in Fig. Motivated by recent achievements in the induction of RSO interaction into a graphene sheet, we have theoretically studied quantum transport properties of a junction consists of ferromagnets, singlet superconductors and RSO interaction. As known, it is possible to change the RSO term non-locally in graphene by applying electric field. This situation provides a spin-switch device which has a capability to block the current with the specific spin direction. Our results demonstrate that in the presence of RSO interaction, there are new types of reflection and transmission probabilities. Among them, those who live in drain lead are our interest because of their non-local nature. Spin-flipped CT and anomalous CAR have negative roles in CSC. Due to these interesting capabilities which can be very crucial in spintronics, graphene junctions may, in principle, be used for spin-current control or spin orbit sensing applications in superconducting spintronics.


This article distinguishes between clique family subgroups and communities in a crisis response network. Then, we examine the way organizations interacted to achieve a common goal by employing community analysis of an epidemic response network in Korea in 2015. The results indicate that the network split into two groups: core response communities in one group and supportive functional communities in the other. The core response communities include organizations across government jurisdictions, sectors, and geographic locations. Other communities are confined geographically, homogenous functionally, or both. We also find that whenever intergovernmental relations were present in communities, the member connectivity was low, even if intersectoral relations appeared together within them. Many countries have struggled with coordinating efforts among diverse organizations in response to crises attributable to disasters and emergencies . Disasten-cliques and k-cores) focus on internal edges, while the community is a concept based on the distinction between internal edges and the outside. We argue that community analysis can provide useful insights about the interrelations among diverse organizations in the ERN.In this article, we distinguish between clique family subgroups and communities in ERNs. Conceptually, a clique is “…a group [in which] all members of which are in contact with each other or are friends, know each other, etc.” which generally refers to a social circle , p. 161,We have not yet found any studies that have investigated cohesive subgroups in large multilevel, multisectoral ERNs through a community lens. With limited guidance from the literature on ERNs, we lack specific expectations or hypotheses about what the community structure in the network may look like. Therefore, our study focuses on identifying and analyzing communities in the 2015 Middle East Respiratory Syndrome Coronavirus (MERS) response in South Korea as a case study. We address the following research questions: (1) In what way were distinctive communities divided in the ERN? and (2) How did the interorganizational relations relate to the internal characteristics of the communities? By detecting and analyzing the community structure in an ERN, we offer insights for future empirical studies on ERNs.1 in which a small number of nodes had a large number of edges and a large number of nodes had a small number of edges . The n-cliques can include nodes that are not in the clique but are accessible. Similarly, k-cores refer to maximal subgraphs with a minimum degree of at least k. Many cliques were identified in the Katrina response network, in which federal and state agencies appeared frequently , and intersectoral relations involve the interaction among organizations across different sectors . Recent studies have suggested that both intergovernmental and intersectoral relations shape ERNs , but fewn-cliques and k-cores) demand an answer to the question: “What is the n- or k-?” The clique and clique-like approaches have a limited ability to define and identify cohesive subgroups in a task-oriented network because they do not clearly explain why the subgroups need to be defined and identified in such a manner. We proposed a different way of thinking about and finding subsets of organizations in ERNs: community.The analysis of cliques is a very strict way of operationalizing cohesive subgroups from a social network perspective , and theWhen a network consists of subsets of nodes with many edges that connect nodes of the same subset, but few that lay between subsets, the network is said to have a community structure . NetworkQ), which shows the quality of partitions, is measured and assessed quantitatively:Modularity  through concerted efforts on the part of those with different capabilities . OrganizIt is equally difficult to set expectations about communities’ internal structure in ERNs. We can expect that, regardless of their types, sectors, and locations, some organizations work