Ecosystem functioning and human well-being critically depend on numerous species interactions above- and belowground. However, unraveling the structure of multitrophic interaction webs at the ecosystem level is challenging for biodiverse ecosystems. Attempts to identify major relationships between trophic levels usually rely on simplified proxies, such as species diversity. Here, we propose to consider the full information on species composition across trophic levels, using Procrustes correlation and structural equation models. We show that species composition data of a highly diverse subtropical forest―with 5,716 taxa across 25 trophic groups― reveal strong interrelationships among plants, arthropods, and microorganisms, indicating complex multitrophic interactions. We found substantial support for top-down effects of microorganisms belowground, indicating important feedbacks of microbial symbionts, pathogens, and decomposers on plant communities. In contrast, aboveground pathways were characterized by bottom-up control of plants on arthropods, including many non-trophic links. Additional analyses based on diversity patterns revealed much weaker interrelationships. Our study suggests that multitrophic communities in our forest system are structured via top-down effects of belowground biota on plants, which in turn affect aboveground arthropod communities across trophic levels. Moreover, the study shows that the consequences of species loss will be more complex than indicated by studies based solely on diversity. Food web analyses have revealed important interaction pathways for subcomponents of these community webs6. However, at the ecosystem level such analyses based on direct feeding observations are only feasible for moderately diverse systems with typically tens to a few hundred species8. In highly biodiverse regions analyzing community webs of higher eukaryotic species and including data on microorganisms at an ecosystem scale requires alternative approaches10. This is because direct observation of the numerous interactions is extremely resource intensive and sometimes hardly feasible for entire communities . In such cases, covariance-based approaches have proven useful in providing a framework for testing hypotheses on the structuring of community webs12.Interactions of multitrophic communities drive ecosystem functions and the provisioning of ecosystem services13. However, diversity proxies are usually not sufficient to unveil the functional structure of community webs15. Finer resolution data on species compositions for a whole-ecosystem-level analysis of community relationships have been used less frequently17. This is despite the fact that correlations among species compositional patterns and analyses of subsets of such webs have revealed the usefulness of these data for identifying key interaction pathways21. Importantly, these webs also include indirect and non-trophic relationships22 that necessarily remain undetected by analyses of feeding interactions, but play important roles in structuring ecosystems23.A frequently used approach to unravel such relationships among highly diverse communities at the ecosystem level relies on simplified proxies, such as species diversity or abundance24) and the causal links in ecological communities 25) have been developed in the past, but they have been used largely independently from each other12. Combining such methods to integrate the large information content of multivariate community data sets into statistical modeling has a high potential to advance our understanding of community webs by helping to develop informed hypotheses on the structure and functional role of such webs in complex ecosystems.The analysis of such relationships across trophic levels faces a major difficulty since there is a wealth of plant, animal, and microbial taxa, for which we do not even have the vaguest idea about how they interact. As the number of possible relationships among species increases exponentially with species richness, statistical tools are required to distinguish probable from possible interactions among taxa in species-rich systems. Ideally, these tools allow identifying the direction of community relationships across multiple trophic levels, i.e. a discrimination of top-down and bottom-up effects. Powerful tools to provide insight into patterns of community congruence among organism groups  and abiotic  characteristics of forest ecosystems. In mature forests, the influence of bottom-up effects of the producer level on higher trophic levels might therefore predominate over potential top-down effects of consumers on trees. Many studies have reported strong bottom-up, tree-controlled impacts on the diversity or composition of individual groups of organisms at higher trophic levels, both belowground33 and aboveground35. However, whether bottom-up control predominates when it comes to the structuring of community associations across the multiple groups of organisms at multiple trophic levels in biodiverse forests remains poorly explored.The structure of community webs is particularly poorly understood for species-rich ecosystems, such as subtropical and tropical forests, which are strongly affected by species interactions