These findings establish the beginning of an atlas of endogenous L1 mRNA expression across a broad range of biological variables that will guide future studies.Expression of L1 mRNA, the first step in the L1 copy-and-paste amplification cycle, is a prerequisite for L1-associated genomic instability. We used a reported stringent bioinformatics method to parse L1 mRNA transcripts and measure the level of L1 mRNA expressed in mouse and rat organs at a locus-specific resolution. This analysis determined that mRNA expression of L1 loci in rodents exhibits striking organ specificity with less than 0.8% of loci shared between organs of the same organism. This organ specificity in L1 mRNA expression is preserved in male and female mice and across age groups. We discovered notable differences in L1 mRNA expression between sexes with only 5% of expressed L1 loci shared between male and female mice. Moreover, we report that the levels of total L1 mRNA expression and the number and spectrum of expressed L1 loci fluctuate with age as independent variables, demonstrating different patterns in different organs and sexes. Overall, our comparisons between organs and sexes and across ages ranging from 2 to 22 months establish previously unforeseen dynamic changes in L1 mRNA expression  L1 DNA , and Gf ,26–29. L, and Gf . L1 sequ, and Gf . Even th, and Gf . Here, wde novo L1 inserts  and 3 at 12.8 mo. Lungs were collected from 5 mice: 2 at 7.6 mo and 3 at 12.8 mo. Only testes and livers were collected from 6 additional mice: 2 at 1.9 mo, 1 at 3.6 mo, and 3 at 22.3 mo. Brains, lungs and ovaries were collected from nine mice: two at 2.2 mo, one at 3.2 mo, two at 8 mo, one at 8.6 mo, one at 8.7 mo and two at 16.5 mo. Uteri were collected from six mice: one at 2.2 mo, one at 8 mo, one at 8.6 mo, one at 8.7 mo and two at 16.5 mo. Testes, brains, livers, and lungs were collected from three rats, all 4.8 mo. Animals used in this study and their inclusion in downstream analyses is shown in 3 were bluntly dissected and then homogenized in 500–1000 ul of lysis buffer  to lyse the cytoplasmic membrane. The mixture was lightly homogenized in a Dounce homogenizer with an autoclaved B pestle, incubated on ice for 5 min and then centrifuged for 2 min at 1000 rpm at 4°C. Supernatant, containing the cytoplasmic fraction, was mixed with pre-chilled 7.5 ml of Trizol and 1.5 ml of chloroform and then centrifuged for 35 min at 4000 rpm at 4°C. The aqueous portion was transferred to 4.5 ml of chilled chloroform, mixed and centrifuged for 10 min at 4000 rpm at 4°C. The resulting aqueous portion was precipitated with 4.5 ml of isopropanol overnight at 80°C, centrifuged for 45 min at 4°C at 4000 rpm, washed with 10 ml of ethanol and re-suspended in RNase-free water.RNA was extracted as previously described . SpecifiCytoplasmic RNA samples were analyzed in an Agilent 2100 Bioanalyzer System according to the Agilent RNA 6000 Nano kit guide. Samples with RIN >8 were submitted for sequencing.Mus musculus 10 (mm10) or Rattus norvegicus 6 (rn6) genomes, and queried for alignments occurring within annotated L1 loci. Bioinformatics analysis was performed as previously described , which produces 150 bp read lengths, and Illumina sequencing, which produces 100 bp read lengths. We clipped 150 bp DNBseq sample reads to 100 bp and completed the analysis for the 150 bp reads and 100 bp reads in parallel to test whether these read length differences would affect the results. The analysis with different read lengths resulted in a difference of two authentically expressed L1 loci between the groups with 150bp reads producing 14 expressed L1 loci and 100bp reads producing 12 expressed L1 loci. For samples sequenced using Illumina sequencing, samples were pooled in groups of 5–7 and applied to a single lane of an Illumina HiSeq 2500/4000 instrument. Data were sorted based on barcodes attached to each individual sample, aligned to either the escribed . These mThe annotation for full-length L1 elements was downloaded from the L1Base 2 database , includiThe annotation for full-length, intact and non-intact L1 elements was downloaded from the L1Base 2 database  and intef, Gf, and A subfamily sequences, each containing two subfamily-specific promoter monomers. The paired-end alignment was performed using STAR v2.3.0e, allowing two alignments and 25 mismatches per read pair. Reads that aligned to the promoter regions in the sense orientation were included in our analysis of discarded reads. RSEM v1.2.31 was used to measure the expression of genes containing L1 loci and total RNA levels  . As the Mus musculus whole genome sequencing and ERR224469 for the Rattus norvegicus whole genome sequencing. Then we used the Bowtie1 alignment program to assign whole genome reads that mapped uniquely to the Mus musculus 10 (mm10) or Rattus norvegicus 6 (rn6) genomes . As. As68). t-test when making comparisons between two groups. Chi-square tests were used when comparing categorical groups. To measure linear correlation between two variables, Pearson correlation test was performed. Statistical analysis was performed with GraphPad Prism.Data are presented as mean with standard error bars. Data were analyzed by two-tailed Student's We previously reported a stringent, custom-designed strategy for aligning and validating L1 mRNA reads originating from full-length L1 loci . For thiThe second key element in our strategy was the inspection of each potentially expressed L1 locus in the Integrated Genome Viewer (IGV)  to confif, Gf, and A  and expressed 11 L1 loci at a higher level than any locus from the other organs . Testes also exhibited higher levels of expression at individual L1 loci. For example, L1 locus UID-5948  had the highest expression in testes with an FPKM of 3.05. In livers, the highest expressed L1 locus was UID-6143 with a 0.037 FPKM. In brains, the highest expressed L1 locus was UID-5181 with a 0.24 FPKM. In lungs, the highest expressed L1 locus was UID-6870 with a 0.83 FPKM. These data demonstrate that there is as much as a 100-fold difference in the expression levels of the highest expressed L1 loci among male organs of the same individual mouse, with testes being the highest and liver supporting the lowest levels of expression   Figure .We compared specific expressed L1 loci between male organs. We found substantial overlap in expressed L1 loci between the same organs collected from different mice. Among all organs analyzed in this study, testis exhibited the greatest degree of similarity with 85% of testes loci (346 loci) shared between all three animals Figures . Liver sIn contrast to this high number of shared L1 loci expressed in the same organs from different individuals, there was minimal overlap between organs collected from the same male mouse. Of the combined 461 L1 loci expressed by all male organs considered, none (0%) were shared by all four organs in any of the mice, four (0.8%) were shared between testis and brain in six mice, 1 (0.2%) was shared between testis and lung in five mice and 1 (0.2%) was shared between testis, brain and liver in six mice Figure .Female organs showed greater heterogeneity of expressed L1 loci than male organs. Of the 34 L1 loci expressed in ovaries, only five L1 loci (15%) were shared by all four samples. Of the 28 L1 loci expressed in uteri, only three loci (10%) were shared by all three samples. Of the 47 L1 loci expressed in female brains, 10 loci (21%) were shared by all four samples. Of the 30 L1 loci expressed in female lungs, 10 (36%) were shared by all four samples Figure . Similarf and Tf subfamilies, the youngest and most active of the mouse L1 subfamilies . The percentage of expressed L1 loci in testes belonging to the Tf subfamily was significantly higher than livers, male lungs, ovaries, female brains and female lungs . The higher numbers of expressed young L1 subfamily members in testes indicate that loci expressed in the testes are more likely to participate in active retrotransposition . The 135 L1 loci uniquely expressed in the 7.6 mo group accounted for 8.57 FPKM (20.6%) of the 41.56 FPKM for total L1 expression observed at 7.6 months . 22.3 mo testes expressed significantly more L1 loci on average than the 12.8 mo group with the 22.3 mo group expressing on average 134 more L1 loci than the 12.8 mo group . Of the 471 L1 loci expressed in testis of all age groups, 168 (36%) were shared between all age groups . Although a low number of expressed L1 loci was detected in livers collected from male mice of all age groups, livers collected from 7.6 mo male mice expressed an average of four more L1 loci, compared to the 1.9–3.6 mo age group . 12.8 mo livers expressed on average three fewer L1 loci than the 7.6 mo age group . 22.3 mo livers expressed on average two more L1 loci than the 12.8 mo age group  and three more than the 1.9–3.6 mo age group . In addition to the increase in the number of expressed L1 loci in brains of older female mice, total levels of L1 expression also increased from an average of 1.25 FPKM in the 2.2 mo group to 3.47 FPKM in the oldest age group  = 3.864, P = 0.05, X2 = 8.8147, P = 0.0029)  = 8.809, P = 0.0024, X2 = 20.219, p < 0.00001) . Thus phase   . 7.6 mo 0.00001) .2 = 9.9157, P = .00703). Similarly, the 21 expressed L1 loci shared between the 16.5 mo female age group and the 12.8 mo male age group is significantly greater than the two expressed L1 loci shared between the 2.2 mo female age group and the 1.9–3.6 mo male age group  = 29.6273, P < 0.00001). Taken together, this finding demonstrates that L1 loci expression is sex-specific and remains so with age even though there is a 10-fold (2–21 loci) increase in the number of shared L1 loci between sexes with age.We have demonstrated that L1 loci are expressed in an organ-specific manner in both male and female mice Figure . To deteX2 = 7.311, P = 0.007, females chi square, X2 = 16.27, P = 0.00006, X2  = 33.9183, P < 0.00001, We compared expression patterns of L1 loci between male and female organs of the same type and age group to better understand L1 mRNA expression in different sexes. Lungs collected from 8–8.7 mo females and 7.6 mo males expressed 30 and 23 L1 loci, respectively, and shared 4 (8%) expressed L1 loci Figure  and male2  = 23.2185, P < 0.00001, X2 = 12.9833, P < 0.0003, females chi square, X2 = 7.3134, P = 0.007, We also compared expressed L1 loci between male and female brains at different ages. Brains collected from 8 to 8.7 mo females and 7.6 mo males expressed 47 and 29 L1 loci, respectively, and shared 13 (21%) expressed L1 loci Figure  and malet-test, brains, P = 0.0006; lungs, P = 0.0001).Our analysis of L1 mRNA expression in mice identified hundreds of expressed L1 loci, allowing us to begin to understand what distinguishes L1 loci that are expressed from those that are not. We next investigated whether intragenic L1 loci are more likely to be expressed. First, by intersecting the genomic coordinates of expressed L1 loci with the known gene coordinates in the mm10 genome downloaded from the UCSC Genome Browser, we identified intragenic, expressed L1 loci and their orientation relative to genes Figure . We founr(92) = –0.1, P = 0.3), we did find that all genes, except one, that contain an expressed L1 locus are also expressed. Thus, gene expression provides a critical favorable environment, but does not determine L1 expression strength.Next, we considered whether expression of intragenic L1 loci correlated with expression of the genes in which they were present. We plotted L1 FPKM levels alongside the FPKM of their corresponding gene expressed in testes collected from 7.6 mo mice Figure . AlthougWe performed transcriptomic profiling of our RNA-sequencing data to identify potential mechanisms contributing to the observed patterns of L1 mRNA expression in testis because mechanisms governing L1 mRNA expression are numerous and complex . We usedt-test, P < 0.0001) and 12.8 mo testes   Figure . Quantif) Figure  and the ) Figure  revealed) Figure  and B. Ht-test, P = 0.01). This is despite the fact that we also observed