We used nationwide population-based data to examine associations between 7-day physician follow-up and 30-day readmission, and further associations of 7-day same physician  and cardiologist follow-up with 30-day readmission for non-ST-segment-elevation myocardial infarction (NSTEMI) or heart failure.Thirty-day readmission rates after acute myocardial infarction (AMI) and heart failure are important patient outcome metrics. Early post-discharge physician follow-up has been promoted as a method of reducing 30-day readmission rates. However, the relationshipWe analyzed all patients 18 years or older with NSTEMI and heart failure and discharged from hospitals in 2010 in Taiwan through Taiwan’s National Health Insurance Research Database. Cox proportional hazard models with robust sandwich variance estimates and propensity score weighting were performed after adjustment for patient and hospital characteristics to test associations between 7-day physician follow-up and 30-day readmission.The study population for NSTEMI and heart failure included 5,008 and 13,577 patients, respectively. Early physician follow-up was associated with a lower hazard ratio of readmission compared with no early physician follow-up for patients with NSTEMI , and for patients with heart failure . Same physician follow-up was associated with a reduced hazard ratio of readmission compared with different physician follow-up for patients with NSTEMI , and for patients with heart failure .For each condition, patients who have an outpatient visit with a physician within 7 days of discharge have a lower risk of 30-day readmission. Moreover, patients who have an outpatient visit with the same physician within 7 days of discharge have a much lower risk of 30-day readmission. Policy makers, clinicians, and payers who seek to improve outcomes in health care are focusing on 30-day readmission rates for patients with acute myocardial infarction and those with heart failure. Early poEarly or timely outpatient follow-up with a physician for further assessment or treatment has been hypothesized to have an effect on reduced readmission among discharged patients with heart failure and those with acute myocardial infarction.–7 The trIn Taiwan, the National Health Insurance Administration has been the sole insurer and implemented national health insurance since March 1, 1995. The coverage rate of national health insurance has reached 99.9%, and almost all health care facilities are national health insurance contracted providers. Every enrollee is free to go to any hospital or clinic, and enjoys comprehensive benefits with a low cost-sharing policy . The National Health Insurance Administration has reimbursed providers mainly on a fee-for-service basis since the beginning of the national health insurance program. The Hospital Readmissions Reduction Program, which, under the Affordable Care Act, requires the Centers for Medicare & Medicaid Services to reduce payments to hospitals with excessive readmission rates regarding acute myocardial infarction and heart failure, has not To better understand the relationship between early post-discharge follow-up and patient outcomes, we used nationwide population-based data from Taiwan to examine whether physician follow-up within 7 days of discharge was associated with a reduction in 30-day readmission for patients with acute myocardial infarction and those with heart failure. We also further determined whether early follow-up with the same physician or with a cardiologist was associated with much better patient outcomes.In this study, we used the National Health Insurance Research Database, provided by the National Health Insurance Administration and managed by the National Health Research Institutes in Taiwan. The database, which is released annually, consists of the following dimensions: inpatient medical benefit claims, ambulatory care medical benefit claims, pharmaceutical benefit claims, contracted medical care institutions, health professionals in contracted medical care institutions, and beneficiaries. Therefore, the database provides an opportunity to examine the relationship between early post-discharge follow-up and patient outcomes.The protocol for this study was approved by the Institutional Review Board of the National Taiwan University Hospital (protocol # 201601056RINB). The dataset we used in this study was secondary data; all information was de-identified by data owners.This study included all patients aged 18 years and over who were discharged from general acute care hospitals in 2010, with a principal diagnosis of acute myocardial infarction without ST-segment elevation –16 and hEarly follow-up was defined as whether discharged patients had an outpatient visit with a physician within 7 days after discharge., 4 The lThe covariates included patient and hospital characteristics. The patient covariates included sex, age, comorbid conditions, medical history, in-hospital treatment , length of stay, baseline medications , medications within 7 days of discharge, low income, rural residence, number of hospitalizations during the past year, and number of office visits during the past year., 23–26.The Charlson-Deyo index was used to quantify patient comorbidities. This indThe hospital covariates included hospital volume , hospital level , teaching status (yes/no), and geographic location . We determined the volume of patients who were treated at hospitals using annual condition-specific volume, and then we divided these “annualized” volumes into tertiles.Our primary outcome was 30-day all-cause readmission, which was defined as any re-hospitalization to any acute care hospital within 30 days from index discharge. HospitalWe used Cox proportional hazard models with robust sandwich variance estimates and propensity score weighting, adjusted for all patient and hospital characteristics, to examine the association between 7-day physician follow-up and 30-day readmission for acute myocardial infarction and heart failure., 36 Cox Moreover, we used propensity score analyses to reduce the selection bias and the potential baseline differences between the early follow-up and the no early follow-up groups., 28 PropFinally, we further used Cox proportional hazard models with robust sandwich variance estimates, adjusted for all patient (including medications after discharge) and hospital characteristics, to examine the individual and combined associations of early same physician and early cardiologist follow-up with 30-day readmission among the early follow-up group. In sensitivity analyses, we changed the definition of early physician follow-up by allowing early follow-up to occur within 14 days after discharge.[Regarding non-ST-segment-elevation myocardial infarction (NSTEMI), we identified 6596 patients discharged from hospital in 2010. We excluded patients under age 18 (N = 0), and patients who had subsequent admission with NSTEMI (N = 397), or had previous admission with NSTEMI during the past 6 years (N = 249). After exclusions , the finThe results of the series of Cox proportional hazard models with robust sandwich variance estimates and propensity score weighting as provided in To further determine the individual and combined associations of same physician and cardiologist follow-up with 30-day readmission among patients with early follow-up, we did not find the synergistic associations between the effects of same physician and cardiologist follow-up. Therefore, an interaction term between same physician and cardiologist follow-up was removed in model 2. Same physician follow-up was associated with a lower hazard ratio of all-cause readmission compared with different physician follow-up for patients with NSTEMI , and for patients with heart failure . Same physician follow-up was also associated with lower 30-day cardiovascular-cause and same-cause readmission. The robustness of our primary results were evaluated by sensitivity analysis. Results were similar when we changed the transitional period from 7 days to 14 days.This study was the first research using nationwide population-based data to examine the association between early physician follow-up and 30-day readmission, and the relative association of early same physician and early cardiologist follow-up with 30-day readmission for NSTEMI and heart failure. For each condition, we found that early physician follow-up was associated with decreased 30-day readmission compared with no early physician follow-up. Moreover, early follow-up with the same physician was associated with lower 30-day readmission compared with early follow-up with a different physician.In Taiwan, about 75% percent of hospitalized patients with NSTEMI and heart failure had an outpatient visit within 7 days of discharge. Most early follow-up care was handled by the same physician who treated the patient during the index hospitalization, and usually by cardiologists. The rates of early physician, early same physician and early cardiologist follow-up in Taiwan were higher than those in the United States .[This study had two major findings about the association between early physician follow-up and 30-day readmission for NSTEMI and heart failure. First, we found that early follow-up with any physician was associated with lower 30-day readmission for each condition. This result is consistent with the finding of Hernandez et al.–43 Thus,It also must be noted that at the patient level, the association between time from hospital discharge to outpatient follow-up with a physician and risk of readmission is confounded by severity of illness. Patients who have more severe acute myocardial infarction or heart failure, or who are medically less stable are not only commonly seen sooner after hospital discharge but also at a greater risk of readmission., 4 ThereAnother notable finding was that early same physician follow-up (physician continuity) was associated with a further reduction in 30-day readmission. This finding is consistent with that of van Walraven et al and of MSome limitations existed in this study. First of all, patients were not assigned randomly. This is an observational and retrospective study; therefore, we cannot assign study subjects randomly. The propensity score weighting was adopted for alleviating selection bias., 37–40 MFinally, in Taiwan, follow-up with a trained and specialized nurse (care manager) is not common until now. This may be because the service is not reimbursed by the NHIA. Based on two related studies, one study regarding discharged patient with heart failure in Northern California, United States finds that early outpatient follow-up with a physician is associated with a lower chance of 30-day readmission, but telephone follow-up with a trained and specialized nurse or pharmacist is not. Another Our national population-based study showed that 7-day physician follow-up was associated with lower 30-day readmission, and physician continuity (7-day same physician follow-up) was associated with much lower 30-day readmission for patients with NSTEMI and those with heart failure. This study may provide evidence in support of guidelines recommending scheduling an early follow-up visit after discharge, and it may provide an evidenced-based approach to improve 30-day readmission following NSTEMI and heart failure.