across trophic levelsHere, we use species composition data of 25 trophic groups of plants, arthropods, and microorganisms—representing a total of 5,716 species and operational taxonomic units—to unravel key community relationships and their potential bottom-up and top-down effects in a highly diverse forest. The data were collected on 27 study plots that represented the range of successional stages and woody plant diversity typically encountered in the highly diverse study region. We developed an approach that combines the strengths of Procrustes correlation analysis of principal components analyses (PCA) and SEM (using the site scores of the first two PCA axes) to analyze below- and aboveground multitrophic community patterns (see Methods). We explored the potential causal links between trophic levels by testing for direct and indirect relationships and the support for bottom-up and top-down control of these relationships, while accounting for potential environmental covariation. Moreover, we compared the community-based relationships to species richness and diversity relationships among the 25 trophic groups to assess the degree to which relationships among taxa are potentially driven by diversity patterns.12. Considering the longevity of trees, they might have a stronger impact on the long-term dynamics of the multitrophic community structure in forests and outweigh the temporally more variable top-down effects of pathogens, herbivores, and soil symbionts. We expected to find a strong discriminative power of species composition data that might complement the more frequently conducted analyses of diversity patterns in biodiverse systems.We hypothesized that the main relationships both below- and aboveground are primarily bottom-up controlled, because plants are key drivers of nutrient flows and environmental conditions in many ecosystemsOur analyses revealed an unexpectedly high number of significant relationships among the community composition patterns of all trophic groups . Both organism groups contribute to nutrient recycling and may therefore be important for the mobilization of soil resources utilized by plants.34. These findings emphasize the important role of plant communities in directly structuring community patterns not only of herbivores, but also of predators and parasitoids35, in the aboveground forest compartment. In this context, it is notable that our SEM analysis showed comparatively more links between plant and predator communities than between plant and herbivore communities. Previous studies have shown that even higher trophic levels, such as predators, can be strongly influenced by plant community composition16, and our results highlight the importance of such, probably largely non-trophic, effects for community patterns at the whole-ecosystem scale. Non-trophic bottom-up effects might occur, for example, through modification of abiotic properties or resource availability. Recent studies have indicated that leaf density, bark structure, litter properties, and other morphological characteristics, which vary among tree species and influence microclimate and habitat space, can significantly affect the species composition of predator assemblages45. In some cases, the relationships between plants and predators could even involve a trophic component, because many “predators” might utilize plant resources, such as nectar from extrafloral nectaries or flowers, in addition to animal prey. This is well-known for ants, but also applies to rather strict predators such as many spiders and wasps46. However, woody plants with extrafloral nectaries are uncommon at our study site47, making a strong impact of such effects less likely. Nevertheless, the results of our study reveal interesting directions for further research on the effects of plant species composition on higher trophic levels.In contrast to the belowground compartment, the strong support for bottom-up control of aboveground biota by plants is in accordance with the hypothesized patterns. Our results conform with previous findings on diversity relationships among individual taxa in our study system as well as in others27. Such top-down effects were implied in our study by the links between herbivores and plants in the top-down model. However, these seem to have less effect on the main relationships, as indicated by the poor fit of the top-down model. Rather, our results point to the intriguing hypothesis that the structuring of aboveground arthropod communities is indirectly influenced by the strong top-down effects that belowground microorganisms have on the plant communities. Such indirect structuring effects across ecosystem compartments, mediated by producer communities, have repeatedly been shown for specific taxa or subcomponents of community webs50, but remain less well explored for the structuring of entire, species-rich ecosystems. While the complexity of our data hinders us from directly testing these indirect effects across compartments, such linkages would have important implications for our understanding of how the effects of biodiversity loss and environmental change might cascade through ecosystem compartments and trophic levels51.The strong support for the bottom-up