upregulation of the basal transcription factors pathway in 7.6 mo testes with 25 of 33 basal transcription factors pathway genes upregulated in 7.6 mo testes compared to 1.9–3.6 mo testes and 30 of 33 basal transcription factors pathway genes upregulated in 7.6 mo testes compared to 12.8 mo testes , we compared the ‘mappability’ of L1 sequences in rn6 and mm10 genomes. This allows us to measure the likelihood of finding unique alignments for RNA-seq reads originating from L1 mRNA transcripts in mice and rats. The ‘mappability’ of L1 sequences in the rn6 and mm10 genome assemblies were calculated by aligning rattus norvegicus and mus musculus paired-end DNA sequencing reads to the rn6 or mm10 genome using the same bowtie alignment parameters utilized in our RNA analysis pipeline . We then plotted the number of uniquely mapped DNA reads to each L1 locus in the mm10 and rn6 genome assemblies , brains , or lungs   Figure . This an) Figure . L1 loci) Figure  and 8C.Calculating mappability correction section of the Materials and Methods. Normalizing to the ‘mappability’ of each locus did not change our comparison of L1 expression between organs and the mappability-corrected FPKM values for mouse testes remained significantly higher than mouse male livers, male brains, male lungs . This difference made us wonder how variability in L1 locus mappability may influence the ability to align L1 reads to unmappable regions and measure L1 FPKM levels between samples. To address this question, we corrected our RNA-seq FPKM values for differences in mappability to observe whether mappability differences between loci would alter our conclusions. We mappability-corrected FPKM values from our male mouse RNA-seq analysis by scaling the number of aligned reads for each locus to 400 reads, the average number of reads for a fully ‘mappable’ L1 locus, and multiplying the number by the original FPKM value . This eqin vivo unresolved (Detection of full-length L1 mRNA from individual loci is critical to understanding their impact on the host including potential to damage genomic DNA. To detect and measure L1 mRNA, methods used must be able to distinguish not only which locus is expressed, but whether that expression arises from the L1 promoter and is not a passive product of read-through transcription ,34,39,41resolved . Even meresolved . Additioresolved . In thisresolved .in vivo analysis of L1 mRNA expression in multiple organs from 18 mice also found that the number of L1 loci differs greatly between organs, with mouse testes expressing significantly more L1 loci (i.e. 409 L1 loci expressed in testes versus 7 L1 loci expressed in liver, Figures Patterns of L1 mRNA expression at the single-locus resolution are remarkably consistent within an organ, with testes from different mice sharing 85% of expressed L1 loci, male livers sharing 71%, male brains sharing 65%, male lungs sharing 52%, ovaries sharing 15%, uteri sharing 10%, female brains sharing 21%, and female lungs sharing 36%. Figures . Our in r = 0.1030, Figure in vivo and in cell lines (If the sequence or epigenetic architecture of genomic domains is responsible for L1 regulation, we would expect that expressed L1 loci would be enriched in the vicinity of expressed genes that might result in the overall domain being more active. The fraction of expressed L1 loci found in genes is quite variable among organs (10–63%, Figure ll lines ,33–35 arde novo somatic integration event (Although similarities in L1 mRNA expression between organs of the same type are not surprising based on previous findings ,33,34, ion event ,102. HowThe ability to monitor changes in both the levels of L1 mRNA expression and numbers of expressed L1 loci allowed us to discover unique and dynamic variations that occur with age in different organs. We found that L1 mRNA expression and the number of L1 loci expressed can change independently with age Figure . Testes In addition to differences between organs and ages, we found that the levels and patterns of expressed L1 loci exhibited sex-specific differences. Male and female mice shared significantly more expressed L1 loci with their respective sex, compared to the L1 loci shared with the opposite sex . The numFocusing only on reproductive organs, male testes share 85% of expressed L1 loci while ovaries and uteri share only 15% and 10% of expressed L1 loci, respectively Figure . We consOverall, we found that expression of individual L1 loci in rodents is strikingly organ specific, with a strong level of sex specificity, establishing the first atlas of endogenous L1 mRNA expression in male and female mice. In addition, there are distinct patterns of increased heterogeneity in expression at different ages in different organs. Our cross organ, sex, and age comparisons establish a baseline of endogenous L1 mRNA expression under normal conditions that can be utilized to understand the potential of these elements to create differential DNA damage in different tissues with age or environmental exposures. Our findings set the stage for identifying mechanisms that permit expression of some but not other L1 loci and mechanisms that govern sexual dimorphism in L1 mRNA expression. These studies also permit comparative exploration of L1 mRNA expression patterns in other L1-harboring organisms to understand the roots of its evolutionary conservation or diversity.http://genome.ucsc.edu/cgi-bin/hgTracks?db=mm10&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr12%3A56694976%2D56714605&hgsid=1015816353_RetTob8ARYR2ZUoUuEvAidjg9sZH and rn6, http://genome.ucsc.edu/cgi-bin/hgTracks?db=rn6&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr1%3A80608553%2D80639261&hgsid=1015816387_WqXYk74yEffaVVS0vEHi5DAjFxPO.The raw data files and analysis files for RNA-seq in this manuscript are available through GEO: GSE158831. The aligned RNA-seq files are available through the following UCSC genome browser links: mm10, gkab369_Supplemental_FilesClick here for additional data file.


Our findings provide a novel conceptof using tunable quantum tunneling for highly sensitive broadbandphotodetection in mixed-dimensional van der Waals heterostructures.Graphene-based vander Waals heterostructures are promising buildingblocks for broadband photodetection because of the gapless natureof graphene. However, their performance is mostly limited by the inevitabletrade-off between low dark current and photocurrent generation. Here,we demonstrate a hybrid photodetection mode based on the photogatingeffect coupled with the photovoltaic effect via tunable quantum tunnelingthrough the unique graphene/Bi Variousmethods have been introduced to overcome limitations by enhancingthe light absorption of graphene-based photodetectors, including plasmonicnanostructures8 and quantum dots.9 Although these approaches have unique advantages,their photodetection is limited to a short spectral range becauseof the sharp resonant absorption.11Lightdetection over a wide spectral range, from the visible tothe mid-infrared, has a great potential for numerous photonic andoptoelectronic applications. In this scenario, graphene can providea versatile platform for broadband photodetection due to its gaplesselectronic band structure.13 In graphene-based van der Waals heterostructures, semiconductingtwo-dimensional transition-metal dichalcogenide materials are typicallyused as they exhibit superior light–matter interaction propertiesthat allow for enhanced light absorption. However, the absorptionis limited within the visible spectral range due to their band gap.14 Combining graphene with narrower band gap materialshas been proposed for broader light absorption despite the large darkcurrent.17 Among them, most of the studies using topologicalinsulators focused on the formation of graphene/topological insulatorheterostructures to induce the photogating effect, utilizing the novelproperties of topological insulators such as graphene-like hexagonalsymmetry, direct narrow band gap, and ultrafast photocurrent alongthe surface.19 As a material candidate to formvan der Waals heterostructures with graphene, topological insulatorshave advantages beyond the aforementioned properties. For example,compared to black phosphorus, which is similar to a topological insulatorin terms of band gap and electrical properties such as mobility andcarrier multiplication, the surface oxidation of black phosphorusis related to the degradation mechanism and environmental instability,20 while the surface oxidation of the topologicalinsulators serves to protect the surface states.22 Moreover, since the topological insulators are Dirac fermion materialslike graphene, a Dirac-source field-effect transistor can be realizedwith the graphene/topological insulator heterostructures.23Hybridgraphene systems combined with mixed-dimensional materialsfor high-sensitivity broadband light detection have emerged from recentdevelopments by assembling materials into van der Waals heterostructures.7 However, the photodetectionperformance using this method is highly sensitive to the size, thickness,and quality of the interlayer, which makes the fabrication processchallenging. As an alternative pathway free from introducing an interlayer,the natural oxidation layer rapidly formed on the surface of topologicalinsulators22 in the ambient environment canbe utilized as the tunneling barrier.26 In particular, the thicknessof the oxidation layer of the topological insulators is saturatedwithin a few hours after exfoliation, and the oxidation process issignificantly delayed over time so that a uniform oxidation layercan be obtained over the entire surface.22Recent studies reported the control overthe dark current in graphene-basedphotodetectors by introducing an interlayer  tunnelingbarrier with enhanced photodetectivity.2Se3 heterointerface enablesincorporation of the quantum tunneling effect into the photodetectionmechanism, as evidenced by the transition of charge carrier transportmechanisms from direct tunneling to Fowler–Nordheim (FN) tunnelingand/or thermionic emission. In our device architecture, the photogatingeffect in the graphene/Bi2Se3 heterochannelis coupled to the photovoltaic effect through the rectifying tunnelingjunction. This significantly enhances the photodetection performance,which is fundamentally different from the typical graphene-based photodetectorspreviously reported.4 Accordingly, the normalized photocurrent-to-dark current ratio (NPDR)is enhanced by around an order of magnitude via electrical tuningof tunneling resistance for detection of light covering the majorphotonic spectral region from the visible to the mid-infrared wavelengths.Our work provides a new perspective on both the tunneling dark currentsuppression and the efficient photocurrent generation for variousphotonic and optoelectronic applications.Here, we demonstrate that the naturally formed oxidation layerat the graphene/Bi2Se3 heterostructure . The Eg2 peak intensity mapping imageof the Bi2Se3 flake . On the other hand, the 2D peak intensitymapping image of graphene, as shown in 2Se3 flake .Our Dirac-sourcefield-effect transistor based on a lateral heterochanneland a vertical tunneling junction is realized by the graphene/Bicroscopy 1b and Raayer see S1a. On t2Se3 flake canbe clearly identified by the AFMimages, as shown in S2. The average thicknessesof the graphene and Bi2Se3 flakes, measuredby AFM, are ∼1.3 and 29.2 nm, respectively (see the Supporting Information for more details on theAFM)29.The graphene layer covering thesurface around the edge of Bi2Se3 (Bi: 5d and Se: 3d) takenafter 24 h from exfoliation. The observed oxidation peaks correspondingto Bi2O3 (at around 26 and 29 eV) and SeO2 (at around 59 eV) represent the existence of the oxidationlayer naturally formed on the Bi2Se3 surface.22 The intensity of the SeO2 peak ismuch lower than that of the Bi2O3 peak, indicatingthat the dominant oxidation layer formed on the Bi2Se3 surface is Bi2O3 rather than SeO2 due to the Se vacancies on the Bi2Se3 surface.32 Note that the oxidation time of 24 h after exfoliationunder ambient conditions