Differentially expressed metabolites and probes were identified in the pairwise comparison between time points by using the early stage as a reference. Metabolic and transcriptomic data were integrated through pairwise correlation and clustering approaches to discover genes linked with particular metabolites or groups of metabolites. These candidate transcripts were further checked for co-localization with quantitative trait loci (QTLs) affecting aromatic compounds. Our findings provide insights into the biological networks of grapevine secondary metabolism, both at the catalytic and regulatory levels. Examples include a nudix hydrolase as component of a terpene synthase-independent pathway for monoterpene biosynthesis, genes potentially involved in monoterpene metabolism , transport , and transcriptional control .Monoterpenes confer typical floral notes to “Muscat” grapevine varieties and, to a lesser extent, to other aromatic non-Muscat varieties. Previous studies have led to the identification and functional characterization of some enzymes and genes in this pathway. However, the underlying genetic map is still far from being complete. For example, the specific steps of monoterpene metabolism and its regulation are largely unknown. With the aim of identifying new candidates for the missing links, we applied an integrative functional genomics approach based on the targeted metabolic and genome-wide transcript profiling of Moscato Bianco ripening berries. In particular, gas chromatography-mass spectrometry analysis of free and bound terpenoid compounds was combined with microarray analysis in the skins of berries collected at five developmental stages from pre- According to the observed associations between metabolite and transcript profiles, we report several genes that may control the accumulation of free and glycosidically bound monoterpenes and additional aroma-related compounds.This work aims at a better understanding of aroma determination in grapevine and at the identification of candidate genes for further functional analysis. To this purpose, we integrated gas chromatography/mass spectrometry-based quantitative analysis of selected metabolites with microarray-based transcriptomic analysis in Moscato Bianco (Vitis vinifera L.) were collected from pre-veraison to over-ripening in 2005, 2006, and 2007  and high-resolution gas chromatography-mass spectrometry  Genome version 1.0 . At the time this platform represented a good compromise between genome coverage, cost and computational effort required for data analysis. RNA from points 2 to 5 was hybridized competitively with RNA from point 1 (pre-veraison), following the dye-swap experiment design  for the Grape (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE76834.Spot intensities were quantified with the software MAIA 2.75  and is publicly available at GEO (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GPL15453. Since this annotation provides every oligo with a text description but doesn't associate it to any gene prediction identifier, we independently achieved this information by blastN alignment against the grape gene sets at CRIBI  Grape Gene Index (VvGI), release 3 . The corresponding annotation is based upon a match between each oligo and the gene set of the 12X version of the grape genome at CRIBI  was used to validate the microarray results. Since RNA from berries collected in 2006 was no more available, new samples  as closest as possible to those analyzed in 2006 were obtained in 2016 by adopting the same sampling procedure and the same protocol for RNA extraction.Vitis vinifera gene predictions perfectly matching with the microarray 70-mers by using Primer3 . Working at probe level instead of gene level was chosen for two main reasons: (1) different probes supposedly matching to the same gene  often show different expression values, which might be an indicator of alternative transcription and (2) the sequence specificity to CRIBI 12X gene predictions is not optimal for a number of probes spotted on the AROS array ; for a detailed assessment of probe specificity, Moscato Bianco genome and transcriptome assembly would be required, which is out of the scope of this work.Different approaches were tested in order to discover transcripts linked with the accumulation of one or more metabolites. In a first identification step of candidates, the most stable expression changes were preferred to the biggest ones, hence the microarray probes with adjusted 2-transformed differentials in the pairwise comparisons 2 vs. 1, 3 vs. 1, 4 vs. 1, and 5 vs. 1). With the goal of identifying aroma regulatory genes we also tested a two-step strategy, which was based on (1) search for candidate metabolism and transport genes by direct correlation with metabolites and (2) expression pairwise correlations between these enzyme/transporter-coding genes and any regulatory gene within the microarray. For this aim, Pearson correlations were computed both between differential gene expression ratios (n = 4) and microarray channel intensities .Pearson pairwise correlation was calculated between transcripts and metabolites across all the time points . Compared to the traditional clustering methods, biclustering algorithms discover local co-expression patterns   between the observed number of probes within each MapMan functional category per cluster and the expected number of probes in that category based on the overall AROS genome array expression distribution.Soft clustering of the metabolite and transcript differentials was performed by using the R/Bioconductor Mfuzz package  we selected a subset of genes with significant expression changes and/or supporting evidence from the literature, like a relevant function in other plant species, co-localization with QTLs for monoterpene content and coexpression with genes involved in the terpene pathway. In particular, the QTL co-localization was stated when the V1 gene predictions fell into the 1-LOD confidence intervals of the QTLs for linalool, geraniol and nerol reported by Doligez et al.  and Batt2 fold changes at the stages 2-5  with respect to the first stage (E-L 31).For the candidate genes assessed by both microarray and real-time PCR analyses , the association between expression and metabolic profiles was further tested by employing a general monoterpene quantification that considers the three seasons  as replicates. To this purpose, the average concentration among these seasons was computed for each metabolite at each developmental stage. Pearson and Spearman correlations were calculated between the transcriptional and metabolic data expressed as logOur study gives an example of the systems biology approach. Systems biology has been successfully applied to the discovery of regulatory and biosynthetic genes involved in the control of metabolite production , with concentrations higher than 600 μg/kg of berries  altered during ripening. The compounds that changed most with respect to pre-veraison (August 17 or stage E-L 34.5 in this work) and then increased during ripening. Free linalool reached its maximum on September 13  and decreased during over-ripening. A similar behavior was observed in 2005 and 2007, even though the peak corresponded to slightly earlier stages , trans-pyran linalool oxide (OxC), trans-furan linalool oxide (OxA) and cis-furan linalool oxide (OxB); (2) geraniol, nerol, cis-8-hydroxy-linalool, benzyl alcohol, 2-phenylethanol, trans-geranic acid, citronellol, hydroxy-diendiol II, trans-8-hydroxy-linalool, linalool, hexanol, trans-3-hexen-1-ol, rose oxide I, rose oxide II and α-terpineol; (3) 4-terpineol and hydroxy-diendiol I + hydroxy-trienol. Additionally, within the second cluster a clear separation could be noticed between linalool on one side, geraniol and nerol on the other side  has a peculiar behavior with respect to the other three linalool oxides  compounds. Metabolite grouping was obtained through hierarchical clustering and principal component analysis by using different metabolic data sets Figure , S4. It e Figure . Opposits Figure .veraison). The two biological replicates assayed at each stage were confirmed to perfectly cluster together , indicating the reliability of the whole transcriptome assay  Pearson correlations could be established only in the absence of Benjamini and Hochberg  correctiCorrelation clustering between transcripts and metabolites resulted in the identification of 419 biclusters, that are groups of probes with a common behavior toward a group of metabolites. The clustered probes and metabolites were found to belong to a number of biclusters ranging from 1 to 10 and from 3 to 182, respectively  were not differentially expressed during Moscato Bianco berry ripening.VvDXR in our study  and HDR , whose expression increases along berry development Figure . The cortrans/cis-8-hydroxy-linalool (by hydroxylation), trans/cis pyranoid/furanoid linalool oxides and polyhydroxylated derivatives or polyols like the odorless hydroxy-diendiol I and II (by epoxidation and hydrolysis). Similarly, C-8 oxygenated geraniol and citronellol derivatives can be formed through hydroxylation, whereas the oxidation to geranial and neral  is supposedly mediated by alcohol dehydrogenases. Geranic acid is another oxidation product of geraniol. Rose oxide is generated from citronellol by allylic hydroxylation and acid-catalyzed cyclization. Citronellol in turn arises from the reduction of geraniol and nerol (hydrogenation).Extensive oxidative monoterpene metabolism has been reported in grapes and wine, with a percentage of linalool oxygenation ranging from 52 to 97%  for CYP genes coexpressed with linalool synthases, as in Ginglinger et al. (Members of the cytochrome P450 (CYP) 71 and 76 families were recently shown to metabolize linalool in r et al. . This inr et al. . Most ofr et al.  but their et al.  and, ever et al. , they enr et al. .VvGT7  insertion of the hydrophobic terpenes into vesicle membranes followed by transport and fusion to the plasma membrane, 2) carrier proteins  that conduct these molecules to the (plasma) membrane, and (3) direct diffusion between the endoplasmic reticulum and/or plastidial (stromule) membranes and the plasma membrane  has been proposed as a candidate transcriptional regulator of (mono)terpene biosynthesis also in grapevine  proteins on the expression of the TIA  biosynthetic genes Str (strictosidine synthase) and Tdc (tryptophan decarboxylase)  in the regulation of light-induced terpenoid biosynthesis in grapes, in agreement with other evidences  and downstream pathways are coexpressed with circadian clock genes and show typical circadian expression profiles  and genes potentially involved in the post-transcriptional regulation  and VvHDR, which probably precedes monoterpene accumulation. Several compounds were affected, especially in their glycosidically bound form. Unsurprisingly, most of the metabolites with no correlation showed an inconsistent profile among seasons  or a decreasing trend along berry ripening . Though not ensuring a punctual conformity to the observations from a single year .This research was sustained by a Short Term Scientific Mission grant awarded to LC by the Institute of Vine and Wine Sciences  and with the financial support provided by the Autonomous Province of Trento (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cell-penetrating peptides (CPPs) can translocate across cell membranes, and thus have great potential for the cellular delivery of macromolecular cargoes. However, the mechanism of