and interact closely—perhaps even more so in such a disruptive situation. Emergent needs for coordination, communication, and collaboration also can trigger organizational interactions that extend beyond the usual or planned structure. Thus, the relations among organizations become dense and evolve into the community in which every member is connected. On the other hand, a community in the task network may not require all of the organizations within it to interact. For example, if a presumed structure is strongly established, organizations are more likely to interact with others within the planned structure following the chain of command and control. Even without such a structure, government organizations may coordinate their responses following the existing chain of command and control in their routine. We may expect to observe communities with a sparse connection among organizations. Thus, the way communities emerge in ERNs is an open empirical question that can be answered by examining the entire network.Several countries have experienced novel infectious disease outbreaks over the past decade  and effoWe broadly define a response network as the relations among organizations that can act as critical channels for information, resources, and support. When two organizations engage in any MERS-specific response interactions, they are considered to be related in the response. Examples of interactions include taking joint actions, communicating with each other, or sharing crucial information and resources  related to performing the MERS tasks, as well as having meetings among organizations to establish a collaborative network.4 published between May 20, 2015, and December 31, 2015 (the outbreak period), and (2) a postevent white paper that the Ministry of Health and Welfare published in December 2016. In August 2016, Hanyang university's research center in South Korea provided an online tagging tool for every news article in the country’s news articles database that included the term “MERS (http://naver.com).” A group of researchers at the Korea Institute for Health and Social Affairs wrote the white paper  based on their comprehensive research using multiple data sources and collection methods. The authors of this article and graduate research assistants, all of whom are fluent in Korean, were involved in the data collection process from August 2016 to September 2017.We collected response network data from the following two archival sources: (1) news articles from South Korea’s four major newspapers5Because of the literature’s lack of specific guidance on the data to collect from archival materials to construct interorganizational network data, we collected the data through trial and error. We collected data from news articles through two separate trials . The authors and a graduate assistant then ran a test trial between August 2016 and April 2017. In July 2017, the authors developed a data collection protocol based on the test trial experience collecting the data from the news articles and white paper. Then, we recollected the data from the news articles between August 2017 and September 2017 using the protocol.de facto decision making unit within the context of the response”  multiple persons or other entities, and that acts as a esponse” , p. 6. I6We also categorized individual organizations into different “groups” using the following criteria. First, we distinguished the entities in South Korea from those outside the country . Second, we sorted governmental entities by jurisdiction  and then also by the functions that each organization performs . For example, we categorized local fire stations differently from provincial fire headquarters because these organizations’ scope and role differ within the governmental structure. We categorized nongovernmental entities in the private, nonprofit, or civil society sectors that provide primary services in different service areas . At the end of the data collection process, 69 organizational groups from 1,395 organizations were identified see .6https://gephi.org/). After identifying communities, the network can be reduced to these communities. In generating the reduced graph, each community appears within a circle, the size of which varies according to the number of organizations in the community. The links between communities indicate the connections among community members. The thickness of the lines varies in proportion to the number of pairs of connected organizations. This process improves the ability to understand the network structure drastically and provides an opportunity to analyze the individual communities’ internal characteristics such as the organizations’ diversity and their connectivity for each community.We employed the Leiden algorithm using Python , which wH) is used as a measure of diversity because uncertainty increases as species’ diversity in a community increases . S indicates the total number of species. The fraction of the population