is set to utilize the uniform oxidation layerwith the stabilized thickness. Although the formation of the nativeoxidation layer is very fast at the initial stage after exfoliation,22 its thickness is known to saturate since the oxidation process issignificantly delayed over time due to the interplay between surfaceexposure and oxygen incorporation.22 Thethickness of the oxidation layer is estimated as ∼2 nm (±0.2nm).2613 First, we investigated the current–voltage (I–V) characteristics of the graphene/Bi2Se3 heterojunction by choosing different metalelectrodes (see the 2Se3 heterointerface (definedas graphene-Bi2Se3), the I–V curves exhibit the nonlinear I–V relationship  dueto charge carrier transport through the graphene/Bi2Se3 heterointerface. The asymmetric rectifying behavior indicatesthat the tunneling junction is formed at the interface, and the tunnelingbarrier heights are asymmetric. The hysteresis effect of I–V curves arises from charge trapping atthe interface. For comparison, we also measure a reference graphenetransistor (defined as graphene&Bi2Se3),where both source and drain are applied to the graphene channel thatpartially covers the Bi2Se3 flake (see the Supporting Information for details on the measurementconfiguration with different electrodes). The I–V curves, as shown in Figure S3a, reveal the typical Ohmic behavior in the reference graphene transistor.Thevan der Waals heterostructures can enable versatile functionalitieswith higher performance than each material in the van der Waals heterostructures.2Se3, as shownin IDS–VDS curve(drain–source current IDS as afunction of drain–source voltage VDS) at gate–source voltage VGS =0 V is divided into nine steps, which are marked by Roman numeralsfrom I to IX. Each step represents the transition point, where thetransport mechanism changes and the resistance state switches to differentresistance states. The oxidation layer naturally formed on the Bi2Se3 surface is known to act as a tunneling barrierin contact with graphene.26 The tunneling resistance is closely related to thepotential barrier at the interface and the electronic density of statesin graphene and Bi2Se3. Hence, the shape deformationof the asymmetric tunneling barrier will have a great influence onthe tunneling current across the interface. The energy band alignmentsbefore equilibrium and between each step is drawn in 36 . The detailed descriptions forthe hysteretic I–V characteristicsand charge carrier trapping processes at the graphene/Bi2Se3 interface can also be found in the Supporting Information.38 Further details onthe energy band alignment are fully discussed in the Supporting Information.46To understand the mechanism of asymmetric rectifying and hystereticcharacteristics of the graphene-Bi4 On the contrary, in our device, the photogating effect is coupledto the photovoltaic effect through the rectifying tunneling junctionacross the graphene/Bi2Se3 heterointerface,which is supported by the observation of asymmetric rectifying andhysteretic I–V characteristics,as shown in 49 Some of the photogenerated carriers accumulated atthe trap states can act as an external bias voltage to shift the Fermi-levelof graphene, and the other carriers injected into graphene or Bi2Se3 will contribute to the photocurrent. On theother hand, the photovoltaic effect is driven by separating photogeneratedelectron–hole pairs through the rectifying junction, whichcan be further controlled by tuning the tunneling resistance.7 Before exploring the photogating effect, we first characterizedthe enhanced photocurrent with the photovoltaic effect, owing to therectifying tunneling junction, as shown in Figure S3. Interestingly, under the same condition of light illumination(at a wavelength of 532 nm with a laser power of 10 μW) focusedonto the same graphene/Bi2Se3 heterojunctionregion, much higher photocurrent is realized through the graphene/Bi2Se3 heterointerface , as compared tothe reference graphene transistor . This is because thephotocurrent generated in the reference graphene transistor is hinderedby the carrier recombination within the graphene channel, while thephotocurrent of the rectifying tunneling junction formed through thegraphene/Bi2Se3 heterointerface is enhancedwith the photovoltaic effect.Most graphene-based photodetectors generallyfocus on one photodetectionmechanism: photovoltaic effect, photogating effect, photo-thermoelectriceffect, and bolometric effect, due to their inherent limitations.VDS in our graphene/Bi2Se3 heterochanneldue to the strong coupling between the photogating and photovoltaiceffects. Here, two different VDS (0.5and 1.5 V) are chosen to define the high and low tunneling resistancestates. Both exhibit high photocurrents, but dark currents are obtainedto be considerably different for a proper comparison. Note that thisis based on the color plots of IPC, asshown in IPC = Ilight – Idark is the photocurrent, Ilight is the drain–source current underlight illumination, and Idark is the drain–sourcecurrent in the dark. In addition, it is found to be more effectivefor modulating the tunneling resistance by tuning positive VDS along the Bi2Se3 side,due to the lower barrier height for electrons on the graphene sidethan that toward the Bi2Se3 side, as estimatedin VDS = 0.5 V), the direct tunneling from graphene to Bi2Se3 will be substantially blocked by the tunneling barrier underthe dark condition, while the photoexcited electrons in graphene canbe easily injected into Bi2Se3 over the lowbarrier height. On the other hand, at the low tunneling resistancestate (VDS = 1.5 V), the dark current ascribed to theFN tunneling and thermionic emission will exceed the current due tophotoexcited electrons. As a result, the dark current will be obtainedto be extremely lower in the high tunneling resistance state (2Se3 heterojunction at VDS = 0.5 V (at a wavelength of 532 nm with a laser power of 100 μW).The photocurrent generation is pronounced around the heterojunctionregion especially near the edge of the graphene channel overlappingthe Bi2Se3 flake, confirming the major photocurrentgeneration originating from the heterointerface due to the built-inelectric fields applied across it.We also find that the tunnelingresistance can be significantly tuned by varying ce state 4b than tce state 4c. As shIDS as a function of VGS) of the graphene/Bi2Se3 heterointerfacein the dark and under light illumination at various wavelengths of532, 730, 1550, and 4000 nm with a light power of 10 μW areshown in VDS = 0.5 V) and VDS = 1.5V). The graphene/Bi2Se3 heterochannel operatesas a field-effect transistor, where the carrier mobility depends onthe tunneling resistance. The high (VDS = 0.5 V) and low (VDS = 1.5 V) tunnelingresistance states lead to the different average carrier mobilitiesof 36.8 and 103.2 cm2 V–1 s–1 for holes and 12.6 and 64.1 cm2 V–1 s–1 for electrons at room temperature, respectively.From the shift of VDirac, we estimatedthat the photogating effect is attributed to the trapping of photogeneratedcarriers at the graphene/Bi2Se3 interface (seethe Supporting Information for detailson the photogating effect due to the trapping of photogenerated carriers).As shown in the transfer curves, there are almost no hysteresis effectsfor the VGS sweep, thanks to the Al2O3 top passivation layer,50 implying that charge trapping at the graphene/Bi2Se3 interface only occurs during the VDS sweep. In particular, the tunneling dark current is obtained tobe quite low, as shown in Ilight/Idark). At VGS = 0 V, althoughthe photocurrents (IPC = Ilight – Idark), asshown in IPC, where Ilight = Idark, does not appearin Ilight to Idark. Unlike thephotogating effect in which one type of photogenerated carriers shouldbe captured in trap states, the photovoltaic effect requires the efficientseparation of created electron–hole pairs. Our results suggestthat the tunneling junction in the graphene/Bi2Se3 heterochannel can be utilized to couple the photogating effect withthe photovoltaic effect to enhance the optical switching ratio bytuning the tunneling resistance.The transfer curves(2Se3 is confirmed by photoresponsivity (R = IPC/Peffective) and photodetectivity . Onthe contrary, the photoresponse characteristics of the reference graphenetransistor  is almost unchangedbetween VDS = 0.5 and 1.5 V. In otherwords, the light absorption in the graphene/Bi2Se3 heterostructure does not guarantee the high photodetectivity. Thishighlights that the charge carrier transport through the graphene/Bi2Se3 tunneling junction is of great importance tocouple the photogating effect with the photovoltaic effect in thegraphene/Bi2Se3 heterochannel for highly sensitivephotodetection.Depending on the tunnelingresistance, the electrically tunable photoresponse of graphene-Biectivity 5b, , whenterface5b can beI) at VDS = 0.5 V and VGS = 0 V is plottedin Supporting Information for details on the relation between light powerand responsivity).514, 6.6 × 103, 3.8 × 103, and 1.1 × 103 W–1 (at VDS = 1.5 V) to ∼2.2 × 105, 1.1 × 105, 3.5 × 104, and 8.0 ×103 W–1 (at VDS = 0.5 V) by effectively suppressing the tunneling dark current.The idea of tuning the tunneling resistance for enhancing the photodetectivityoffers a new insight to realize the broadband photodetection by couplingthe photogating effect with the photovoltaic effect.52The dependence of photoresponsivityon light intensity  to FN tunneling and/or thermionic emission at the high biasvoltage (low tunneling resistance state), as described in 2Se3 junction.As an alternative pathway free from an artificial introduction ofan interlayer at the interface, our findings demonstrate a new perspectiveof utilizing the oxidation layer naturally formed at the graphene/Bi2Se3 interface for both dark current reduction andefficient photocurrent generation. We confirmed that the naturallyformed oxidation layer can act as a tunneling barrier. We furtherobserved the tunable tunneling resistance and offered direct evidencefor the asymmetric tunneling barrier heights using the tunneling equations.36 An additional advantage of utilizing the naturally formed oxidationlayer is that this approach is not limited by the size, thickness,and quality of the interlayer so that large-scale devices are achievableas long as Bi2Se3 is large enough, making theentire fabrication process simple. This is similar to the currentsilicon technology, where naturally formed silica plays a key role.Another novelty of our work is describing the transition of chargecarrier transport mechanisms through the graphene/Bi2Se3 interface, which is essential for coupling between photogatingand photovoltaic effects. To the best of our knowledge, the hysteresiseffect of I–V curves in graphene/Bi2Se3 heterojunction is first observed in this work,implying the trapping of charge carriers at the interface. This observationsuggests that the trap-assisted photogating effect can be inducedin the graphene/Bi2Se3 heterochannel by trappingof photogenerated carriers,49 which can be coupled with thephotovoltaic effect to effectively enhance the photocurrent owingto the rectifying tunneling junction.7In other studies, several attempts have been madeto control thedark current by utilizing the ultrathin interlayer such as Ta2Se3 interface,26 we have explored a breakthroughway to improve the photoresponse characteristics of the graphene/Bi2Se3 heterochannel by suppressing the tunnelingdark current and injecting the photogenerated carriers. We have foundthat the tunneling resistance of the graphene/Bi2Se3 heterojunction can be tuned to couple the photogating effectwith the photovoltaic effect in the graphene/Bi2Se3 heterochannel. The transition of charge carrier transportmechanisms through the graphene/Bi2Se3 interfaceis a key signature to modulate the optical switching ratio.7 The practical application to improve the device performance throughthe interface engineering  or the materialcombination , which is beyond the scope of this study, willbe a promising research direction. This study will provide usefulinformation for designing novel photodetectors for highly