this cellular uptake process is not yet fully understood. In this study, a time-lapse single-particle light-sheet microscopy technique was implemented to obtain a parallel visualization of the translocating process of individual human immunodeficiency virus 1 (HIV-1) transactivator of transcription (Tat) peptide conjugated quantum dots (TatP-QDs) in complex cellular terrains. Here, TatP-QDs served as nanoscale dynamic pens, which depict remarkable trajectory aggregates of TatP-QDs on the cell surface. Spectral-embedding analysis of the trajectory aggregates revealed a manifold formed by isotropic diffusion and a fraction of directed movement, possibly caused by interaction between the Tat peptides and heparan sulfate groups on the plasma membrane. Further analysis indicated that the membrane deformation induced by Tat-peptide attachment increased with the disruption of the actin framework in cytochalasin D (cyto D)-treated cells, yielding higher interactions on the TatP-QDs. In native cells, the Tat peptides can remodel the actin framework to reduce their interaction with the local membrane environment. Characteristic hot spots for interaction were detected on the membrane, suggesting that a funnel passage may have formed for the Tat-coated particles. This finding offers valuable insight into the cellular delivery of nanoscale cargo, suggesting an avenue for direct therapeutic delivery. Numerous barriers can be encountered during the delivery of drugs , which sIn 1988, an 11-aa-long segment (47-57:YGRKKRRQRRR) in the trans activator of transcription (Tat) protein in the human immunodeficiency virus (HIV), also known as the Tat peptide (TatP), was found to display an effective cell-penetrating capability . An in vSemiconductor quantum dots (QDs) exhibit the unique optical properties of high emission efficiency, wavelength tunability, and long-term stability, making them appealing as in vivo and in vitro fluorophores . The abiThe N terminals of Tat peptides  were biotinylated. Conjugated TatP-QDs were prepared by incubating 20-nm diameter streptavidin-coated QDs (Qdot-585 from Invitrogen) in phosphate buffer saline (PBS) with excess biotinylated TatP  by filtering out TatP-QDs according to manufacturer’s instructions. To perform single-particle imaging of TatP-QD translocation, a culture medium containing appropriate TatP and TatP-Qdot585 was added to a freshly prepared cell culture at a final concentration of 1 v/v) fetal bovine serum without phenol red. Before performing the single-particle tracking, we plated the cells in a slide with eight-well chambers. Once a 70%–80% confluence had been reached, the HeLa cells were deprived of serum for 24 h. To disrupt their actin filaments, the cells were pretreated with a culture medium containing 10 HeLa cells were cultured in Dulbecco’s Modified Eagle’s medium with 10%  to ensure both high spatial resolution and high photon collection efficiency. However, the objective lens had a limited depth of field (500 nm). We invoked an astigmatism created by a cylindrical lens  to encode the fluorophore depth as an elliptically distorted point spread function PSF; see , therebyS = 5 to 400 photons per PSF spot by adjusting the exposure time of the sCMOS camera. This approach yields an estimate of the localization-error function D on the S plane, where p denotes x, y, or z. These plots display our overall localization errors of fluorophores. As shown, we achieve a lateral localization accuracy of 27 nm and an axial localization accuracy of 52 nm at a sufficiently strong signal. The lateral coordinates of the fluorophores can be determined with fairly constant errors for D, confirming the ability to localize fluorophores within 1 A film of 100-nm-diameter fluorescent beads randomly immobilized in 1% agarose gel matrix was prepared to determine the 3D localization accuracy of our apparatus. We took 100 images of the sample with a fixed imaging focal plane and localized the fluorescent beads in a fixed light sheet. We varied the measured signal from D < 0.1 Single-particle trajectories were recorded for as long as 100 s, with a frame time of 25 ms. The localized coordinates of the fluorophores were extracted from a set of images acquired by synchronously scanning the position of the light sheet and that of the imaging focal plane. Connecting the acquired location coordinates to generate 3D trajectories was challenging. We carried out multiple particle tracking by solving a linear- assignment problem  to identWe prepared a cell-culture medium containing 5 The first step in cellular internalization may involve some form of interaction between the cationic peptides and the surface of the cell. The strong anionic charge present on the glycosaminoglycan (GAG) chains of PGs makes them favorable first-binding sites for cationic Tat peptides ,19,20,21We prepared a cell-culture medium containing 1 z-coordinates in the living cell. The determination of cell profile is limited by the diffraction effect of the objective lens used, which yields a resolution of 200 nm on the laterial plane and 500 nm in the axial direction. As indicated in the top inset, the initial approaching trajectories of some Tat-QDs resemble directed movement under the force field, and the motion becomes more diffuse as the TatP-QDs come closer to the cell surface. A longer duration of observation to accumulate more approaching events revealed remarkable trajectory aggregates at selected regions of the plasma membrane (Without external interaction, these Tat-QD nanoscale probes are expected to traverse the extracellular space through a random walk search, attach to the membrane, and then diffuse to find a suitable entrance site. membrane b. Each cThe binding affinity of TatP for HSPGs is greater than that for anionic lipids by two to three orders of magnitude. Given that the anionic GAG chains of PGs on the plasma membrane ,19,20,21n different realizations of the local environment with corresponding interaction potentials n-dimensional functional space to a 3D Euclidean space. Recently, Wang and Ferguson used the generalized Takens Delay Embedding Theorem [As TatP-QDs translocate across the plasma membrane of a living cell, probing particles can record the influences of the cellular environment on their trajectories. We considered the trajectory equation , which y Theorem  to generAs the structure revealed in mbedding  to extramanifold  for the γ and a thermally fluctuating force f satisfying the fluctuation–dissipation theorem A particle freely diffusing in a 3D Euclidean space yields an isotropic The findings of a recent study indicated that on attachment to a membrane surface, Tat peptides can remodel the actin framework in an actin-encapsulated GUV . Howeverour plot ,28. The involved . An attrThe mathematical foundation of the above method was detailed in our previous publication . Here, wells see b, indicaz = 0 plane. As displayed in We analyze each trajectory aggregate by selecting segments that fall within 2% variance of the We used spectral embedding to classify 23,382 TatP-QD trajectories measured on 30 cells. The resulting circular or V-shaped distributions in the Macchi et al. documented the translocation ability of a specially designed 9-aa peptide fluorophore conjugate, which self-aggregated at selected plasma membrane regions within seconds of peptide administration . A diffu seconds . The cel seconds ,20,21. D seconds . The int seconds .Ruan et al. reported that within 5 min of 1-nM TatP-QD addition, the cell outer surfaces were visibly stained . At 30 mIt has been proposed that when two oppositely charged biomolecules are brought into contact in a solution phase, a large proportion of the mobile counter ions that previously surrounded each isolated biomolecule are released into the bulk solution , which iMechanistic insights into the binding-mediated cellular translocation of CPP are critical to the design of successful CPP-based therapeutic delivery systems. We developed a light sheet optical microscope to track TatP-QDs in parallel with high spatial resolution. We focused on the initial step in the translocation of individual TatP-QDs in the complex cellular terrain shortly after peptide administration. To investigate the mechanism underlying the trajectory aggregation of TatP-QDs on living cells, we used spectral embedding to extract an intrinsic low-dimensional manifold from the experimentally measured trajectories. Our result suggests that GAGs play a significant role in redirecting the TatP-QD entry process toward spatially restricted sites on the plasma membrane. The eigenmodes in the direct translocation of TatP-QDs were found to comprise isotropic diffusion and anisotropic directed movements. We used Recently, the cellular toxicity of unmodified CPPs had been assessed , which sic cargo . The act


The graphene (rGO) and carbon nanotube (CNT) were adopted to enhance the thermal conductivity of CL-20-based composites as conductive fillers. The microstructure features were characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD), and tested the properties by differential scanning calorimeter (DSC), static electricity accumulation, special height, thermal conductivity, and detonation velocity. The results showed that the mixture of rGO and CNT had better effect in thermal conductivity than rGO or CNT alone under the same loading (1 wt%) and it formed a three-dimensional heat-conducting network structure to improve the heat property of the system. Besides, the linear fit proved that the thermal conductivity of the CL-20-based composites were negatively correlated with the impact sensitivity, which also explained that the impact sensitivity was significantly reduced after the thermal conductivity increased and the explosive still maintained better energy.The online version of this article (10.1186/s11671-018-2496-3) contains supplementary material, which is available to authorized users. CL-20 -based composites could possibly replace various explosive compounds such as RDX and HMX to produce high-performance explosives because of its excellent properties of density and energy. However, it cannot be quickly transmitted after experiencing rapid high-low temperature changes since its poor thermal property, which is easy to form the “hot spot” and seriously endanger the safety and reliability of the weapon system . TherefoIn CL-20-based composites, polymer coating plays an efficient and economical role in enhancing the mechanical and thermal resistance of explosive crystals, and graphite is a helpful ingredient used in composites , 6. Now,π-conjugated two-dimensional structure with a large phonon mean free path and high electron mobility, providing a large contact area and providing a two-dimensional path for phonon transport  and impact sensitivity (cm), respectively. Just as we can see, the thermal conductivity and sensitivity showed a clearly positive relationship, which also means as the thermal conductivity increases, the sensitivity of the explosive can be significantly reduced. It also proves that improving the thermal conductivity of the explosive system by adding carbon nanomaterials as thermal conductive fillers did help to reduce the mechanical sensitivity of explosives.Furthermore, in this study, we performed a linear fit of the thermal conductivity and the special height of the coated samples. As shown in Fig. The theoretical detonation performances  and actual detonation velocity for the raw CL-20 and coated samples are shown in the Table In summary, CL-20-based composites with rGO and CNT did help to increase the thermal conductivity of the explosive system. The fitted formula and curve proved that the improvement of thermal conductivity has a great influence on the sensitivity of the explosive system, and the impact sensitivity of the coated samples were effectively reduced due to the increase of thermal conductivity. In addition, the addition of carbon materials had little influence on the energy of the explosive system. Finally, there are still some shortcomings in this study, such as the effect of different ratios of rGO and CNT on the experimental results had not been considered, so this part will be further explored in the following work.Additional file 1:Experimental details and equations. (DOCX 20 kb)