that constitutes a species, i, is represented by ip below and then multiplied by the natural logarithm of the proportion  is the proportion of possible edges presented in the graph, which is the ratio between the number of edges present and the maximum possible. It ranges from 0 (no edges) to 1 . A graph’s clustering coefficient (C) is the probability that two neighbors of a node are neighbors themselves. It essentially measures the way a node’s neighbors form a 1-clique. C is 1 in a graph connected fully.While limited, density and the average clustering coefficient can capture the basic idea of a subgraph’s structural cohesion or “cliquishness” . A graphThe MERS response network in the data set consists of 1,395 organizations and 4,801 edges. Organizations coordinated with approximately three other organizations (average degree: 3.44). However, six organizations coordinated with more than 100 others. The country’s health authorities, such as the Ministry of Health and Welfare (MOHW: 595 edges), Central MERS Management Headquarters (CMMH: 551 edges), and Korea Centers for Disease Control and Prevention (KCDC: 253 edges), were found to have a large number of edges. The Ministry of Environment (304 edges) also coordinated with many other organizations in the response. The National Medical Center had 160 edges, and the Seoul Metropolitan City Government had 129.Q) was 0.584, showing that the community detection algorithm partitioned and identified the communities in the network reasonably well. In real-world networks, modularity scores “…typically fall in the range from about 0.30 to 0.70. High values are rare”  at the center of the response network included a large number of organizations, with a knot of intergroup coordination among the groups surrounding those two. These communities included organizations across government jurisdictions, sectors, and geographic locations . The domOther remaining communities were (1) confined geographically, (2) oriented functionally, or (3) both. First, some communities consisted of diverse organizations in the areas where two MERS hospitals are located—Seoul Metropolitan city and Gyeonggi Province (Communities 3 and 5). Organizations in these communities span government levels and sectors within the areas affected. Second, two communities consisted of organizations with different functions and performed supportive activities . These communities included intergovernmental relations within geographic locations. Secondly, communities of organizations with a specialized function showed relatively high diversity or connectivity. These included organizations from governmental and nongovernmental sectors and had no leading or dominating organizations. For example, Communities 11 and 12 had intersectoral relations but no intergovernmental relations. Thirdly, within each community of fire organizations in different geographic locations, one provincial or metropolitan fire headquarters was linked to multiple local fire stations in a star network. These communities, labeled IGF, had low member diversity and member connectivity, while they were organizationally and functionally coherent.We use the community detection method to gain a better understanding of the patterns of associations among diverse response organizations in an epidemic response network. The large data sets available and increased computational power significantly transform the study of social networks and can shed light on topics such as cohesive subgroups in large networks. Network studies today involve mining enormous digital data sets such as collective behavior online , an e-maWe find two important results. First, the national public health ERN in Korea split largely into two groups. The core response communities’ characteristics were that (1) they were not confined geographically, (2) organizations were heterogeneous across jurisdictional lines as well as sectors, and (3) the community’s internal structure was sparse even if intersectoral relations were present. On the other hand, supportive functional communities’ characteristics were that (1) they were communities of heterogeneous organizations in the areas affected that were confined geographically; (2) the communities of intersectoral, professional organizations were heterogeneous, densely connected, and not confined geographically; and (3) the communities of traditional emergency response organizations  were confined geographically, homogeneous, and connected sparsely in a centralized fashion.These findings show distinct features of the response to emerging infectious diseases. The core response communities suggest that diverse organizations across jurisdictions, sectors, and functions actually performed active and crucial MERS response activities. However, these organizations’ interaction and coordination inside the communities were found to be top down from the key national health authorities to all other organizations. This observation does not