model in the aboveground compartment does not necessarily preclude potential top-down effects from contributing to the structuring of community patterns across trophic levels52.It is notable that both tree and herb layer plant community composition showed a large number of links with higher trophic levels (in both the above- and belowground compartments). While this reflects the degree to which taxa are associated with specific vegetation strata, it particularly highlights the important role of the herb layer (which provides the recruits for the next generation of tree species) in the structuring of the community webs in species-rich forests12, which, however, was conducted in a much less complex, experimental grassland system and did not differentiate among groups of herbivores or predators. On the other hand, our results are consistent with those of previous studies on individual trophic groups in our study system, which found that many effects of woody plant species richness or diversity acted on higher trophic level abundance rather than on richness or diversity patterns54. Moreover, species richness relationships among plants, arthropods, and microorganisms in our studied forests were found to be highly non-linear across spatial scales39. These results underline that addressing taxon-specific responses to the mechanisms underlying the structuring of community relationships at the local scale requires consideration of species identities and distributions. Analyses based on species richness or diversity may therefore strongly benefit from being complemented by analyses of community composition data55.The analyses of species richness and diversity patterns yielded fewer and qualitatively different links across trophic levels compared to the community composition analyses. This shows that our approach can provide insight into the structuring of ecological communities that apparently are not revealed by analyses of richness or diversity patterns. The comparatively weak connections across trophic levels in the richness and diversity analyses  deviate from the findings of a similarly comprehensive study33. Our study shows that in addition to such environmental effects, interactions among organism groups play an important role in structuring community relationships across trophic levels.The relationships shown in the community and diversity webs were controlled for changes in environmental conditions among study plots. Nevertheless, strong effects particularly of the first environmental PCA axis (PC1) on many organism groups indicate that the structuring of multitrophic communities of course also depends on abiotic conditions that vary spatially or with succession. The environmental variables particularly associated with PC1 were local temperature patterns and soil nutrient conditions (C and N concentrations). Many previous studies have highlighted the importance of these environmental parameters on the abundance and species composition of above- and belowground taxaIn summary, our results show how detailed community analyses that go beyond simplified diversity metrics can help to reveal important relationships and their relative dependence on top-down and bottom-up control across ecosystem compartments even in highly species-rich ecosystems. Our analytical approach emphasizes the importance of species identities and community composition in revealing many of the trophic and non-trophic linkages that contribute to structuring biodiverse ecosystems, linkages that may go unnoticed with more aggregated diversity data. Our approach allows for the simultaneous incorporation of species-level data, and their potential top-down or bottom-up effects, for the multitude of organism groups that make up ecosystems and their functioning. At the same time, it allows controlling for covariation that might arise from shared environmental influences, which means that our method can help to reveal direct or indirect species interactions. Our findings indicate that top-down control of microbial plant symbionts and pathogens has a strong structuring effect on the plant communities in our biodiverse forest system. These effects might indirectly cascade to the aboveground compartment via bottom-up effects of plants on arthropod communities. Ultimately, an in-depth mechanistic understanding of the observed patterns will benefit from direct observations of interactions among species to validate our correlational approach, but obtaining such data for the full set of thousands of species in biodiverse ecosystems is illusive. Our approach might be modified to help identify key species sets for further experimental and observational research, for example by the sequential filtering of species from the community matrices that contribute significantly to explaining community concordance.Schima superba Gardn. et Champ. and Castanopsis eyrei (Champ. ex Benth.) Tutch. Mean annual temperature is 15.3 °C and mean annual precipitation ca. 2000 mm , Zhejiang province, South-East China . The reserve comprises about 8,000 ha of evergreen mixed broadleaved forest on sloping terrain . Dominant tree species are  mm ref. .57.In 2008, we established 27 study plots of 30 m × 30 m in the reserve. We used a