Although TEs are highly repetitive in the genomes and transcribed in specific stress conditions or developmental stages, the trans-acting regulatory roles of TE-derived RNAs have been rarely studied. It was only recently that TEs were investigated for their regulatory roles as a form of RNA. Particularly in plants, TEs are ample source of small RNAs such as small interfering (si) RNAs and micro (mi) RNAs. Those TE-derived small RNAs have potentials to affect non-TE transcripts by sequence complementarity, thereby generating novel gene regulatory networks including stress resistance and hybridization barrier. Apart from the small RNAs, a number of long non-coding RNAs (lncRNAs) are originated from TEs in plants. For example, a retrotransposon-derived lncRNA expressed in rice root acts as a decoy RNA or miRNA target mimic which negatively controls miRNA171. The post-transcriptional suppression of miRNA171 in roots ensures the stabilization of the target transcripts encoding SCARECROW-LIKE transcription factors, the key regulators of root development. In this review article, the recent discoveries of the regulatory roles of TE-derived RNAs in plants will be highlighted.Transposable elements (TEs) are often regarded as harmful genomic factors and indeed they are strongly suppressed by the epigenetic silencing mechanisms. On the other hand, the mobilization of TEs brings about variability of genome and transcriptome which are essential in the survival and evolution of the host species. The vast majority of such controlling TEs influence the neighboring genes in  Transposable elements (TEs) are the major constituent of many eukaryotic genomes. Especially in the cereal crops , more than 80% of their genomes are made up of transposons . TEs areSince TE mobilization can be mutagenic, the host genomes have evolved elaborate mechanisms to suppress their activities . TEs areIn addition to siRNAs, many plant miRNAs have been suggested to be evolved from TEs . AlthougDecreased DNA methylation 1 (DDM1), a gene encoding ATP-dependent chromatin remodeler in Arabidopsis, global DNA methylation level is dramatically reduced, thereby numerous TEs are reactivated  have higher levels of siRNA854 compared to ddm1 F2. The ubp1 mutants show strong susceptibility to osmotic stress and similar phenotype was also observed in ddm1 F6 but not in ddm1 F2 plants. Therefore, the targeting of Athila6A-derived siRNA854 to UBP1 transcript and alteration of resistance to abiotic stresses provides insight into how TEs adapted to changing environment in plants. In addition to UBP1, Athila6A-derived easiRNAs can target other genic mRNAs including AMS and HHP2 . Two allelic transcription factor genes, WRKY45-1 and WRKY45-2, were previously shown to have opposing effects in the resistance to Xanthomonas oryzae pv. oryzae (Xoo). WRKY45-1 allele produces TE-siRNA815 from WANDERER_OS-type DNA TE located in the intron. TE-siRNA815 then recognizes the complementary sequence and deposits DNA methylation through RdDM pathway in the intron of ST1 locus, which is critical in the resistance against Xoo. On the other hand, WRKY45-2 allele lacks such siRNA producing region that ensures stable ST1 expression contributing to the pathogen resistance.A more recent paper by Arabidopsis .Since easiRNAs are mainly produced in the epigenetic mutants, it has been questioned if easiRNAs have a function in natural conditions. Two recent studies answered this question by demonstrating the roles of easiRNAs in the hybridization barrier in bidopsis . The vegctivated . Pollen-ctivated . Higher ctivated . When th barrier . The exaDRM2 that encodes a de novo DNA methyltransferase . The targeting of miRNA820 to DRM2 is evolutionarily conserved in the Oryza genus and the repression of DRM2 gene results in strong reduction in DNA methylation and transcriptional upregulation of many TEs. Therefore, miRNA820 can be seen as an anti-silencing factor encoded within a TE that works at the post-transcriptional level. Similarly, UBP1 is the Arabidopsis homolog of TIA-1 in mammals which is known to suppress the viral translation of Tick-Borne Encephalitis Virus  transcription factors which are critical regulators of root development (MIKKI evolved from retrotransposons in rice and was positively selected to suppress miR171 in root. This in turn stabilizes the mRNAs of SCLs which are essential in the root development. Similarly, Brachypodium genome that are able to interact with miRNAs, however, their target mimicry activities are yet to be confirmed.In mammals, the majority of lncRNAs are derived from TEs and exhibit strong tissue-specific expression pattern . Similaret mimic . Indeed,elopment . TherefoArabidopsis natural accessions revealed that the TE landscape is very dynamic and the transcriptomic, epigenomic as well as phenotypic variations are attributed to TEs (Transposon-derived RNAs have been underestimated for a long time and their biological function have just started to be unveiled. The fact that TEs are repeated in the genome has significantly hampered the investigation of transposons so far. For example, the short length of the next-generation sequencing reads causes drastic ambiguity and imprecision in mapping the TE reads. Recent advance of the long read sequencing of PacBio  and Oxfod to TEs . Taken aThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Capacitive biosensors are an emerging technology revolutionizing wearable sensing systems and personal healthcare devices. They are capable of continuously measuring bioelectrical signals from the human body while utilizing textiles as an insulator. Different textile types have their own unique properties that alter skin-electrode capacitance and the performance of capacitive biosensors. This paper aims to identify the best textile insulator to be used with capacitive biosensors by analysing the characteristics of 6 types of common textile materials  while evaluating their impact on the performance of a capacitive biosensor. A textile-insulated capacitive (TEX-C) biosensor was developed and validated on 3 subjects. Experimental results revealed that higher skin-electrode capacitance of a TEX-C biosensor yields a lower noise floor and better signal quality. Natural fabric such as cotton and linen were the two best insulating materials to integrate with a capacitive biosensor. They yielded the lowest noise floor of 2 mV and achieved consistent electromyography (EMG) signals measurements throughout the performance test. Wearable sensing systems is a trending technology that embeds electronic systems such as biosensors into a garment to provide long-term personal health monitoring capabilities without geographical boundaries ,2,3. LifGenerally, there are two types of biosensors, which are wet-contact electrode and non-contact biosensor. Conventional wet-contact electrodes require direct electrical contact between electrode and skin to measure bioelectrical signals emitted from the human body. Usage of wet-contact electrode also require complex skin preparation and a reliance on conductive gel (Ag-AgCl) to reduce the skin-electrode impedance to achieve better bioelectrical signal quality . As a reEvery type of textile material has its own electrical and physical properties such as moisture absorption, relative permittivity, and thickness. These properties impact the performance of a capacitive biosensor by affecting noise levels, signal resolution, consistency, and accuracy of the bioelectrical signal measurements. Ueno et al. (2007) developed a mattress with fabric electrodes integrated to measure the electrocardiography (ECG) of a patient . A cottoThis paper aims to explore and evaluate the capability of six common textile materials to be used as textile insulators for capacitive biosensors. The six textile materials being reviewed in this paper are cotton, linen, rayon, nylon, polyester, and polyvinyl chloride textile (PVC-textile). This paper summarizes the physical and electrical properties of the six textile materials which are commonly used in clothing, bedding, and wearable items. A TEX-C biosensor was developed and presented in this paper. All six textile materials were integrated with the TEX-C biosensor to compare and analyse their characteristics. The performance of these TEX-C biosensors were validated on three subjects, the results of which were benchmarked against the performance of conventional wet-contact electrodes on the same three subjects.There are two main categories of textile materials which are natural fabric and synthetic fabric. Natural fabrics are composed of natural materials derived from the fibers of animals and plants. Synthetic fabrics are composed of man-made materials. The natural fabrics used in the experiment are cotton and linen while the synthetic fabrics used in the experiment are rayon, nylon, polyester, and PVC-textile. Cotton is a natural fiber made from cotton plants. It is commonly used as an insulator for a capacitive biosensor. 100% cotton textile was used in this research study. It is an absorbent and breathable textile which is widely used in clothing . Linen iThe thickness of each type of textile was measured using a digimatic caliper series 500 from Mitutoyo with a resolution of 0.01 mm. Each type of textile was cut into a rectangular shape. The thickness of each textile was measured 4 times from 4 different sides of the textile. It is important to note that the thickness measured from 4 different sides of each individual textile consistently yielded the same value. The thickness of each type of textile being used in the experiment were recorded in The resistance of each textile material was also validated to ensure these materials were neither non-conductive nor contaminated by any conductive substance. Each type of textile material was placed in between two copper plates. A Fluke 117 multimeter was used to measure the impedance between the two copper plates. The Fluke 117 multimeter was set to 0.01 MΩ range with the accuracy of ±1.5%. 