speak to the quality of interactions in the centralized top-down structure, but one can also ask how effective such a structure can be in a setting where diverse organizations must share authority, responsibilities, and resources. Second, infectious diseases spread rapidly and can break out in multiple locations simultaneously. The subgroup patterns in response networks to infectious diseases can differ from those of location-bound natural disasters such as hurricanes and earthquakes. While some organizations may not be actively or directly involved in the response, communities of these organizations can be formed to prepare for potential outbreaks or provide support to the core response communities during the event.If intergovernmental relations operate in a community, the community’s member connectivity may be low, regardless of member diversity.professional organization communities’  member connectivity may be dense andemergency response organization communities’  member connectivity may be sparse.If community members are functionally similar,Second, we also find that the communities’ internal characteristics (diversity and connectivity) differed depending upon the types of interorganizational relations that appeared within the communities. Based on these analytical results, two propositions about the community structure in the ERN can be developed:The results suggest that the presence of intergovernmental relations within the communities in ERNs may be associated with low member connectivity. However, this finding does not imply that those communities with intergovernmental relations are not organizationally or functionally cohesive. Instead, we may expect a different correlation between members’ functional similarity and their member connectivity depending upon the types of professions, as seen in 2(a) and (b).Organizations’ concerted efforts during a response to an epidemic is a prevalent issue in many countries . The 201The findings of this study offer a practical implication for public health emergency preparedness and response in the country studied. ERNs’ effective structure has been a fundamental question and a source of continued debate . The ansThis study’s limitations also deserve mention. Several community detection methods have been developed with different assumptions for network partition. Some algorithms take deterministic group finding approaches that partition the network based on betweenness centrality edges  or inforWhile we reviewed the data sources carefully multiple times to capture the response coordination, communication, and collaboration, the process of collecting and cleaning data can never be free from human error. It was a time-consuming, labor-intensive process that required trial and error. Further, the original written materials can have their own biases that reflect the source’s perspective. Government documents may provide richer information about the government’s actions but less so about other social endeavors. Media data, such as newspapers, also have their limitations as information sources to capture rich social networks. Accordingly, our results must be interpreted in the context of these limitations.In conclusion, this article examines the community structure in a large ERN, which is a quite new, but potentially fruitful, approach to the field. We tested a rapidly developing analytical approach to the ERN to generate theoretical insights and find paths to exploit such insights for better public health emergency preparedness and response in the future. Much work remains to build and refine the theoretical propositions on crisis response networks drawn from this rich case study.Click here for additional data file.Supplemental Material, Kim_Kim_Oh_et_al_Online_Supplement for Community Analysis of a Crisis Response Network by Yushim Kim, Jihong Kim, Seong Soo Oh, Sang-Wook Kim, Minyoung Ku and Jaehyuk Cha in Social Science Computer Review


To investigate prognostic values of serum biomarkers of soluble intercellular adhesion molecule 1 (sICAM-1), macrophage migration inhibitor factor (MIF), interleukin 1 From August 2017 to November 2019, 122 consecutive IPF patients treated in our center were classified as stable IPF and AE-IPF based on the newly published international guidelines. Serum levels of four biomarkers at admission were measured by the enzyme-linked immunosorbent assay (ELISA). The primary endpoint was 3-month mortality. The log-rank test and logistic regression analysis were used to evaluate the effects of these biomarkers for survival in patients with AE-IPF. Cox proportional hazards analysis was performed to evaluate the prognostic values of serological biomarkers and clinical data. p < 0.001), IL-1β (p < 0.001), MIF (p < 0.001), and su-PAR (p < 0.001) in patients with IPF were significantly increased compared to those in healthy controls. All the four biomarkers were elevated in patients with AE-IPF compared to those with stable IPF. The 3-month mortality in AE-IPF was 56.1% (23/41). Increased levels of MIF (p = 0.01) and IL-1β  were independent risk factors for 3-month mortality in patients with AE-IPF.  