stratified sampling design to capture the typical range of woody plant species richness (25–68 species per plot) and successional age (from <20 to >80 years since the last logging events) encountered in the GNNR. The study plots were randomly spread across the accessible parts of the reserve39.Our analyses were based on 25 groups of plants, arthropods, and microorganisms, with a total of 5,716 species or operational taxonomic units that are characterized, in the case of heterotroph organisms, by specific functional characteristics of feeding ecology and trophic rank57), and species forming the herb layer (<1 m plant height41).Plants, as the stand-structuring organisms, were subdivided into woody species forming the tree and shrub layers , ectomycorrhizal fungi (ECM), saprophytic fungi, parasitic fungi, and the eight most abundant bacterial phyla .54 into strictly predatory ants and omnivores that, in addition to scavenging and hunting, also feed on plant-based resources such as honeydew. Herbivores/primary consumers (termed herbivores hereafter) comprised moth and butterfly caterpillars (Lepidoptera), weevils (Coleoptera: Curculioninae), longhorn beetles (Coleoptera: Cerambycidae), and bark beetles (Coleoptera: Scolytinae). Macrofaunal decomposers were millipedes (Diplopoda) and isopods (Isopoda) .Arthropods were parasitoids, predators, herbivores/primary consumers, and macrofaunal decomposers. Parasitoids comprised parasitic wasps . Predators were spiders (Arachnida: Araneae), centipedes (Chilopoda), cavity-nesting solitary wasps , and ants (Hymenoptera: Formicidae). Because many ant species are not strict predators, we subdivided the ant data based on the trophic position of the ant genera57. At the same time, herb layer plant communities were surveyed with abundance and cover estimates in the central 10 m × 10 m of each plot (<1 m height41).The woody plant communities of each plot were inventoried completely, with all tree and shrub individuals >1 m height, in 200858 and the V3-V5 region of the bacterial 16 S rRNA genes59. Sequence datasets were further quality filtered, normalized to enable an unbiased comparison among plots to 10,000 fungal ITS and 20,000 bacterial 16 S rDNA reads per plot using MOTHUR60. Sequences were clustered into species-level operational taxonomic units (OTUs) using CD-HIT-EST at 97% pairwise similarity threshold59. Bacterial 16 S OTU representative sequences were assigned taxonomy against the Silva SSU reference database while fungal ITS OTU representative sequences were classified against the UNITE database40. Non-target taxa OTUs as well as singletons, doubletons and tripletons  were removed from the dataset. For further details on sample processing and sequencing see ref. Microorganisms were sampled with soil cores . Soil cores were sieved, cool-transported to the field lab and freeze-dried for molecular analysis. Microbial DNA was extracted from 1 g of each of the composite freeze-dried soil samples using the MoBio soil DNA extraction kit. Fungal and bacterial communities were analyzed by pyrotag amplicon sequencing of the fungal ITS62 against the functional reference dataset40. The bacterial dataset was split into phyla , because the functional grouping of bacterial communities is currently challenging38. The community data for most of these phyla were highly correlated (Procrustes correlations P < 0.001 and t >0.8 in many cases) and showed similar Procrustes correlation patterns with plants and other below ground taxa. Because this indicates highly redundant information among bacterial groups, we used Acidobacteria (highly correlated with Actinomycetes and Gammaproteobateria and exhibiting similar Procrustes correlation patterns as these two groups across the plants and other below ground taxa), Alphaproteobacteria, Bacerioidetes and Chloroflexi for further analysis. Delta- and Betaproteobacteria were excluded from the analysis, as they showed no significant Procrustes correlations with plants and other belowground taxa. The four retained taxa altogether accounted for more than two-thirds (73%) of the abundance and 67% of the OTUs within the eight most abundant phyla and can therefore be assumed to play a key role in structuring major community relationships of bacteria in the belowground compartment of our study system.The fungal reference sequences were assigned to ecological functional groups on the basis of sequence similarity using the default parameters of the GAST algorithm39. Epigeic spiders, centipedes, epigeic ants, weevils, isopods and diplopods were sampled with pitfall traps (4 traps per plot from March to September 200953). Beating of understory trees and shrubs was used to sample Lepidopteran larvae, arboreal spiders, and ants . Cavity-nesting predatory wasps and the associated parasitic wasps were sampled with reed-filled trap nests (2 traps per plot from September 2011 to October 201263). Longhorn beetles, bark beetles, and canopy ants were sampled with flight interception traps (4 traps per plot from May to August 201039). In addition, ants were sampled with standardized protein and carbohydrate baits (36 baits per plot in May 201247). All arthropods were identified to morphospecies or, where possible, species.Arthropods