sensitivebroadband photodetection.Based on the asymmetric tunneling barrier formed at the graphene/Bi2Se3 into van der Waals heterostructures. The Bi2Se3 flakes were mechanically exfoliated from bulkmaterial and transferred onto the highly doped Si substrates witha 285 nm thick SiO2 layer preprocessed with solvent cleaningand O2 plasma treatment. The Bi2Se3 flake surface was naturally oxidized under ambient conditions for24 h. Owing to the rapid surface oxidation of topological insulators,22 there was no need to introducean additional interlayer such as an insulating layer grown by atomiclayer deposition (ALD) or h-BN layer before the graphene transfer.In order to form several heterostructures on each substrate at thesame time, large-area monolayer graphene grown by chemical vapor deposition,purchased from Graphenea, was wet-transferred onto the substrates.42 For the complete and smooth coverage of the graphene layer overthe entire Bi2Se3 flake, we selected the Bi2Se3 flakes with a few tens of nanometer thick,which allowed us to minimize the defects caused by the steep surfacemorphology around the flake edges. Each graphene channel was patternedto a regular shape with electron beam lithography  and reactive ion etching (Oxford Instruments PlasmaLab 80 Plus).The lateral heterochannel was defined to be the patterned grapheneribbon and transferred Bi2Se3 flake, while thevertical tunneling junction was formed in the overlapping regions.The heterojunction area was estimated to range from 50 to 100 μm2, with an average of 83.7 μm2. Ti/Au electrodesof 5/75 nm were patterned with EBL and deposited through electronbeam evaporation (MASA IM-9912) followed by a lift-off process. Themetal electrodes on the graphene channel and Bi2Se3 flakes were patterned to be orthogonal and parallel to thegraphene channel, respectively. As a passivation layer, a 10 nm thicklayer of Al2O3 grown by ALD at 150 °C was used to prevent the surface modification from theadhesion of oxygen or water molecules. After completing the devicefabrication, an optical microscope (Olympus BX60) and Micro-Raman(WITec Alpha 300 RA+) system using 532 nm continuous wave laser wereused to characterize the graphene/Bi2Se3 heterostructure.The graphene covering the Bi2Se3 flake edgewas identified by AFM Dimension Icon (Bruker). XPS was performed onthe large area Bi2Se3 flakes using a KratosAxis Ultra ESCA spectrometer with a monoenergetic Al Kα (1486.96eV) source. The pass energy was ∼20 eV, and the X-ray spotsize was ∼200 μm. Since X-rays penetrate only the topfew layers of flakes, the XPS is useful for quantitative analysisof the surface chemical composition (the outer few nanometers) regardlessof the flake thickness.Our heterojunctionphototransistor was fabricated by integrating graphene and Bi2Se3 flakes. Thephotocurrent measurements covering from the visible range to near-infraredrange were conducted in the WITec system combined with two sourcemeters.The light beams from continuous wave lasers at 532 nm (WITec focusinnovations), 730 nm (Thorlabs MCLS1), and 1550 nm (Photonetics) werefocused onto the heterojunction through an objective lens . The optical microscopy platform system allowed us to focusthe laser beam on desired positions in the sample. The diameters ofthe light spot were around 0.87, 1.18, and 2.49 μm, respectively.The photocurrent measurements in the mid-infrared range were conductedin a home-built femtosecond laser-based microscopic system combinedwith two sourcemeters. The duration and repetition rate of the incidentpulse were 230 fs and 2 kHz. The laser at 4000 nm is focused to coverthe graphene/Bi2Se3 heterojunction region bya parabolic mirror. The diameter of the light spot was ∼20μm.The sample holder was designed in a sizefitting into a fixingholder in a probe stage. After device fabrication, the device chipswere mounted onto each printed circuit board (PCB) attached to thesample holder and wire-bonded to the PCB. All the electrical measurementswere carried out in an optical microscope (WITec Alpha 300 RA+) ora home-built femtosecond laser based microscopic system with two sourcemeters(Keithley 2400 and 2401) at room temperature under ambient conditions.The gate voltage was applied to the Si substrate, while the sourceand drain voltages were applied to the metal electrodes connectedto the graphene channel or Bi


Graphene is an excellent 2D material that has extraordinary properties such as high surface area, electron mobility, conductivity, and high light transmission. Polymer composites are used in many applications in place of polymers. In recent years, the development of stable graphene dispersions with high graphene concentrations has attracted great attention due to their applications in energy, bio-fields, and so forth. Thus, this review essentially discusses the preparation of stable graphene–polymer composites/dispersions. Discussion on existing methods of preparing graphene is included with their merits and demerits. Among existing methods, mechanical exfoliation is widely used for the preparation of stable graphene dispersion, the theoretical background of this method is discussed briefly. Solvents, surfactants, and polymers that are used for dispersing graphene and the factors to be considered while preparing stable graphene dispersions are discussed in detail. Further, the direct applications of stable graphene dispersions are discussed briefly. Finally, a summary and prospects for the development of stable graphene dispersions are proposed. In graphite, single layers of graphene are stacked into many layers by π–π interactions. Graphene is an allotrope of carbon where sptructure ,2. Graphtructure . Graphentructure , highly tructure ,6, and ttructure , it has tructure , and is tructure . Graphentructure , conducttructure ,12, flextructure , electrotructure , sensingtructure , and drutructure . GeneralThe chemical vapor deposition (CVD) process is a straightforward method to prepare graphene, although special types of equipment are needed. In this method, gaseous molecules are deposited on a substrate which are used to grow graphene. The gaseous molecules are combined in the reaction chamber at ambient temperature where they come into contact with the substrate, producing graphene on the substrate ,18. The Pyrolysis is a solvothermal method used for the chemical synthesis of graphene in a bottom-up process. Thermal reactions of sodium and ethanol are carried out in a closed vessel, graphene sheets were successively detached by sonication . PyrolysSelf-assembly is a bottom-up method. Here, graphene is prepared by self-assembling the carbon molecules using sugar derivatives or organic molecules as a carbon source ,25. For Epitaxial graphene on silicon carbide (SiC) is a sublimation process whereby heating SiC to high-temperature results in graphene ,28. In tThe chemical exfoliation method is a top-down method for the synthesis of graphene. Chemical exfoliation includes two steps, the interlayer distance between graphene layers is first increased, then, by using the intercalating compounds, graphites are exfoliated and thus single-layered graphene is produced . GraphenMechanical exfoliation is a top-down method considered as a simple method for the synthesis of graphene. In graphite, graphene layers are stacked by the Van der Waals force, the Van der Waals forces are weakened by sonication, leading to exfoliation. Thus, graphene layers can be prepared from graphite by mechanical exfoliation techniques including micromechanical cleavage using Scotch tape , ultrasoThere are many reviews available about graphene, its derivatives, and its composites for different applications ,51,52,53D = 18.0 MPa1/2, δP = 9.3 MPa1/2, or δH = 7.7 MPa1/2. The Hildebrand solubility parameters are the sum of D, P, and H Hansen parameters or the square root of the cohesive energy density [N-formyl piperidine, vinyl pyrrolidone, 1,3-Dimethyl-2-imidazolidinone, bromobenzene, benzonitrile, N-methyl-pyrrolidone (NMP), benzyl benzoate, N-N′-dimethylpropylene urea, γ-butyrolactone (GBL), dimethyformamide (DMF), N-ethyl-pyrrolidone, dimethylacetamide, cyclohexylpyrrolidone, dimethylsulfoxide (DMSO), dibenzyl ether, isopropylalcohol (IPA), chlorobenzene, 1-octyl-2-pyrrolidone, 1-3 dioxane, ethyl acetate (EtOAc), quinoline, benzaldehyde, ethanolamine, diethyl phthalate, N-dodecyl-2-pyrrolidone, pyridine, dimethyl phthalate, formamide, ethanol (EtOH), vinyl acetate, acetone, water, ethylene glycol, toluene, heptane, hexane, and pentane have been demonstrated [2 and 23 Mpa1/2, respectively. Solvents that have similar surface tension to graphene will be effective in preparing stable graphene dispersions. The energy required to exfoliate graphite into graphene is balanced by the surface energies of the solvent and graphene [Graphene is used in various fields; however, many applications need graphene dispersions instead of graphene powders. Graphene flakes, after exfoliation from graphite by ultrasonication, aggregate because of the Van der Waals force between graphene layers . Thus, r density . Differe density ,68. Grapnstrated . Graphennstrated . The stugraphene . The pol−1, respectively, showed stable dispersions. Further, these ionic liquids partially exfoliate graphite into single or few-layered graphene [Other than normal solvents, ionic liquids such as 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide and 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide, which have surface tensions of about 30 and 40 mN.mgraphene . This diPretreated graphite flakes by tip sonication, and subjected to bath sonication, attained graphene concentrations up to 20 mg/mL. Re-dispersion of pretreated graphene results in good quality graphene dispersions with concentrations of at least 63 mg/mL . Even afTo overcome the difficulties in preparing stable graphene dispersion using solvents, surfactants are used. As discussed in the earlier sections, stable graphene dispersions can be prepared only if the solvent’s surface tension and Hildebrand solubility parameters match graphene’s parameters. To prepare stable graphene dispersions using a solvent that does not match graphene’s parameters, surfactants are added. The electrostatic attraction or intermolecular force between surfactants and graphene helps in stabilizing the graphene surface with surfactants and for the even distribution of graphene in the solution.Highly stable graphene dispersion and exfoliation of graphite were obtained using PVPyr with soap solution . NaphthaIn this section, graphene dispersions using polymers are discussed further. As in the earlier sections, factors to be considered for the preparation of stable graphene dispersions using polymers  are discThe polymers poly(4-vinyl pyridine)-block-poly(ethylene oxide) (PVP-b-PEG) and poly-block-poly(4-vinyl pyridine) (PTFEMA-b-PVP) were prepared using chosen monomers . Then the prepared polymers (PVP-b-PEG and PTFEMA-b-PVP) were used to disperse graphene in alcoholic and aqueous mediums. As well as dispersing graphene, using these polymers, graphite was partially exfoliated into few-layered graphene ,118,119.PVPyr with a molecular weight of 10,000 g/mol was used to disperse expanded graphite in different solvents DMF, DMSO, NMP, water, EtOH, and MeOH . PVPyr dGraphene–polymer composites can be studied by several techniques such as transmission electron microscope (TEM), scanning electron microscope (SEM), atomic force microscope (AFM), X-ray diffraction (XRD), Raman spectroscopy, Turbiscan, and thermogravimetric analyses (TGA). −1) corresponds to the sp2 graphitic carbon. The D band (~1355 cm−1) is mainly generated due to the breathing mode of aromatic rings from the backbone and the band around 2700 cm−1 is referred to as a 2D band, a second order of the D band. Broader G and D bands reflect higher disorder in the graphitic nature. The D band will be barely visible and the 2D band will be sharp in single-layer graphene [D/IG will be 0.3 for pristine graphene, an increase in this value for composites suggests defects on edge or base [D/IG values for GO-SDBS/SDS composites compared to GO suggests a decrease in defects [Briefly, TEM and SEM analyses reveal the morphology and size of graphene sheets, and the elements that are present on graphene sheets by elemental mapping. In addition, TEM and SEM studies will suggest the thickness of graphene sheets. As with TEM and SEM analyses, AFM can be used to study the morphology of graphene–polymer composites. The height profile will provide the thickness of graphene sheet from which one can calculate the number of graphene layers. Graphene exfoliated using a mixture of water and alcohol showed graphene sheets with lateral dimensions between several hundred nanometers and micrometers from AFM and TEM measurements. Cross-sections of graphene sheets by TEM showed step heights of ~0.9 and ~0.57 nm suggesting the presence of mono- and bi-layered graphene sheets, respectively . Typicalgraphene ,135,136.graphene . The shigraphene . The brographene . General or base . A decre defects . In orde defects ,137,138. defects ,140,141.