Eighty-one patients were diagnosed with stable IPF, and 41 AE-IPF patients were enrolled in the study. Serum levels of sICAM-1 (β, and MIF had prognostic values for 3-month mortality in AE-IPF. This study provided a clue to promote our understanding in the pathogenesis of the disease. We showed the higher serum levels of IL-1 Idiopathic pulmonary fibrosis (IPF) is a progressive, interstitial lung disease with unknown etiologies , 2. The β (IL-1β) have been reported to be associated with another severe condition, acute respiratory distress syndrome (ARDS), which shares several pathophysiological features with AE-IPF [Increasing evidences indicate that acute inflammation may be responsible for the occurrence of AE-IPF rather than an abrupt fibrosis aggravation. In addition, the activation of abnormal coagulation and fibrinolysis pathways has been implicated in AE-IPF for elevated levels of plasma D-dimer and fibrin degradation product (FDP) observed in patients with AE-IPF . Proinflh AE-IPF , 8. Alsoh AE-IPF , 10. Coah AE-IPF . HoweverIn this study, we measured serum levels of these four cytokines in patients with IPF and age-matched healthy controls. Next, we compared their differential expressions between patients with stable IPF and AE-IPF. And then, we investigated their prognostic values for predicting 3-month mortality in patients with AE-IPF and compared them with the existing clinical data.From August 2017 to November 2019, 122 consecutive patients with IPF were admitted to the Department of Pulmonary and Critical Care Medicine, Nanjing Drum Tower Hospital. The diagnosis criteria of stable IPF and AE-IPF were based on the updated international guidelines and made by a multiple disciplinary team consisted of experienced respiratory physicians and radiologists. Briefly, the criteria for a diagnosis of IPF were as follows: (a) exclusion of other known causes of interstitial lung disease (ILD), (b) the presence of a UIP pattern on HRCT in patients not subjected to surgical lung biopsy, and (c) specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy. The diagnosis of AE-IPF was acute worsening or development of dyspnea typically less than one month with new emerging GGO on the background of the UIP pattern in HRCT. Other conditions leading to a clinical exacerbation such as acute heart failure and pulmonary embolism should be excluded [Secondary interstitial lung fibrosis was excluded through clinical and laboratory investigations. To assess the prognostic value of coagulation dysfunction in patients with IPF, patients who had combination of other thrombotic diseases including acute-stage cerebral infarction and deep vein thrombosis or who had received anticoagulation therapy within 6 months were excluded. The stable patients have to be in a stable phase for at least 3 months before being enrolled in the study.2/FiO2 ratio were collected. Pulmonary function data at admission were available in 61 patients (50 patients with stable IPF and 11 patients with AE-IPF). Variables including forced vital capacity (FVC), FVC% predicted, diffusing capacity of the lung for carbon monoxide (DLCO), and DLCO% predicted were recorded. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated within 24 hours after the patients were diagnosed with AE. The primary endpoint was 3-month mortality. Survival status was confirmed by reviewing medical documents and telephone follow-up. Survival time of AE-IPF was calculated from the diagnosis of AE to death.Baseline demographic information; clinical characteristics and lab examinations including lactate dehydrogenase (LDH), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, and albumin (ALB); and blood routine examination including white blood cell count and neutrophil percentage and the PaOForty-five age- and-gender-matched healthy controls were from the Physical Examination Center of Nanjing Drum Tower Hospital. This study was approved by the Ethics Committee at Nanjing Drum Tower Hospital .Peripheral blood samples (5 mL) were collected using standardized venipuncture procedures. Blood samples of patients with stable IPF were collected at the first day of admission. Blood samples of patients with AE-IPF were collected when the diagnosis of AE-IPF was confirmed. Serum samples were separated by centrifugation and stored at −80°C.