2 while the top copper plate was 875 mm2 in size. A foam piece was placed on top of the parallel-plate capacitive structure to keep the top copper plate and the textile material flat. A 1.8 kg load was placed on top of the foam piece to ensure the parallel-plate capacitive structure stay firmly in place. An Agilent U1733C handheld LCR meter was used to measure the capacitance of the parallel-plate capacitive structure at 1 kHz. This LCR meter has resolution of 0.01 pF and accuracy up to ±0.2%. The relative permittivity of the textile material, rε was calculated using Equation (1) and recorded in oε is the constant value of the vacuum permittivity, 8.854 × 10−12 F/m;mC is the capacitance measured by the LCR meter;tA is the area size of the top copper plate which is 875 mm2;td is the thickness of the textile material.Textiles normally present a low relative permittivity as they are very porous materials and the presence of air approaches the relative permittivity to 1. However, the textile material, textile density, and manufacturing process do alter the relative permittivity value. Therefore, the relative permittivity value for each sample of textile material was measured using parallel-plate capacitive model ,25,26,27sC, can be calculated using Equation (2).oε is the constant value of the vacuum permittivity, 8.854 × 10−12 F/m;rε is the relative permittivity of the textile material;A is the copper electrode’s area size, 510 mm2;d is the thickness of textile which control the distance between skin and electrode.A TEX-C biosensor was designed and developed based on the parallel-plate capacitive model. It was fabricated on a dual-layer printed circuit board (PCB). One side of the PCB was used as an electrode while the other side contains buffer circuitry as shown in d and rε which control the value of skin-electrode capacitance for a TEX-C biosensor as shown in Equation (2). The distance between the electrode and skin surface was determined by the thickness of the textile material. Although there is a concern that the thickness of a textile might vary due to strain and compression, but these textiles were thin and the value of thickness were measured from 4 corners to avoid discrepancy. Therefore, as long as the TEX-C biosensor is fixed firmly on the human body, the thickness variation throughout the experiment is minimal. The relative permittivity for the different types of textile materials were measured and recorded in Different types of textile materials have unique The environmental temperature, humidity, and subject’s perspiration are factors that might affect the relative permittivity of a textile material. The humidity of the environment and subject’s perspiration would reduce the dielectric strength of the textile with absorbent characteristics and introduce additional substance between the electrode and human body. Thus, it was essential to perform the experiment in an enclosed and controlled environment to minimize the changes of room temperature, humidity, and subject’s perspiration. All the experiments and validations were performed in an air-conditioned electronics laboratory with the room temperature controlled at 23 °C.The TEX-C biosensor was connected to a data acquisition system which contained a bandpass filter, an analogue-to-digital converter (ADC), a negative feedback electrode, and a host computer. The hardware architecture of a TEX-C data acquisition system is illustrated in The validation process of TEX-C biosensor was divided into two sections; which are the biosensors’ characterization and the biosensors’ performance evaluation. The six types of TEX-C biosensors shown in The characterization experiment was performed to analyse the initial characteristics of TEX-C biosensors. The experimental results also served as a baseline value for the performance evaluation. This experiment consisted of two subsections which were the noise floor measurement and the EMG burst signal measurement. EMG signals are weak electrical signals that range from 0.1 mV to 100 mV . The noinoiseV) recorded from the three subjects’ bicep brachii using the six types of TEX-C biosensors and the wet-contact electrode. The experimental result showed that the skin-electrode capacitance was inversely proportional to the noiseV value of the TEX-C biosensor. The lower the skin-electrode capacitance, the higher the noiseV. Nylon insulated TEX-C biosensor recorded the highest noiseV which is 32.80 mV while it had the lowest skin-electrode capacitance value of 11.49 pF. Polyester insulated TEX-C biosensor recorded the second highest noiseV which is 4.67 mV with the second lowest skin-electrode capacitance value of 33.24 pF. With the third lowest skin-electrode capacitance of 39.56 pF, rayon insulated TEX-C biosensor recorded the third highest noiseV of 2.79 mV. Cotton insulated TEX-C biosensors had the highest skin-electrode capacitance of 58.96 pF, thus it also recorded the lowest noiseV of 1.65 mV among different types of textile materials. Linen insulated TEX-C biosensors had the second highest skin-electrode capacitance of 45.22 pF, therefore, it recorded the second lowest noiseV, which is 1.99 mV. PVC-textile insulated TEX-C biosensors yielded a slightly different behavior due to its non-porous characteristic as compare to other textile samples. Although PVC-textile insulated TEX-C biosensors had a skin-electrode capacitance value closed to cotton which is 58.65 pF, but it recorded noiseV of 2.52 mV, 0.87 mV higher than cotton insulated TEX-C biosensors. Firstly, the process of noise floor measurement required the three subjects to keep their bicep brachii at ease so that no EMG signals were generated. CMV can be represent by the following Equations (3) and (4). Equation (5) was derived by substituting Equation (2) into Equation (4).CMI is the induced current from the human body;CZ is the impedance between the skin and the TEX-C biosensor.Generally, it was expected to observe low amplitude voltage spikes from the output of the TEX-C biosensors which is known as noise floor . The noisC is inversely proportional to the CMV which was aligned with the results shown in d and rε were contributing factors to the common mode noise. Base on Equation (5), reduce the thickness or increase the relative permittivity of the textile are alternatives to reduce the amplitude of the common mode noise. The CMV can also be suppressed by implementing a negative feedback between the measurement system and the human body as shown in noiseV was recorded. A 50 Hz/60 Hz notch filter implementation to the measurement system is recommended to further reduce the amplitude of the common mode noise. The electronic system also generated noise such as the thermal noise which is unavoidable. Thermal noise is contributed by the motion of the charge carriers. The root-mean-square (RMS) voltage of the thermal noise, TV can be calculated using the following Equation (6).Bk is the Boltzmann’s constant, 1.38 × 10−23 J/K;T is the temperature of the system in Kelvin;R is the resistance value of a resistor;f is the bandwidth which the noise is measured.∆Equation (4) proved that noiseV recorded in noiseV of the TEX-C biosensor, the lower the signal-to-noise ratio.Secondly, the EMG burst signal measurement was used to validate the capability of the TEX-C biosensors to acquire the EMG signals from human body. Each subject was required to contract the bicep brachii muscle three times within 10 s to generate 3 EMG burst signals. This experiment was repeated using the six types of TEX-C biosensors on each subject. Most of the textile samples tested in the experiment had a smooth surface. When the subjects were contracting their bicep brachii, the TEX-C biosensor would tend to have a minimal variation of its position due to the changes in body surface. The friction between the copper electrode and textile material created unwanted electrical charges that translated to the voltage spike in the measurement. As a result, there were multiple voltage spikes before and after the EMG burst signal as shown in The characterization test recorded a baseline result of each TEX-C biosensor. The performance evaluation test evaluated the consistency and accuracy of the TEX-C biosensors in EMG signal measurements. The performances of these TEX-C biosensors were benchmarked with the conventional wet-contact electrode (Ag-AgCl) because it is commonly used in clinical applications. noiseV of a TEX-C biosensor is an important factor to capture a high resolution EMG signal. The EMG signals measured by the rayon and PVC-textile types of TEX-C biosensor and wet-contact electrode were slightly mismatched. Rayon and PVC-textile types of TEX-C biosensor measured higher amplitude and shifted the EMG signals in comparison with the EMG signals measured by the wet-contact electrode. The smooth surface of the textile material might cause some minimal movement of the TEX-C biosensor during muscle contraction. As a result, the measurement system was capturing a slightly offset signal in time in comparison with the wet-contact electrode while maintaining the same amplitude. In contrast, the signals acquired by the nylon and polyester types of TEX-C biosensor are completely different from the signals acquired by the wet-contact electrode. The signals shown in The EMG signals measured by the cotton and linen types of TEX-C biosensor and wet-contact electrode were similar. These results show that the low The TEX-C biosensors were tested on three subjects. The correlation results of the EMG signals measured using the TEX-C biosensors and the wet-contact electrode were shown in Overall, the measurement results of natural fabric-insulated TEX-C biosensors recorded lower noise floor and higher correlation values compared to the synthetic fabric. The variation of between the EMG signals’ amplitude and shifted signals measured by natural fabric-insulated TEX-C biosensors were insignificant. The experimental results showed that the performance of different insulators for the TEX-C biosensor was determined by the noise level of each type of sensor. The lower the noise floor, the higher the resolution of the bioelectrical signal measured and better results correlation with conventional wet-contact electrode. The noise level of a TEX-C biosensor is determined by the types of textile insulator because they are the only skin-electrode interface connecting the bioelectrical measurement system to the human body. A high-resolution bioelectrical signal is always preferable to maintain the accuracy and reliability of the measurement result and reduces the complexity of post signal processing.Wearable sensing systems have an enormous potential to improve the process of medical treatment and rehabilitation by extending the functionality of smart garments. Different types of textile materials have unique physical and electrical properties that will alter the performance of a TEX-C biosensor. Six types of TEX-C biosensors were evaluated in this paper in terms of noise level, signal resolution, and measurement consistency. The experimental results revealed that every type of textile material has its own unique relative permittivity and thickness that alter the skin-electrode capacitance of a TEX-C biosensor. It is recommended to choose a thin textile material with high relative permittivity as an insulator to maximize the skin-electrode capacitance of a TEX-C biosensor. High skin-electrode capacitance will result in low noise floor and yield a better performance. Natural fabrics such as cotton and linen with high skin-electrode capacitance were recommended textile materials for use as an insulator for the TEX-C biosensor. The EMG signals measured by the cotton type of TEX-C biosensor were consistent, highly correlated with the EMG signals measured by the conventional wet-contact electrode, and yielded the lowest noise floor. The EMG signals measured by the linen type of TEX-C biosensor were slightly inconsistent but correlated with the EMG signals measured by the conventional wet-contact electrode and also yielded a low noise floor. The other TEX-C biosensors insulated by synthetic fabrics such as rayon, nylon, polyester and PVC-textile with low skin-electrode capacitance had relatively high noise floors, which reduced the accuracy and consistency of the EMG signal measurements.