−3 S/cm compared to rGO alone [g of 43.2 MPa, 2.62 GPa, and 105 °C, respectively [3, porosity of about 98.8%, a contact angle 142° revealing the hydrophobicity of the surface, and adsorption capacity increase to 96 times its own weight [−2 was attained [−1 [Graphene–polymer composites improve the properties of pristine polymer materials ,143,144.GO alone . pH- andGO alone . NanofibGO alone . 1D singGO alone . GraphenGO alone . FreestaGO alone . GO modiGO alone . GraphenGO alone ,155,156.GO alone ,158. GO GO alone . The effGO alone . CompareGO alone . GraphenGO alone . GO–polyGO alone . The effGO alone . DispersGO alone . DiffereGO alone . Bio-basectively . Graphenectively . Cellulon weight . Moreoven weight . Ultra-hn weight . Anilineattained . Li and ined [−1 . A diameined [−1 . Homogenined [−1 . The comined [−1 . Many applications of polymer–graphene composites exist, however, only applications such as 3D printing, scaffolds, coating, and supercapacitor are discussed where graphene dispersions are directly utilized .3D printing has developed a method of fabricating complex structures that cannot be reached by other methods . 3D prin2+ [−5 mm per year [Graphene coating applications have multiple advantages such as increasing the resistance to oxygen and water, improving electrical and thermal conductivities, increasing the hydrophobicity on the surface, and preventing scratching and abrasion. However, the presence of the polymer along with graphene helps their use in coating applications ,194,195.2+ . Graphenper year . Graphenper year . The antper year . −1 at a current density of 0.5 A g−1 [−1 at a current density of 1 A g−1. Polymer–graphene composites are widely used in energy storage applications. Polymers play an important role as binders in preparing electrodes. However, the usual binders such as polyvinylidene fluoride and polytetrafluoroethylene are not conductive which can decrease the energy density of supercapacitors . Thus, c.5 A g−1 ,213. Hyd2 sensor [2 g−1 was observed using a GO/PU sponge [3 g-1 [Graphene–polymer can be used to prepare thin films which find applications such as sensors, shielding, field-effect transistors, photodetectors, and gas separation membranes . A thin 2 sensor . Graphen2 sensor ,217. Thi2 sensor . The pre2 sensor . Thin fi2 sensor . rGO/CNC2 sensor . An rGO 2 sensor . PU sponU sponge . GraphenU sponge . PEDOT: e [3 g-1 . Monolaye [3 g-1 . A smarte [3 g-1 . Ondansee [3 g-1 . Electroe [3 g-1 . In addie [3 g-1 ,228,229.2) and solubility parameters . Surfactants are added to prepare stable graphene dispersions if the solvent’s surface tension and solubility parameters do not match with graphene’s parameters. In stable graphene dispersions using surfactants, electrostatic attraction or intermolecular force between surfactants and graphene surfaces are involved. Graphene with surfactants restricts the applications, thus combining polymers with graphene opens the way for the involvement of graphene dispersions in various applications. To prepare stable graphene dispersion using polymers, the interaction or affinity between polymer molecules and graphene surface should be considered. Thus, in this review adhesion forces between different types of monomers and graphene surfaces were included. The graphene dispersions which are directly used for applications were briefly discussed. This review further opens the way for future perspectives on the factors to be considered while choosing, solvents, surfactants, or polymers to stabilize graphene surfaces. However, further studies are to be concentrated on the investigation of the interaction between stabilizing molecules and graphene surfaces. If we know the interaction between stabilizing molecules and graphene surfaces, we can tune the graphene surfaces with an appropriate stabilizer for particular applications. Therefore, understanding the interactions is very important and this information is lacking. With this understanding, several milestones can be achieved, which will help to design and develop polymers, and molecules to prepare stable graphene dispersions with high graphene concentrations.Graphene is used in the multidisciplinary fields and many reviews are available regarding graphene-based composites for various applications. However, there is a lack of information on the preparation of stable graphene dispersions. The preparation of stable graphene dispersions is still under investigation. In this review, the preparation of stable graphene dispersions in different solvents using different graphene sources was presented. The factors to be considered for the preparation of stable graphene dispersion were discussed. For preparing stable graphene dispersion using solvents, solvent’s surface tension and solubility parameters should match with graphene’s surface tension (40 mJ/m


To describe a case of pediatric sarcoidosis which initially presented as papillary conjunctivitis before manifesting as bilateral lacrimal gland swelling without other known systemic involvement.A 10-year-old female presented to the pediatric ophthalmology clinic with complaints of bilateral eyelid swelling, tearing and itching for approximately 1 month. Her history and exam were most consistent with allergic conjunctivitis, for which she was started on a standard topical regimen. Despite initial improvement, she re-presented with significantly worsened eyelid swelling and minimal allergic symptoms. Enlargement of the lacrimal glands were palpable at this time. Lacrimal gland biopsy was obtained which demonstrated noncaseating granulomas. Systemic workup did not reveal evidence of disease involvement elsewhere.Sarcoidosis in the pediatric population may present in a myriad of ways and is well-known to mimic other disease entities. We present a case of pediatric sarcoidosis which presented initially as papillary conjunctivitis before manifesting as bilateral lacrimal gland swelling without systemic involvement. Sarcoidosis is a multisystem disease characterized by granulomatous inflammation. Triggers of sarcoidosis flare with the T-cell-mediated inflammatory response are not known. Genetic associations and infectious or environmental triggers have been posited, however definitive links have not been determined. While pulmonary and skin involvement are most common in adult presentations of sarcoidosis, ocular involvement occurs in 25–60% of patients . HallmarNOD2) gene that causes the classic triad of uveitis, rash, and polyarthritis with onset in the first few years of life [The disease is typically diagnosed in adulthood; however, it may present at any age. Early-onset childhood sarcoidosis (onset at less than 5 years) is distinguished from later-onset or adult-type childhood sarcoidosis, which often demonstrates pulmonary and other systemic involvement. Blau syndrome, which may represent the same disease as early-onset childhood sarcoidosis, is an autosomal-dominant monogenic granulomatous syndrome associated with mutation in the nucleotide binding oligomerization domain containing 2  may provide additional support, but lack the sensitivity and specificity for definitive diagnosis , 4.A ten-year-old African-American female presented to the pediatric ophthalmology clinic in referral from her primary care provider for evaluation of bilateral eyelid swelling, tearing and itching for approximately one month. Her past medical history included premature birth, jejunal atresia with resection and jejuno-ileal primary anastomosis, short gut syndrome, asthma, and mild eczema. The patient’s birth history was complicated by Human Immunodeficiency Virus (HIV) positive testing of her mother, but with normal prenatal ultrasounds and negative congenital HIV testing, and was otherwise uncomplicated. Her family history included allergic rhinitis and asthma in her mother, and there was no known family history of sarcoidosis or granulomatous disease. The patient’s asthma was first suspected when she presented at seven months old with wheezing and cough that responded well to albuterol concerning for reactive airway disease. She is now followed by a pediatric pulmonologist for moderate persistent asthma with pulmonary function tests that revealed a moderate obstruction pattern with normal lung volumes and diffusing capacity of lung for carbon monoxide. She is treated with an inhaled corticosteroid for asthma control and albuterol as needed for symptom exacerbation.Her presenting ophthalmologic exam was notable for bilateral papillary conjunctivitis and mild superficial keratopathy, as well as mild boggy lid edema. She was started on ketotifen fumarate and artificial tears for presumed allergic conjunctivitis. Five months later at her follow-up exam, she had persistent symptoms and exam with giant papillary reaction of the palpebral conjunctiva of both upper eyelids. Upon referral to an allergist, she was found to have normal serum IgE level, and skin testing did not identify a likely allergen exposure. She had been diagnosed with eczema clinically in the past by her primary care provider and was confirmed by allergist. Inflammatory markers were elevated including sedimentation rate 38 mm/hr. (reference range 0–20 mm/hr) and C-reactive protein 4.18 mg/dL (reference range 0–1 mg/dL); however, serum ACE and lysozyme were normal, and chest radiograph did not reveal hilar lymphadenopathy. At this point, the worsening palpebral reaction and overall picture including history of atopic disease were felt to best support a diagnosis of vernal keratoconjunctivitis. She was started on a topical regimen including corticosteroid, olopatadine and tacrolimus ointment with mild improvement in lid swelling.NOD2 gene mutation associated with Blau syndrome was not performed due to lack of uveitis, rash, and arthritis seen in this disease.She was next seen approximately 6 weeks later when she presented to the pediatric emergency department with significant worsening of bilateral upper eyelid swelling Fig. . Her exaEight months after initial presentation, biopsy of the right lacrimal gland was performed in an anterior transseptal fashion through the temporal upper lid crease. Histopathologic evaluation of the lacrimal gland specimen demonstrated chronic-appearing inflammatory changes with poorly-formed noncaseating granulomas and widespread destruction of normal acini and gland structures. Staining for CD68 marker for epithelioid cells showed multiple foci of macrophage infiltration at sites of granulomatous inflammation consistent with sarcoidosis Figs.  and 3. SShe was started on treatment with oral prednisone ~ 2 mg/kg/day at the same time of the lacrimal gland biopsy 8 months after initial presentation with gradual improvement in upper eyelid swelling. Subcutaneous methotrexate 15 mg/m2 weekly was added to therapy 6 weeks later as a steroid-sparing agent, and she was able to taper off steroid over the next 2 months. Serial slit lamp exams have demonstrated no evidence of intraocular inflammation, iris nodules, or vascular changes. At the patient’s last visit, 28 months out from initial