were sampled during the main growing seasons of the years 2008–20122O suspension), soil carbon (C) and nitrogen (N) content , and soil C:N ratio were determined from a bulk sample of nine soil cores (0–10 cm) per plot (taken in summer 200957).To account for potential covariation among organism groups due to similarities in the response to general plot characteristics, important spatial and environmental variables were included in our analyses. These variables characterize variation in both above- and belowground conditions that is due to spatial location or the successional age of the study plots. Latitude and longitude, plot elevation (m above sea level), slope (°), and degree of ‘northness’  were assessed during plot establishment in 2008. Mean annual temperature and mean January and July temperatures per plot were obtained from continuous measurements with HOBO data loggers . Soil pH . All remaining arthropods were assigned to the aboveground compartment. Tree- and herb-layer plants were considered as the links between both compartments, as they can strongly determine both belowground  and aboveground  ecosystem structure. As specified below, we first tested for congruence in community patterns among the studied organism groups, and then constructed overall models of community relationships based on these congruence patterns.24 in the R package vegan64, based on the site scores of principal components analysis (PCA) of species’ relative abundances. Standardizing the abundance data is necessary as sampling methods differ among organism groups and using raw species abundance data in PCA is not generally recommended65. Procrustes analysis has the advantage over simple linear correlation that it takes into account the full multivariate information of community data. It uses uniform scaling and rotation of the ordination solutions to minimize the sum of the squared residuals between data points of two datasets66. Significance of the correlations was assessed with the protest permutation procedure64, with 999 permutations. Statistical tests based on protest have been shown to be more powerful than Mantel tests for detecting community associations24. The expected number of false discoveries owing to multiple testing was calculated to adjust P-values67.Community congruence across organism groups was tested with Procrustes correlation analysislavaan68 to determine potentially causal links between the community patterns of the 21 organism groups we retained for analysis. Due to the large number of groups, and because relationships between the below- and aboveground organisms of our study can be assumed to be primarily mediated via the plant level, we conducted separate analyses for the below- and aboveground compartments, with tree- and herb layer plants as key structuring organisms included in all analyses. SEMs on community patterns were based on the site scores of the first two PCA axes for each organism group. These are the axes with the highest information content, representing the covariance structure of the species’ relative abundance patterns, and explaining on average 53.2% ± 16.5% SD of the total variance for the organism groups considered in our study. As similarities in community patterns among groups might be influenced by environmental conditions , we included the site scores of the first two axes of a principal components analysis on the 13 environmental and spatial parameters assessed for our study plots as covariables in the SEMs  in the R-package 25. The same procedure was applied to selecting significant organism-environment links. Relationships across trophic levels (e.g. plants- >herbivores) were fit as direct causal pathways, relationships within trophic levels (e.g. between predators) as covariances.Because of the large number of potential links, we assembled the starting configuration of the initial SEM models in three steps: (i) we only considered relationships between organism groups with significant (P < 0.05) Procrustes correlations. Of these relationships, we (ii) only selected the most significant one out of the four possible correlation combinations between the first two PCA axes of the two groups. Finally, we used (iii) modification indices provided in the SEM output to identify missing pathways, that are required to obtain adequate model fit, and we added these pathways sequentially to the model until a non-significant global solution was achieved12. Final model fits were indicated by a non-significant chi-square test (P > 0.05), low AIC, and low (<0.1) root mean square error of approximation 25.The initial models were simplified through stepwise removal of uninformative paths, until a minimum adequate model was obtained, based on the resulting reduction in the Akaike Information Criterion (AIC). This minimum adequate model can be viewed as the most parsimonious solution to explaining community patterns across organism groups and trophic levels, where only the most influential relationships are retained51) or top-down (i.e. by consumers) controlled, we fit two alternative models for both the above- and belowground compartments. In the bottom-up model, the direction of the paths and thus the flow of causality was from the producer level (plants) to the higher trophic levels (bottom-up control). In the top-down model, path direction was reversed . We considered fitting separate models most adequate to evaluate the support for overall bottom-up vs. top-down control. The relative support for bottom-up or top-down control was inferred by comparing the final models’ AIC values.To determine whether the community webs were primarily bottom-up , with either species richness or Shannon diversity of the organism groups instead of community-data PCA site scores as the data source.http://china.befdata.biow.uni-leipzig.de/datasets/587.Data are available at Supplementary PDF File