The use of mobile technology in e-learning (M-TEL) can add new levels of experience and significantly increase the attractiveness of e-learning in medical education. Whether an innovative interactive e-learning multimedia (IM) module or a conventional PowerPoint show (PPS) module using M-TEL to teach emergent otorhinolaryngology–head and neck surgery (ORL-HNS) disorders is feasible and efficient in undergraduate medical students is unknown.The aim of this study was to compare the impact of a novel IM module with a conventional PPS module using M-TEL for emergent ORL-HNS disorders with regard to learning outcomes, satisfaction, and learning experience.This pilot study was conducted at an academic teaching hospital and included 24 undergraduate medical students who were novices in ORL-HNS. The cognitive style was determined using the Group Embedded Figures Test. The participants were randomly allocated (1:1) to one of the two groups matched by age, sex, and cognitive style: the IM group and the PPS group. During the 100-min learning period, the participants were unblinded to use the IM or PPS courseware on a 7-inch tablet. Pretests and posttests using multiple-choice questions to evaluate knowledge and multimedia situational tests to evaluate competence were administered. Participants evaluated their satisfaction and learning experience by the AttrakDiff2 questionnaire, and provided feedback about the modules.P<.001) and competence  after 100 min of learning. Although there was no significant difference in knowledge gain between the two groups , competence gain was significantly lower in the IM group compared with the PPS group . However, the IM group had significantly higher scores of satisfaction , pragmatic quality , and hedonic stimulation  compared with the PPS group. Qualitative feedback indicated that the various games in the IM module attracted the participants’ attention but that the nonlinearly arranged materials affected their learning.Overall, the participants had significant gains in knowledge  Generalism is one of the most important aspects of the novel 6-year program of undergraduate medical education (UME) that was implemented in Taiwan in 2013. The goal of UME is to provide graduates with core knowledge and skills at the highest level of competency and then to become general physicians  is 5-5290C. Emergent ORL-HNS disorders are sensitive and acute and require many consultations for the patients to receive appropriate point-of-care service and follow-up . We seleTo design effective instructional material, we analyzed our tasks and topics and needs of 10 undergraduate students after traditional ORL-HNS lectures . We thenSubsequently, the content was translated into an e-learning app including a novel gamified IM module and a conventional visual-auditory text-image PPS module. We created an 80-min storyboard for each module, and both modules had the same design of user interface . We alsoThe PowerPoint Show (PPS) ModuleIn the PPS module, we used video lectures to present the visual-auditory text-image context (multimedia learning) that was intended to reduce the cognitive load . We recoThe Interactive Multimedia (IM) ModuleThe content for the novel IM module was derived from and corresponded to the textbook-based learning material of the conventional PPS module. In the IM module, we used a game-based learning method to implement the instruction, in which the learners operated a character to run, jump, and interact with other characters (in a parkour style) to obtain learning materials (7 text-image slides per disorder) in the four domains of the 10 disorders . The insr=.91, P<.001). Major bug fixes were performed before the pilot study.Two investigators from the study team reviewed the instructional content of each module using the Software Evaluation Checklist . This chThe inclusion criteria were as follows: (1) age >20 years and (2) undergraduate medical students . The exclusion criteria were (1) previous ORL-HNS training and (2) declining to participate.There were six different face-to-face assessments in this study.FD and >12 as FI in this study.The 25-item Group Embedded Figures Test (GEFT) was given to the students after enrollment to assess their cognitive style . The relemergent ORL-HNS disorders. Each textbook-based MCQ was designed to be answered within 90 seconds. We established a pool of 100 MCQs and performed empirical analysis according to previous test results to determine the test difficulty and item discrimination. Before this study, the instructional content was reviewed by 2 members of staff to determine whether it was sufficient to answer all of the questions. They also used a table of specifications to ensure that there was a match between teaching and testing. Moreover, they performed judgmental analysis of the items and subsequently revised the poorly constructed items or removed the questions with an inappropriate (too easy or extremely difficult) level of difficulty. Accordingly, we constructed two different 10-question MCQ tests with the same levels of difficulty (moderate difficulty) and discrimination (good discrimination).In this study, the participants were required to complete the same MCQ pretest and another different posttest immediately after the M-TEL. A 15-min 10-question standard MCQs were used to evaluate the students’ knowledge  with regard to The participants were required to complete the same MST pretest and another different posttest immediately after the M-TEL. The MST was a variation of the key feature test for assessments of clinical reasoning ability involving knowledge and intellectual skills  . A key flearner satisfaction after the M-TEL. GSS was measured using a visual analogue scale from 0 (very dissatisfied) to 10 (very satisfied).We used the global satisfaction score  to measure user learning experience. The AttrakDiff2 questionnaire was developed to evaluate the acceptance of technical innovations focusing on user experience [We used the AttrakDiff2 questionnaire to compare perience . The cenquality of learning. Each participant in this pilot study also provided anonymous feedback about the quality of the module used after the M-TEL.We used anonymous feedback to assess The students were unblinded after randomization. The students in the PPS group used an app on a 7-inch tablet to watch video lectures in 10 linear-designed sessions and review the instructional materials in an ordinary office environment for 100 min. Meanwhile, the IM group played a parkour-like game to find and read the instructional materials, completed small game-based quizzes, and reviewed the instructional materials.The percentage change in MCQ score (ie. “knowledge gain”) after the M-TEL was the primary outcome measure. The percentage changes in MST , GSS, and AttrakDiff2 questionnaire scores were the secondary outcomes.There were 6 students who helped to establish and evaluate the M-TEL system for emergent ORL-HNS disorders . In this pilot feasibility study, we needed to confirm that the students could gain knowledge and competence significantly. We estimated the sample sizes by a priori calculation  and found that we needed at least 7 subjects for knowledge gain and at least 21 subjects for competence gain. Due to a fixed block size of 6, we determined that the sample size of the pilot study was 24.U test as appropriate. Categorical variables were analyzed using Fisher exact test. Effect size and 95% CI were estimated using the Hodges-Lehmann method for Mann-Whitney U test and Wilcoxon signed rank test and odds ratio calculation Fisher exact test to improve the quality of the reporting of our results. Statistical analyses were performed using G*Power 3.1.9.2 software , Graph Pad Prism 7.00 for Windows , and IBM SPSS Statistics 23.0 .Due to the relatively small sample size in the pilot study, we analyzed all variables using a nonparametric approach. Descriptive statistics were expressed as median and 95% CI. Percentage (%) changes  in the MCQ and MST were calculated. Differences between groups were analyzed using the Wilcoxon signed-rank test or the Mann-Whitney Twenty-four volunteers  were recruited in the pilot study. P<.001; compared with the neutral value of 0) and a significant improvement in MST score  after 100 min of learning.Overall, all participants showed a significant improvement in MCQ score , PQ , HQ-S , HQ-I , and ATT .The M-TEL positively impacted the GSS  and competence , whereas the IM group had a significant improvement in knowledge  but not competence .P=.55), the percentage change in MST in the IM group was significantly lower than that in the PSS group . P=.01), PQ , and HQ-S scores  compared with the PPS group.Although the percentage change in MCQ was not significantly different between the two groups ,” contained “enjoyable small game-based quizzes,” and was an “amazing learning experience.” However, they also considered it “difficult to use and follow,” that it contained “nonlinear instructional materials” and “some tough games.”To the best of our knowledge, this is the first study to investigate the benefits of M-TEL to improve knowledge and competence of emergent ORL-HNS disorders. Our findings indicate that using well-designed M-TEL instructional materials can help undergraduate medical students to reinforce their existing knowledge (intermediate effect) and competence  of such a sensitive and important subject and provide an enjoyable learning experience . In addition, our findings suggest that an IM module has the potential to provide an instructional approach to enhance knowledge as effectively as a PPS module. Although the PPS module was superior to the IM module with regard to competence gained , the students preferred the IM module to the PPS module because of it being more efficient and enjoyable to use . However, qualitative feedback recommended that both modules needed to have better quality of design and function. Since the development of the IM module was more time-consuming (3 months vs 1 months) and more expensive  than that of the PPS module, the IM module needs to be further improved with regard to competence gain in the future. For example, we can modify the IM model according to the teaching strategies and principles of instructional design and pedagogy used in virtual patient cases to support the development of clinical reasoning skills .Some caveats of our study merit comment. First, we included a convenience sample which may have led to exclusion bias. A more even distribution of the cognitive styles will provide more accurate data. However, FD volunteers are not frequently encountered in our undergraduate medical students (less than 10%). Moreover, it is very difficult to perform probability sampling at a regular medical school. Second, we did not investigate social interaction, self-motivation, and self-regulation (important elements of e-learning) in detail -25. The The role of M-TEL, especially as it pertains to the undergraduate medical student, is evolving. It is superior to classical learning in that it provides opportunities to learn outside of the classroom via the Internet and computer software . A systeMost previous studies have compared interactive e-learning with text-based learning or classroom lectures. Fundamental differences among these learning methods such as a learner-focused design  and unliUnlike traditional classroom lectures, learners can start and stop M-TEL (or text-based learning) at any time or place of their choosing . When M-The use of different learning strategies is one of the most important prerequisites of academic success among undergraduate medical students and can lead to a positive attitude toward learning . M-TEL u