presentation, she had no other systemic manifestations of sarcoidosis and was doing well on methotrexate.Anterior uveitis is by far the most common ocular complication of sarcoidosis in both early- and late-onset childhood sarcoidosis, with estimated prevalence of 21–58% in childhood-onset sarcoidosis [Sarcoidosis presenting with ocular involvement alone makes the diagnosis a difficult one without tissue biopsy. Intraocular disease involvement is characterized by the International Workshop on Ocular Sarcoidosis (IWOS) criteria ; howeverThe lacrimal glands are the most commonly involved orbital structures in sarcoidosis, with reported prevalence of 42–63% in studies of orbital and ocular adnexal sarcoidosis –9, and 7Demirci et al found that only 37% of biopsy-proven orbital and adnexal sarcoidosis patients in their series had known systemic disease; over the course of follow-up, only half of these patients subsequently developed evidence of systemic disease [Mavrikakis et al described 20 patients, in 18 (90%) of whom orbital inflammation was the presenting symptom of sarcoidosis, with 2/20 (10%) demonstrating anterior uveitis prior to development of orbital symptoms. Over half  had lacrimal gland infiltration. Although 19/20 patients had histopathology consistent with sarcoidosis on orbital biopsy, only 50% subsequently demonstrated systemic disease, and of these 60% were asymptomatic [Yanardag et al found that 9 of 516 (1.74%) sarcoidosis patients had biopsy-proven lacrimal gland involvement. Five of these patients (55%) had no radiographic evidence of pulmonary disease, and 2 (22%) had no other systemic findings of sarcoidosis. Serum ACE was not measured [Review of the literature shows that lacrimal gland sarcoidosis associated with systemic disease is variable. Lacrimal gland biopsies performed at Wills Eye Hospital demonstrated histopathology consistent with sarcoidosis in 20% of patients without known systemic disease . Of thes disease . Mavrikaith 2/20 % demonstBelanger et al reported a case series of orbital inflammation in pediatric patients [Chlamydia infection based on history and presentation. This literature review of isolated lacrimal gland sarcoidosis at presentation highlights the importance of close monitoring over time for the evolution of systemic disease.While all the studies above described adult or mixed patient populations, patients . Two-thiThe reason why the lacrimal gland is so frequently involved in sarcoidosis is unclear. Like the parotid gland which is also commonly involved in sarcoidosis, the lacrimal gland is also an exocrine gland and has similar structure with acinar cells and mucus tubules. They both have important functions in lubrication and protection from the external environment. However, genetic and immunological characteristics of these glands that increase susceptibility to sarcoid disease are unclear.Mombaerts et al published a case series of seven patients with orbital granulomatous inflammation, none of whom had systemic evidence of sarcoidosis at presentation or at follow-up (study average 9.5 years). All cases were unilateral, and most presented with pain. Patient age ranged from three to 65 years. The authors classified these patients as representative of a “granulomatous variant of orbital pseudotumor.” In this study, the authors argued against labeling isolated orbital granulomatous disease as a limited or forme fruste sarcoidosis on the basis of both non-granulomatous and granulomatous components of inflammation in the studied specimens, as well as unilateral presentation, extralacrimal inflammation (not involving optic nerve or extraocular muscles), and normal serum ACE levels [In the absence of systemic findings, some authors debate whether a diagnosis of sarcoidosis can be made. E levels . OrbitalE levels . ResponsWhile bilateral lacrimal gland enlargement has been described as a presenting sign of sarcoidosis in adults, this presentation in pediatric patients is less well-represented in the literature. This case is unusual for a presentation of significant bilateral lacrimal gland swelling with histopathologic evidence of noncaseating granulomas in the absence of definitive systemic signs of sarcoidosis. Additionally, the presentation of giant papillary conjunctivitis with subsequent lacrimal gland inflammation consistent with sarcoidosis has not been reported in the literature. Although it is certainly possible that our patient suffered from allergic conjunctivitis simultaneously with sarcoid-associated lacrimal gland inflammation, it is noteworthy that with worsening lacrimal gland inflammation, she had persistent giant papillary reaction in the temporal palpebral conjunctiva, without significant allergic symptoms. This case agrees with the existing literature in that sarcoidosis can have diverse presentations, and tissue diagnosis may be essential to diagnose even if laboratory and radiographic evidence are lacking. Systemic disease may develop late so long-term monitoring and interdisciplinary management are crucial to optimize outcomes.


The COVID-19 pandemic prompted widescale use of clinical simulations to improve procedures and practices. We outline our deployment of a virtual tabletop simulation (TTS) method in primary care (PC) clinics across Alberta, Canada. We summarise the quality and safety improvements from this method and report end users’ perspectives on key elements.Our virtual TTS used teleconferencing software alongside digital whiteboards to walk clinic stakeholders through patient scenarios. Participants reviewed and rehearsed their workflows and care practices. The goal was for staff to take ownership over gaps and codesigned solutions. After simulation sessions, follow-up interviews were conducted to collect feedback.These sessions helped PC staff identify and codesign solutions for clinical hazards and threats. These included the flow of patients through clinics, communications, redesignation of physical spaces, and adaptation of guidance for cleaning and personal protective equipment use. End users reported sessions provided neutral spaces to discuss practice changes and built confidence in delivering safe care during the pandemic.TTS has not been extensively deployed to improve clinical practice in outpatient environments. We show how virtual TTS can bridge gaps between knowledge and practice by offering a guided space to rehearse clinical changes. We show that virtual TTS can be used in multiple contexts to help identify hazards, improve safety and build confidence in professional teams adapting to rapid changes in both policies and practices. While our sessions were conducted in Alberta, our results suggest this method may be deployed in other contexts, including low-resource settings. COVID-19 has strained healthcare systems globally.In Alberta, COVID-19 pandemic simulations initially prioritised acute care settings, focusing on emergency departments and critical care units. This prioritisation was based on an assumption that acute care facilities would experience the largest and most immediate patient surges.Outside the acute care system, however, there was neither a capacity to deliver simulations nor familiarity among community-based clinicians with their methods and aims. As independent fee-for-service contractors to the provincial ministry of health, Alberta’s PC physicians fall outside AHS’ purview and thus the reach of AHS-led simulations. Despite a growing need for guidance on how to deal with the ‘seismic effect’This prototyping and scaling work relied on theory that assumes ‘latent conditions’We begin with a detailed description of the PC-focused TTS sessions, which our team prototyped, piloted and scaled over the course of the pandemic. Specifically, we describe the preparation, facilitation and debriefing components of the method. We next summarise the quality and safety improvement outcomes from the simulation sessions. We then present the results of a thematic analysis of follow-up interviews focused on end users’ experiences of the novel method. Our analysis shows that end users found the method valuable, particularly in its balance between facilitative codesign and authoritative expertise. We conclude by highlighting the value of virtual TTS to improve IPC policy implementation in PC settings. We suggest this underutilised method may be of value to multiple user groups to improve pandemic preparedness and response.Our research team conducted 20 TTS with PC teams across Alberta from April 2020 to April 2021. A total of 163 PC team members attended these sessions , and a sample of 10 participants participated in follow-up interviews. Of the PC clinics that participated, 9 were rural and 11 were urban. These numbers also include urgent care clinics that functioned both as primary and acute care centres in rural settings.The first two TTS were completed in person, with the use of a printed floor plan and tokens, and facilitated by an HF-qualified moderator (MJB), with an additional research team member taking notes on a whiteboard. As the pandemic progressed and inperson meetings were curtailed by public health measures, we transitioned to virtual sessions that used teleconferencing and interactive whiteboard software to provide similar interactivity. These virtual sessions were facilitated by the same moderator and supported by a medical advisor with a combination of IPC and HF experience (JMD). Participants from both inperson and virtual TTS sessions were included in our analyses.After making initial contact with an interested PC clinic, our team shared a two-page document outlining the value proposition, methodology and action points of an IPC-focused TTS in the pandemic context . Clinics10.1136/bmjstel-2020-000854.supp1Supplementary dataTaking an engaged scholarship approach,Before the TTS, an email with step-by-step instructions was sent to all participating clinic staff , who wer10.1136/bmjstel-2020-000854.supp2Supplementary dataAs part of the contact and intake process, the moderator encouraged a variety of stakeholders to attend and participate in the sessions as a way to improve cross-team understandings of roles, promote cohesion and improve buy-in for ownership of developed solutions. Within these recommendations, PC clinics nominated key personnel to participate in TTS sessions. These included clinic personnel who were involved in either direct patient care or the creation and implementation of policies and procedures within or across clinics. Physicians, registered nurses, operations coordinators, medical office administrators and clinic managers all participated.In an effort to balance representation from across the clinic with conversational efficiency, participation was capped at eight, with a minimum of four participants required for optimal interactivity and exchange. In addition, an unlimited number of non-participant observers could also attend the sessions. Observers included clinic administrators, members from the clinic who were not selected to participate, healthcare staff from other clinics and members of our research team. Observers were asked to refrain from participating in the sessions unless the moderator or other participants asked for feedback during scenarios or the debrief. This was planned to allow participants to be able to elaborate on their thinking and decision making without interruption.Sessions lasted for 2–3 hours. Participants were first invited to familiarise themselves with the MURAL workspace by using a purpose-built introductory page. This page allowed them to experiment with icons, tokens and other whiteboard functions in a neutral space. The moderator then began each session by providing an overview of the TTS objectives that emphasised the neutral, non-evaluative nature of the session and highlighted it as an opportunity to identify and codevelop solutions to hazards and threats. This set up a confidential, mutually respectful and quality improvement (QI) focused environment to work in. Once participants were comfortable with the MURAL workspace, the moderator