β , MIF , and su-PAR  according to the manufacturers' instructions, and every sample had a duplicate. The mean minimum detectable dose by the ELISA kits was 8.81 pg/mL.Commercially available enzyme-linked immunosorbent assay (ELISA) kits were adopted to measure the serum levels of sICAM-1 and IL-1U tests. Student's t-test was applied to compare continuous clinical variables when they satisfied a normal distribution. Categorical variables were compared by the chi-square test. Survival of AE and stable IPF patients was evaluated using the logistic regression analysis and log-rank test. The rank correlation analysis was performed to evaluate the associations between cytokines and clinical data. Logistic regression analysis was used to filtrate important confounders regarding the prognosis of AE-IPF. If the regression coefficient of the variables was statistically significant, it will be introduced in multivariate models. Cox proportional hazards analysis was used to identify significant predictors of 3-month mortality in patients with AE-IPF. p values < 0.05 were considered to be significant. Data analyses were performed using SPSS statistical software version 22.0.Numerical variables were expressed as mean ± SD. Differences of biomarkers among groups were examined by Mann-Whitney 2/FiO2, FVC% predicted, and DLCO% predicted were significantly lower in patients with AE-IPF than in those with stable IPF. An elevated serum D-dimer level was observed in patients with AE-IPF compared to those with stable IPF (p < 0.001).During the study period, 122 consecutive patients with IPF were admitted to the Department of Pulmonary and Critical Care Medicine, Nanjing Drum Tower Hospital. They were 102 males (83.6%) and 20 females (16.4%), with mean age of 65.8 ± 8.6 years old. Among them, 81 patients were diagnosed with stable IPF  and 41 patients with AE-IPF . In this study, 30.3% (37/122) were newly diagnosed with IPF. All AE patients were admitted because of the aggravation of dyspnea and respiratory failure, and 41.5% (17/41) of them also have suspectable pulmonary infections. At admission, 85.4% (35/41) of AE patients have a preceding diagnosis of IPF and 6 patients were newly diagnosed with AE-IPF. The flowchart is described in During hospitalization, 14 patients with AE-IPF  received corticosteroid pulse therapy (methylprednisolone 500-1000 mg/d for 3-5 days). Three patients with AE-IPF  received lung transplantation. In total, there were 35 patients died in the follow-up and 25 of them were AE-IPF. The mean survival time of patients with AE-IPF was 5.4 months from diagnosis of AE-IPF, and 23 of them died within 3 months. The 3-month mortality of AE-IPF was 56.1% (23/41).p < 0.001), IL-1β (p < 0.001), MIF (p < 0.001), and su-PAR (p < 0.001) in patients with IPF were significantly higher than those in healthy controls. Serum levels of sICAM-1 (p < 0.001), IL-1β (p < 0.001), MIF (p = 0.038), and su-PAR (p < 0.001) in patients with AE-IPF were significantly higher than those in patients with stable IPF . The baseline levels of serum IL-1β were correlated with WBC count , CRP , LDH , and ESR . The serum levels of sICAM-1 were correlated with WBC count , not with CRP, ESR, and LDH. The serum levels of MIF were not correlated with any of these clinical parameters. However, in patients with AE-IPF, the serum levels of su-PAR were not correlated with D-dimer. In addition, the serum levels of sICAM-1, IL-1β, and MIF were not correlated with these inflammatory-related laboratory data. Therefore, in patients with AE-IPF, it is meaningful to analyze the impact of these biomarkers on 3-month mortality.In all patients, Spearman's rank correlation coefficient revealed that the serum levels of su-PAR were correlated with D-dimer (p = 0.007), su-PAR (p = 0.033), and IL-1β (p = 0.018) were associated with poor prognosis in patients with AE-IPF. However, higher levels of sICAM-1 were not a risk factor for survival. We performed survival analysis in patients with AE-IPF. Firstly, all these biomarkers were analyzed as continuous variables. Then, categorizations of these variables were taken into consideration when the former were not appropriate. The normal range of IL-1β in our center laboratory was less than 5 pg/mL. The log-rank test was performed according to the clinical cut-off levels and demonstrated that the increased levels of IL-1β (>5 pg/mL) were associated with higher 3-month mortality in patients with AE-IPF (p < 0.001) (p = 0.012) .The mean follow-up time in patients with AE-IPF was 7.6 months (range from 3 to 23 months). Logistic regression analysis revealed that higher serum levels of MIF (< 0.001) . The bas= 0.012) . Logisti2/FiO2 ratio, APACHE II score, and WBC count . The elevated serum levels of IL-1β (>5 pg/mL) were associated with worse survival after adjustment for related markers . After adjustment for demographic information  in multivariate model 2, the above conclusion is appropriate . In addition, only a handful of AE-IPF patients in our study underwent bronchoalveolar lavage, which limited the possibility to compare the levels of these biomarkers in BALF and serum.β, MIF, and su-PAR were observed in AE-IPF. The increased levels of IL-1β and MIF were risk factors for 3-month mortality in patients with AE-IPF. Our study provided evidences that acute inflammatory response and coagulation abnormalities may participate in the pathogenesis of AE-IPF.In conclusion, increased levels of sICAM-1, IL-1