Understanding the association between parental socioeconomic position and self-harm in adolescence is crucial due to its substantial magnitude and associated inequality. Most previous studies have been either of cross-sectional nature or based solely on self-reports or hospital treated self-harm. The aim of this study is to determine the association between parental socioeconomic position and self-harm among adolescents with a specific focus on gender and severity of self-harm.A total of 165,932 adolescents born 1988–1994 who lived in Stockholm at the age of 13 were followed in registers until they turned 18. Self-harm was defined as first time self-harm and severity of self-harm was defined as hospitalized or not. Socioeconomic position was defined by parental education and household income. Cox proportional hazards regression were used to estimate hazard ratios (HR) with 95% confidence intervals (CI).Analyses showed an association between parental socioeconomic position and self-harm. Among adolescents with parents with primary and secondary education compared to tertiary parental education the HR were 1.10 (95% CI 0.97–1.24) and 1.16 (95% CI 1.08–1.25) respectively. Compared to the highest income category, adolescents from the lower income categories were 1.08 (95% CI 0.97–1.22) to 1.19 (95% CI 1.07–1.33) times more likely to self-harm. In gender-stratified analyses, an association was found only among girls. Further, restriction to severe cases eliminated the association.This study suggested that low parental socioeconomic position is associated with self-harm in adolescence, predominantly among girls. The desertion of an association among severe cases may be explained by differences in suicidal intent and underlying psychiatric diagnosis. Efforts to prevent self-harm should consider children with low parental socioeconomic position as a potential target group. Self-harm refers to a range of behaviors in which individuals deliberately initiate actions with an intention to harm themselves regardless of types of motivation or the extent of suicidal intent , 2. ThisDue to the magnitude and gender difference associated with self-harm among adolescents, it is of great importance to further understand the mechanisms of self-harming behavior. The existing literature show that many different factors such as adverse childhood effects , 19, bulThe majority of available studies regarding the association between socioeconomic position (SEP) and self-harm have been cross-sectional in design and based on either solely diagnoses of self-harm in inpatient care or on self-reports of non-clinical self-harming behaviors. Self-harm treated in outpatient care has not been studied much yet. In this longitudinal study, we exploit Sweden’s extensive and high-quality registers for both inpatients and outpatient cases of self-harm based on a large population of adolescents in Stockholm. The overall aim of this study is to determine the association between parental socioeconomic position and risk of self-harm among adolescents with a specific emphasis on gender difference and severity of self-harm.This cohort study was based on the Stockholm Youth Cohort (SYC), a record-linkage comprising all children aged 0–17 years who lived in Stockholm County at any time from 2001 to 2011. Data in SYC is derived from national and regional administrative and health care registers. Adolescents in SYC were identified through the total population register  and linkThe study population consisted of 169,262 adolescents comprising of seven birth cohorts, born between 1988 and 1994, who lived in Stockholm County at the age of 13, withdrawn from SYC. The study period extended from 2001 to 2011, with each of the seven birth cohorts being followed for 5 years, from age 13 to 17. Adolescents with missing values on at least one of the explanatory variables or the outcome variable (n = 3300) were excluded and the final study population consisted of 165,932 adolescents.First-time self-harm, from here-on referred to as self-harm, was the main outcome of the study and was ascertained through individual record linkage to national administrative registers and regional health care registers, covering all pathways of diagnosis and care related to self-harm, except private clinics. The registers were: (1) the VAL database, a Stockholm County register on public health care services which includes out-patient, in-patient and primary care, (2) the Cause of Death register and (3) Pastill, a clinical database covering all visits to child and adolescent psychiatry in Stockholm. Self-harm was defined according to the tenth revision of the World Health Organization (WHO) Classification of Diseases (ICD-10)  in the VAL database, Cause of Death register and Pastill. In Pastill, self-harm was additionally defined by a diagnosis of suicidal attempt and by self-harm as a contact reason. Only the first episode of self-harm during age 13–17 was used.Severity of self-harm was defined based on the level of care rendered to individuals: those who received inpatient care for self-harm were considered as severe cases and those who received outpatient care for self-harm were considered as less severe cases. The most common reasons to be hospitalized for self-harm in Stockholm County is suspected or identified suicidal attempt. It is also more common among those hospitalized to have substance related disorders and, to some extent, anxiety disorders as underlying psychiatric diagnoses, whereas psychosis and bipolar disorders, neurodevelopment disorders as well as disruptive, impulse-control and conduct disorders were less common in both groups. Depressive disorders and anxiety disorders are the most common comorbid psychiatric diagnoses in self-harm both with and without hospitalization. Hospitalization requiring admission for at least one night was considered as inpatient care.Socioeconomic position (SEP), the main exposure, was measured the year the adolescent turned 12. SEP was measured in two ways, parental education and household disposable income. Information on SEP was extracted from the longitudinal integration database for health insurance and labor market studies (LISA). Level of education was categorized into three categories based on number of years of completed education: up to 9 years (primary education), 10–12 years (secondary education) and >12 years (tertiary education). The highest educational achievement of either parent was used to define parental education. Household disposable income was categorized into quintiles, with consideration of year of income determination in addition to the actual income to ensure that approximately equivalent income groups were compared over time. The first and fifth quintiles represented the lowest and highest household income categories respectively.Demographic factors—age, gender and parental country of birth—were assessed using information from the Total population register. Age was used as a continuous variable. Parental country of birth was categorized in three groups: Sweden if a single parent or both parents were born in Sweden, outside Sweden if a single parent or both parents were born outside of Sweden, and mixed if one parent was born in Sweden and the other outside Sweden.Social and economic factors used in this study were number of parents in the household and receipt of welfare benefit. A household was regarded as having received welfare benefit if anyone in the household received benefit, once or several times, during the year the adolescent turned 12; the data was extracted from LISA. History of mental disorder of biological parent was defined when a biological parent was hospitalized for at least one night due to any mental disorder. The information was obtained from the National Hospital Discharge register from 1964 until the adolescent turns 13 years old.The characteristics of the cohort were described using descriptive statistics. Incidence rates for self-harm were calculated per 100,000 person-years. Proportionality of the hazard assumption was checked using log minus log graph. Analyses were performed using Cox proportional hazard regression to assess the association between self-harm, SEP and other relevant covariates and to estimate hazard ratios (HR) with corresponding 95% confidence intervals (CIs). Time under risk was calculated using the entry date defined as the date the adolescent turned 13 years of age, and the exit date as the date of the first-time diagnosis of self-harm, date of death of any cause, date of moving out of Stockholm County or the end of follow-up, whichever came first.Stratified analyses were performed by severity of self-harm, to assess the role of severity of the self-harm; and by gender to address gender differences. We considered receipt of welfare benefits, parental country of birth, number of parents in the household and mental disorder of biological parent as potential confounders/mediators. SAS version 9.3 was used for all statistical analyses.A summary of the characteristics of the cohort is presented in Table A total of 3230 adolescents had a documentation of self-harm during the study period, which correspond to an incidence rate of 400 per 100,000 person-years, substantially higher for girls than boys. The incidence rate of self-harm was highest among adolescents whose parents had primary education and lowest among adolescents whose parents had tertiary education. The incidence rate of self-harm was highest among adolescents from households with 2nd quintile income category and lowest among adolescents from households with 5th income quintile category.First-time self-harm among boys was most common at age 17 and least common at age 13. Among girls, first-time self-harm was most common at age 14 and least common at age 13  cases of self-harm in this study helps to address this rarely studied portion of the self-harming population and to make more comprehensive conclusions. The gap in the data caused by missing information about the parental education, household income and other covariates were few ranging between 1.3 and 2.0% (n = 3300). And there was no significant difference found in risks of self-harm because of these missing values. Using multiple variables to assess SEP, which measures different aspects of the concept, helped to give a broader perspective as underlying pathways are multifaceted and complex. Literature suggested that variables which measure SEP should not be used interchangeably as they measure different aspects of socioeconomic positions and refer into different causal mechanisms , 55.One limitation in this study lies in the use of health care registers and limits our analyses to cases of self-harm for which care has been sought. Compared to other recent population-based survey studies, the figures for self-harm are lower in this study which indicate that many adolescents who self-harm do not seek treatment . The tenAnother concern in this study was a possible non-differential misclassification of parental SEP and other social characteristics which could have occurred due to two reasons. First, only one household was recognizable for adolescents who passed equivalent or different amount of time residing in the homes of separated parents, as children in Sweden are registered at a single address . Second,The association between parental SEP and self-harm among adolescents suggests that prevention strategies should apply the principle of proportionate universalism giving emphasis to underprivileged sections of the population, within a population-wide strategy, to avoid broadening of health inequalities. In light of the above-mentioned limitations, further longitudinal studies incorporating survey data into the register data are recommended to estimate the magnitude of the problem by including adolescents with self-harm who are not seeking medical care. There is also a need for further studies to understand in depth the reasons why SEP affects girls more than boys. Finally future studies focusing on further investigating the relation between SEP and the different methods of self-harm, taking gender differences into consideration, are recommended.This study suggested that low parental SEP is associated with a higher risk of self-harm in adolescence, predominantly among girls. This association was not found among more severe cases of self-harm which may indicate that differences in health utilization between socioeconomic groups, showed in earlier studies, are less pronounced if adolescents suffer from self-harm with suicidal intention or substance-related disorders as underlying psychiatric diagnosis.