introduced the next page that showed both the simulation agenda and the learning objectives for the session.The moderator and the medical advisor then guided the participants through the preselected clinical scenarios, asking them to move avatars through the MURAL whiteboard space and stopping at critical junctures to ask IPC-focused questions. Our approach here relied on the principles of ‘cognitive walkthroughs’, a usability evaluation method often used in the field of HF engineering and user design.Both the moderator and the medical advisor were well versed in AHS and local IPC policies and best practices. As such, they acted both as facilitators and consultants. In this way, the hazards and threats identified during sessions led to solutions codesigned by the participants with moderator and medical advisor input. Examples here included the designation of ‘dirty’  examination rooms or the placement of hand hygiene stations. In instances where solutions were unclear, or disagreements about changes to structure or process occurred, the moderator facilitated conversations focused on achieving workable consensus.A minimum of 20 minutes was reserved at the end of each session to allow participants to ask any lingering questions or cover discussion points. To conclude the session, the moderator summarised key codesigned solutions and recommendations, ensuring these were converted into action points for those attending the TTS. In the 3 days following the session, the moderator and up to two assistants, as well as the medical advisor and other research team members, would create a summary document report on clinic-specific recommended changes and/or suggestions that arose from the session. This report was generated out of a rapid analysis of the discussions and codesigned solutions presented during the session. The moderator and the medical advisor would ensure that any codesigned solutions were in alignment with IPC guidance provided by local health authorities. As part of checking solutions, the moderator and the medical advisor had access to AHS-IPC experts and our research team’s expert in infectious diseases and IPC (JC).Additional guidance from these discussions came to be included in these reports, which were returned to clinic staff as a comprehensive reference document to assist in making appropriate changes in structure, policies and practices. The content from clinic-specific reports was then aggregated and de-identified to produce a ‘key learnings’ document that identified common hazards, IPC considerations and best practices for patient management.Following the simulations, research team members with expertise in the sociology of QI and semistructured interviewing (RF and ML) conducted follow-up interviews (n=10) with selected session participants. Ethnographic interviews are an accepted method for gathering perspectives on QI interventions in outpatient healthcare contexts.The second portion of the interviews then focused on key elements in the method as experienced by participants. These qualitative data, aggregated from across the interviews, were analysed to identify not just the benefits that participants associated with the TTS sessions, but the key elements of the method as put into practice by our research team. Our analysis used coded thematic analysis,Although many participating clinics had designed and implemented new standard operating procedures (SOPs) to deal with COVID-19, these had often been developed without consideration of the physical and social structures related to clinical processes. Of the 20 participating clinics, the majority (n=13) had drafted SOPs but had not fully communicated them to the staff. Clinical SOPs were not comprehensive and drew on the limited guidance available to the specifics of primary care IPC.During each of the TTS sessions, our team worked alongside participants to develop structurally (and thus hazard) sensitive protocols for managing patient entry and exit from the clinic, which included the following:Monitoring and enforcing clinic-specific mandates for hand hygiene and mask donning as patients entered.Ensuring patients were individually given masks rather than allowed to take them from a box and risk contamination.Rescheduling patients who screened positive for COVID-19 symptoms.Scheduling blocks of time exclusively devoted to patients with COVID-19/ILI so as to avoid possible exposure of other patients.Assigning cleaning responsibilities to specific staff as patients left examination rooms.Ensuring patients properly disposed of temporary masks on exiting the clinic.The TTS sessions also provided PC staff with the opportunity to identify and create SOPs around communication challenges, which included the following:Implementation of consistent messaging for patient screening.Standardisation of COVID-19/ILI notations in the clinic’s electronic medical record system.Finally, redesigning physical space and the flow of patients, clinicians and samples through the clinic to meet IPC guidance was a major focus of the recommendations we produced after each TTS session. Designating and separating the clinics into ‘dirty’ and ‘clean’ zones was also mentioned by the moderator and the medical advisor in every TTS. Few participating clinics had designated zones in place or had SOPs that created consistent, practical locations for the examination and isolation of patients, hand hygiene stations, PPE supplies, and essential medical supplies that should be accessible when working with patients with COVID-19. Working alongside the PC teams, the moderator and the medical advisor guided participants in every session to refine SOPs related to physical space usage:Redeployed parking lots and patients’ cars as call-in waiting rooms.Redesigned waiting rooms to achieve distancing and improve flow.Standardised approaches to completing chart work either in a ‘dirty’ zone as an examination finished or later in a ‘cold’ zone.Introduced appropriate signage and clear visual indicators about which zone a staff member was in, what sort of activity ought to occur there and whether the area required cleaning.Established standards for the transfer of patient samples between collection points and storage areas in the clinic.A consistent challenge for the moderator and the medical advisor was a deficit in appropriate or applicable guidance in a range of IPC areas. Specifically, a lack of decontamination and cleaning procedures guidance was a major source of anxiety for many participating clinics. While less concerning to the participants, our team identified and sought to remediate a major gap in the guidance available to PC clinics on the effective and appropriate use of PPE. This gap in guidance contributed to deviations from provincial PPE best practices at every participating clinic, including such examples as double gloving, double masking and uncertainty regarding the frequency of PPE replacement.During each simulation, we provided PC teams with best practices for environmental cleaning that were based on provincial acute care guidance. While posting donning and doffing checklists for PPEThe thematic analysis of our semistructured follow-up interviews found that the TTS sessions were seen as effective at both cementing existing IPC practice and introducing new policies and procedures. One PC physician participant described how their TTS had included:enough detail that we felt very confident in the stuff that we were already doing, but then also there [were] a lot of different blind spots with fairly simple solutions. (Participant 37)Pleased to leave the session with not just ‘action lists’, but the confidence to implement them, the same participant noted that clinic staff:all found it to be valuable to some degree, because there’s a lot of practical points that we have applied since. (Participant 37)In addition to these pragmatic and confidence-building benefits, participants identified a number of key elements to the methodological approach described above. These elements included the facilitative approach used by the moderator and the medical advisor, the pragmatic value of the scenarios, the virtual delivery platform and the cross-system perspective brought by our research team.The combined contribution of the moderator and the medical advisor was called out as important by one participant, who noted:‘What if the person has to go to the washroom now? And how do you do this?’ There was enough foundation that people felt confident, and there was great insight from [the moderator and medical advisor] to be able to ask other questions so that all of the teams left knowing that they benefited from participating. (Participant 41)[The moderator and clinical advisor] were able to throw other things at [us by], posing other scenarios: Participants noted the importance of both the expertise of our team members and the method’s capacity to flexibly introduce new hazards and threats for consideration. Beyond this, the moderator and the medical advisor had built the conversational foundations for PC personnel to feel safe and confident as they rehearsed and experimented with high-stakes IPC issues.In addition to the importance of setting the tone of the sessions as collaborative, safe spaces, TTS participants identified the scenarios as key elements in the method’s success. These scenarios were viewed by participants to be relevant and realistic, with one participant noting that:the scenarios were definitely true to what we are seeing in our clinic. (Participant 38)This was echoed and expanded on by another participant, who noted that:…Each one of the [scenarios] was definitely something that we could potentially see at the clinic, and had seen [previously]…[and gave us a chance] to think about, ‘what is the best IPC method for maintaining a safe environment for the patient, as well as staff, and then future patients after [a COVID-19] patient leaves?’ (Participant 37)Virtual delivery of the sessions was identified as another element in the method’s success. The combined use of Zoom and MURAL was seen as catering to multiple learning styles and delivering an interactive and engaging experience. As one participant indicated:The [avatar] system worked well to visualize it. So it facilitated different learning strategies for visual learners vs didactic learners, auditory learners. It was helpful in that sense. (Participant 39)Finally, our focus on deploying a single TTS delivery team across multiple PC clinical sites in the province was seen as an element of the sessions’ success. Our team was able to recognise common challenges and share effective solutions, gaining a cross-jurisdictional perspective that helped to anticipate clinical needs, gaps and hazards ahead of time. As one participant pointed out:I felt like it was very useful because there were things that the [research] team brought up that we didn’t think of. And that was…because they had experience doing this in other clinics and in other settings so they were able to draw from their experience and shoot different scenarios to us that we hadn’t thought of. (Participant 38)End users found that sessions provided safe, neutral spaces to discuss and debate SOPs while being guided to identify hazards and threats by facilitator consultants from our research team. The sessions were seen as providing benefits in the form of pragmatic, actionable lists of changes, and the confidence to engage in QI.Clinical simulations, including tabletop exercises, have been widely used both as effective educational toolsWhile simulations of all kinds have been deployed as a response to COVID-19,TTS is a less common, but nonetheless proven, technique in healthcare QI that has been used to uncover and address latent conditions in complex healthcare environmentsWith a broad range of IPC hazards and threats identified and mitigated in novel or changed structures and SOPs by PC teams over the course of the sessions, the case for their effectiveness is clear. Beyond being a path to new, consensus-driven SOPs covering patient flow, communication and the