Increasing interests in stretchable electronic devices have resulted in vigorous research activities, most of which are focused on structural configurations. Diverse structural configurations are available for stretchability, including stiff-island, serpentine, and buckled structures. With easily deformable shapes and simple fabrication processes, buckled structures have the potential to realize stretchability. However, conventional buckled structures exhibit stretchability only in a single-axis direction. In the present study, a new type of cross-buckled structure, which can overcome the limitations of conventional buckled structures is developed. The stretchable thin film solar cells with the cross-buckled structure showed stable mechanical and electrical characteristics under both stretching and compressing conditions. The cross-buckled structure for stretchable electronic devices is expected to broaden the fields of wearable electronics, stretchable displays, and biocompatible applications. Rendering stretchability to electronic devices involves accommodating for stretching, flexing, bending, and other deformations along one or more axes11. However, conventional active device materials, mostly metals and semiconductors, are too rigid and brittle to achieve the required stretchability in electronic devices13. Therefore, most studies are focused on modifying the structural configuration to develop stretchable electronic devices using conventional active device materials.Increasing demand for high-performance applications such as wearable devices, bio-inspired electronics, and aerospace equipment has instigated rapid progress in the field of stretchable electronics16. In particular, the buckled structure is a widely used configuration in stretchable devices and fabrication of buckled structure is well-established18. Various kinds of stretchable electronic devices using buckled structures have been reported as their mechanical properties can be easily modified by controlling the period and height of the single-buckled structure20. However, in conventional buckled structures, stretchability of the buckled device is ensured only along a single axis and is mostly dependent on the stretching conditions of the same axis. Therefore, a new approach is needed to improve the performance of stretchable electronic devices using the established buckled structures.In the field of stretchable electronics, a variety of structures has been employed, including serpentine, stiff-island, and buckled structuresIn this study, we developed cross-buckled structures that can overcome the abovementioned limitations of conventional buckled structures, for the realization of stretchable electronics. The cross-buckled structure with orthogonally positioned buckled ribbons is a reliable structure even under multi-directional strains and can be fabricated using simple transfer printing process. We investigate the effect of compressive strain on the cross-buckled structures for the first time by testing the reliabilities of single- and cross-buckled structures under compressive strain, as opposed to previously reported studies, which mostly focused on deformation along a single-axis during stretching. The easily amendable size and spacing of the cross-buckled structure can lead to the manufacture of diverse semiconductors as stretchable electronic devices in textile patterns. Stretchable textile electronics based on cross-buckled structures will have a significant impact on various high-performance applications demanding stretchability.21. Before transferring the device layer to the stretchable substrate, silicon dioxide (SiO2) was deposited on the bottom of the detached device layer through the patterned shadow mask. The patterened SiO2 acts as a functional group for the formation of chemical bonds with the stretchable PDMS substrate22. By controlling the number of intervals between the chemical bonds, buckles with different periods and heights can be formed. Cross-patterned device layers were fabricated by repeating the transfer printing process of the device layers on the biaxially pre-strained substrate. After the transfer printing process, the cross-buckled structure was obtained by releasing the biaxial prestrains.Figure 24. Among them, controlling the intervals between each chemical bond is the easiest approach to develop a particular configuration of the buckled structure. Figure Controlling the period and the height of the buckled structure is crucial for the fabrication of the cross-buckled structure because the upper buckled ribbon at the intersectional area of the cross-buckled structure should have no contact with the bottom buckled ribbon. First, controlling the period and the height of the single-buckled structure were verified by fabricating buckled aluminum electrode which is a widely used metal electrode for electrical interconnections. In general, the period and the height of buckled structures are affected by various parameters such as amount of prestrain, mechanical properties of the material, thickness of the material, and intervals of each chemical bondAs a first demonstration of the cross-buckled structure, we manufactured cross-buckled aluminum electrodes by a simple transfer printing process. Contrary to conventional buckled structures, prestrains were applied biaxially on the stretchable substrate. Therefore, the configuration of the cross-buckled structure appeared quite different from those of conventional buckled structures. Figure 25. The amount of the tensile strain is proportionally asymmetrical compared to that of the compressive strain, which induces minor deformations to the cross-buckled aluminum electrode. In Fig. Figure The electrical reliability of the cross-buckled aluminum electrode was confirmed by a lighting test using light emitting diodes (LEDs). Figure sc), the open circuit voltage (Voc), and the fill factor (FF)  Fig. . In addiFF) Fig. . Thus, t25. The deformation of the cross-buckled thin film silicon solar cell under the compressive strain was found to be much less than that under the tensile strain. Therefore, the characteristics of the cross-buckled thin film silicon solar cell were stable even under the compressive strain caused by the application of 50% of the tensile strain.As mentioned before, the application of single-axis directional tensile strain to the stretchable substrate resulted in orthogonal compressive strain. Thus, we also demonstrated the stability of the cross-buckled thin film silicon solar cells under compressing for the first time, whereas most of the studies on buckled structures are focused on the configuration and the properties during stretching. Figure Figure In this study, although we demonstrated only 6 lines of cross-buckled thin film silicon solar cells on a laboratory scale, the simple and optimized fabrication process can be expanded to produce textile structures. In addition, the thin film silicon solar cell is a promising candidate for applications such as portable power supply for wearable electronics. Thus, the textile thin film silicon solar cells with the cross-buckled structure can function as portable power supplies by attaching them to the surfaces of fabrics or human skin.We developed cross-buckled structures of thin film silicon solar cells that exhibit reliable mechanical and electrical characteristics under multi-directional tensile and compressive strains. The properties of the cross-buckled thin film silicon solar cells were stable under various types of deformation including twisting, bending, folding, and stretching, whereas conventional buckled structures exhibit limited stretchability only in single-axis direction. As demonstrated in multi-directional stretching, the properties of the cross-buckled structure were also verified under the compressive strain induced by orthogonal stretching. We employed simple transfer printing process and biaxial prestrain to fabricate the cross-buckled structure. This technique can be easily modified and adapted to the desired configuration of stretchable electronic devices by controlling the intervals of each chemical bond. We also demonstrated that the cross-buckled thin film silicon solar cells can be fabricated in textile pattern through optimized repetitive transfer printing process, thus broadening the scope of the cross-buckled structures. The stretchable cross-buckled structures can be applied to various stretchable electronic devices without the need for optimization of complex processes to meet the target configuration. This attempt to manufacture new type of buckled structures to realize stretchability encourages future developments in the area of stretchable electronics.Conventional soda-lime glass was cleaned with acetone, isopropyl alcohol, and deionized water in a sonication bath. A 100 nm thick germanium layer was deposited on the cleaned glass substrate by electron-beam evaporation. The germanium oxide layer was formed by dry oxidation of germanium at 510 °C for 45 min using a conventional furnace.Uniform layers of thin film silicon solar cells were deposited by cluster-type plasma enhanced chemical vapor deposition (PECVD) and sputtering. First, a 500 nm thick aluminum doped zinc oxide (AZO) layer, as the bottom electrode, was deposited on the substrate at the substrate temperature of 200 °C by sputtering. The p-type, the n-type, and the intrinsic amorphous silicon layers were deposited at thicknesses of 13, 25.7, and 460 nm, respectively, at 250 °C by PECVD. Subsequently, a 300 nm thick AZO layer, as the top contact layer, was deposited on the thin film silicon layers by sputtering at the substrate temperature of 200 °C. Finally, a 100 nm thick aluminum layer, as the top electrode, was deposited on the top AZO layer by thermal evaporation.2 was deposited on the bottom of the aluminum electrode using a patterned shadow mask to form localized chemical bonds. The aluminum electrode was transfer-printed onto the prestrained PDMS substrate. By releasing the prestrain, the stretchable PDMS substrate was elastically relaxed back to its original shape, and the areas of the aluminum electrode between the localized chemical bonds popped up, forming the buckled structure at specific intervals.The aluminum electrode was patterned by the lift-off technique. Polyimide was spin-coated on top of the aluminum electrode to encapsulate all the device layers, and was patterned by reactive ion etching (RIE). Encapsulated aluminum electrode was separated from the substrate by etching the sacrificial layer with deionized water using the PDMS stamp as the transferring holder. SiOThe top and bottom AZO layers were etched with dilute hydrochloric acid and the thin film silicon layers were etched by RIE. Polyimide was spin-coated on top of the thin film silicon solar cells to encapsulate all the device layers, and then patterned by the RIE. The width and length of a single solar cell ribbon are 1.24 mm and 14.46 mm, respectively. The thin film silicon solar cells were separated from the substrate by same transfer printing process with buckled aluminum electrode. All the thin film silicon solar cells were transfer-printed onto the biaxially prestrained substrate in the shape of textile using the PDMS stamp. By releasing the biaxial prestrain, the squeezed buckled structure was positioned in the middle of the buckles by biaxial compressive strains, and large buckles were formed in the intersectional area of the cross-buckled thin film silicon solar cells due to the absence of chemical bonds.The properties of the solar cell were determined under AM 1.5 G illumination  at 25 °C. The cross-buckled thin film silicon solar cells were subjected to tensile and compressive strains using a stretching machine in order to verify the mechanical and electrical reliability.