safe retasking of physical space, the TTS sessions provided pragmatic, confidence-building forums for PC staff to understand and implement otherwise vague IPC guidance. In addition to identifying IPC hazards and threats, and addressing these with recommendations delivered to each clinic, our end users identified a number of beneficial elements that might otherwise be obscured in the method’s technical details. The approach taken by the moderator and the medical advisor to co-creating the scenarios and facilitating the TTS sessions was particularly important here.It is critical to position the moderator and the medical advisor as neither fully authoritative ‘outsiders’ nor locally committed ‘insiders’ to the sessions. Rather, we suggest a carefully nurtured ‘alongsider’ statusOur facilitation work leveraged an engaged scholarshipThe TTS method as described here and delivered to Albertan PC teams sought to balance ‘alongsider’ skills—the empathetic management of virtual sessions that were responsive to and codeveloped from local priorities—with outside expertise. This consultative expertise and authority drew on empathy and a depth of knowledge in HF techniques and the practical application of often vague IPC guidance, as well as cross-cutting awareness of Alberta’s health system.While this intervention was largely viewed as successful in supporting PC teams during COVID-19, there were a number of challenges to overcome in piloting these simulations.The transition from inperson to virtual sessions presented a unique set of problems. End users were required to have stable, broadband internet connections, a particular challenge in rural settings. They were also required to quickly learn and adapt to the novel technology of MURAL, with the moderator taking time to help them become familiar with the interface. Ensuring all participants felt comfortable moving tokens and avatars around the floor plan took upwards of 5 min, which occasionally delayed the start of the session. In rare cases, end users could not connect to the MURAL space, or could not use both Zoom and MURAL simultaneously.The virtual format posed a challenge in developing rapport between moderator and session attendees. In some cases, participants were reluctant to share their video and/or contribute to the session. In other cases, end users would talk over one another, which interrupted the flow of discussion. They often did not understand the format of the simulation until the session had begun, which required the moderator to repeat instructions or provide additional clarification to attendees. In rare instances, end users were suddenly disconnected from the session or had to take an urgent, patient-related phone call.Our evaluation component relied on anecdotal testimonies of non-randomised participants. In addition, our interviewers, occassionally also attended the simulation sessions. This introduced selection, confirmation and recall bias in the questioning and participants’ feedback. Further, no quantitative measures or surveys were provided as part of the follow-up evaluation process.While TTS are increasingly used in healthcare settings and disaster preparedness, they have not been extensively deployed in pandemic contexts to improve clinical practice in outpatient settings. Our results suggest that virtual TTS can be used in multiple contexts to help identify hazards, improve safety and build confidence in professional teams who are adapting to rapid changes in both policies and practice. While our application was restricted to PC in Alberta, this low-cost, high-impact method may be deployed in other settings globally, including low-income and middle-income countries. The virtual delivery of TTS may also provide value in other disaster responses and humanitarian emergencies, both reactively, as in our example or, preferably, proactively.The COVID-19 pandemic has greatly strained the health systems and further established simulation as a critical tool in assisting healthcare workers to adapt to the rapid pace of change.Tabletop simulations (TTS) are a widely accepted effective tool for education and quality improvement in healthcare, but have been underused in primary care.This paper describes a novel, virtual application of TTS to support primary care clinicians as they adapt their infection prevention and control practices to the pandemic.We highlight our interdisciplinary team’s approach which used non-evaluative facilitation and provided evidence-based recommendations.Our method assisted primary care personnel to codesign solutions to latent hazards and threats in their clinics.Virtual TTS offer a low-cost and effective means to support front-line pandemic responders in a variety of contexts, including those in low-income and middle-income countries.


Survival analysis demonstrated that sarcoidosis patients were also at increased risk for all-cause mortality compared to controls .(1) Background: Inflammation plays a pivotal role in atherosclerosis, and the association between chronic inflammatory states and ischemic heart disease (IHD) has been shown in several rheumatic diseases. Persistent inflammation might also be a risk factor for IHD in sarcoidosis patients. (2) Methods: Demographic and clinical data of 3750 sarcoidosis patients and 18,139 age- and sex-matched controls were retrieved from the database of Clalit Health Services, Israel’s largest healthcare organization. Variables associated with IHD were assessed by a logistic regression model. To assess for variables that were related to increased risk of all-cause mortality, the Cox proportional hazards method was used, and a log-rank test was performed for survival analysis. (3) Results: Both groups were composed of 64% females with a median age of 56 years. An association between sarcoidosis and IHD was demonstrated by a multivariate analysis (adjusted odds ratio (OR) 1.5; 95% confidence interval (CI) 1.36–1.66). Long-term follow-up revealed increased mortality among sarcoidosis patients: 561 (15%) deaths compared to 1636 (9%) deaths among controls ( Ischemic heart disease (IHD) is considered a leading cause of premature mortality worldwide ,2. PotenMost research on the association between sarcoidosis and IHD or related cardiac entities has, to date, been conducted in relatively small cohorts. In their study on 124 sarcoidosis patients, Zöller, Li, Sundquist, and Sundquist found that the standardized incidence ratio (SIR) for coronary heart disease (CHD) was 3.11 in the first year after the first sarcoidosis-associated hospitalization . In thisThis retrospective cross-sectional study was conducted using the database of Clalit Health Services (CHS), the largest healthcare organization in Israel, which contains over 4.4 million medical records that were available for analysis. CHS is a health organization that provides state-mandated medical insurance in Israel and operates several university-affiliated hospitals and many clinics throughout the country.Data on patients with a diagnosis of sarcoidosis were retrieved, and each sarcoidosis patient was age- and sex-matched to a non-sarcoidosis control subject randomly selected from the CHS database. Only exact matches were included, and frequency matching was utilized.Data retrieved included any diagnosis that was added to patients’ files since the electronic medical records system was introduced into CHS  and until 2016. A diagnosis of sarcoidosis or IHD was defined as at least one documented diagnosis by a physician, either in an outpatient clinic or hospital records.t-tests to evaluate differences between the study and control groups. Variables associated with IHD were identified by a multivariable analysis employing a logistic regression model. Variables related to increased risk of all-cause mortality were assessed by the log-rank test and survival analysis by the Cox proportional hazards method. Statistical analysis was performed using R Statistical Software .We used chi-square and The study population included 3750 sarcoidosis patients and 18,139 age- and sex-matched controls .p < 0.001). A higher proportion of IHD was observed among sarcoidosis patients  than among the controls  (p < 0.0001).The characteristics of the study population are presented in p < 0.001) deaths for the control group over a period of 15 years. Lastly, Cox proportional hazards methods  deaths compared with 1636 . A diagnosis of coexisting IHD and sarcoidosis was associated with the lowest survival probability, while a diagnosis of IHD without sarcoidosis was also associated with reduced survival probability but to a lesser extent. Patients with a diagnosis of sarcoidosis and no IHD had a higher survival probability, which, however, was also reduced compared with the control group .An increased risk for IHD was reported in many autoimmune diseases, including rheumatoid arthritis, lupus nephritis, inflammatory bowel disease, and Bechet’s disease ,15,16,17While cardiac sarcoidosis is a rare but well-described entity that can cause arrhythmias, congestive heart failure, and sudden death , only a Another study on cardiovascular disease in sarcoidosis patients was conducted by Ungprasert, Crowson, and Matteson , who folSome new evidence of sarcoidosis as a risk factor for atherosclerosis and CAD recently emerged. In 2017, Kul et al. conducted a study that included 40 sarcoidosis patients and 42 healthy controls, all without any known traditional risk factors for CAD, in which coronary flow velocity reserve (CFVR) was measured along with other clinical variables . SarcoidIn 2018, a systematic review and meta-analysis of selected studies reported that sarcoidosis was associated with increased arterial stiffness and, therefore, with a higher risk for subclinical atherosclerosis . The autSeveral mechanisms through which sarcoidosis could affect the cardiac vasculature and cause IHD have been proposed, apart from direct involvement of the coronary arteries in cardiac sarcoidosis. One likely explanation is that atherosclerosis is associated with systemic inflammation—a notion that is currently widely accepted . The mecOur study has several limitations that bear mention. Since this is a retrospective cross-sectional study, the evaluation of the association between sarcoidosis and IHD could be biased by several unidentified confounders. Specific variables that could not be evaluated due to data unavailability were disease severity and disease duration. Information on both of those parameters could have possibly influenced the risk stratification for IHD among sarcoidosis patients and provided more information on that parameter. It should be noted that diagnoses in the CHS database could be made by several types of physicians and in a variety of clinical scenarios. There is, therefore, potential incoherence regarding the diagnosis of IHD in our study, and we were unable to validate the diagnoses due to the size of the study’s groups. Another limitation due to the study’s design is that data regarding the chronological order of IHD and sarcoidosis diagnoses are lacking, and, therefore, we could not conclude which condition preceded the other. Additionally, immunosuppressive and glucocorticoid therapy might also influence IHD risk, given that treatment with immunosuppressive therapy not only indicates disease severity but also possibly acts as an independent risk factor for IHD . The stuThe results of the current study, taken together with those in the relevant literature, serve to support the need to raise the level of awareness of clinicians to the cardiovascular health of sarcoidosis patients. Given the increased mortality in the cohort with coexisting sarcoidosis and IHD that was demonstrated in the results of our study, it is reasonable to argue that treatment and follow-up of sarcoidosis patients should focus not only on the primary disease but also on the possible comorbidity of atherosclerosis and IHD. This calls for managing other risk factors for cardiovascular disease to reduce the subsequent risk of morbidity and mortality among patients with sarcoidosis.