Autophagy is an evolutionarily conserved and intricately regulated cellular process in which damaged or aggregated proteins, organelles, and pathogen-derived components are engulfed by double-membrane structures, termed autophagosomes, and targeted for lysosomal degradation . The autAutophagy is induced upon infection by many different viruses from diverse families, yet the impact of the autophagic host response on viral replication is highly virus and cell-type specific . Some viA major family of antiviral molecules with approximately 80 members in humans are tripartite motif (TRIM) proteins, which are characterized by the presence of an N-terminal Really Interesting New Gene (RING) domain, one or two B-boxes, and a coiled-coil domain . While mA recent series of studies showed that autophagy and antiviral cytokine responses are intricately interconnected ,4. SeverInterestingly, recent studies demonstrated that several TRIM proteins are key regulators of both viral- and non-viral-induced autophagy, further supporting the intricate intertwining of IFN-mediated innate immunity and autophagy. In a cDNA screen, 31 out of 61 tested TRIM proteins triggered green fluorescent protein (GFP)-LC3B puncta formation, indicative of autophagy induction . An indeAt least two different mechanisms of action have been proposed for TRIM proteins acting in antiviral autophagy. Some TRIM proteins act as specific cargo receptors that directly recognize viral components and target them for degradation by autophagy. Other TRIM proteins regulate the activity of key signaling proteins involved in different steps in the autophagy pathway .The concept of TRIM proteins acting as “autophagy receptors” by recognizing viral proteins as cargo has been most well characterized for TRIM5α, which was initially discovered as an antiviral restriction factor that recognizes the HIV capsid protein . While OIndependent screening approaches identified several TRIM proteins that play essential roles in both nonviral and viral-induced autophagy, suggesting a key role for these TRIMs in the autophagic process –16. The The recent discovery of the role of TRIM proteins in viral autophagy opens up an entirely new area of research in antiviral intrinsic immunity. Whereas the mechanism of autophagy regulation is unknown for most TRIM proteins, it is becoming clear that some TRIM proteins act as receptors recognizing viral molecules, while others are critical components of the autophagy machinery that mediates virus clearance. Although most viruses induce autophagy, the viral signals that trigger autophagy as well as the upstream signaling pathways initiated upon virus-induced autophagy are not very well defined yet. Furthermore, as key autophagy proteins are known to be targeted by viral pathogens in order to evade or manipulate autophagic flux, it is likely that autophagy functions of TRIM proteins are targeted by specific viruses as well. Along these lines, the central role of TBK1 in IFN-mediated immunity is antagonized by a myriad of viral pathogens; however, it remains to be determined whether viral evasion strategies also target TBK1’s activity in autophagy-mediated antiviral defense. Moreover, many proteins known to play key roles in antiviral cytokine responses (including TRIMs and TBK1) have recently emerged as important regulators of autophagy. While some TRIM proteins regulate autophagy-mediated clearance of viral components, others direct the destruction of host innate immune components (such as inflammasome proteins or IRF3) via autophagy. Thus, it will be fascinating to investigate the dual roles of these molecules in both autophagy and cytokine responses during viral infection. Future discoveries in the area of autophagy-mediated host defenses by TRIM proteins may unveil new opportunities for therapeutic intervention in viral infectious diseases.


Pulmonary arteriovenous malformations are rare vascular abnormalities that permit direct communication between the pulmonary artery and vein. During pregnancy, pulmonary arteriovenous malformation carries an increased risk of enlargement and rupture, which could lead to life-threatening hemothorax. This is the first case reporting successful thoracoscopic surgery for a pregnant woman with pulmonary arteriovenous malformation rupture-related hemothorax.We present a case of a 32-year-old pregnant Asian woman (31 weeks’ gestation) whose pulmonary arteriovenous malformation ruptured, leading to right-sided spontaneous tension hemothorax. First, an emergency cesarean section for hypovolemic shock-related fetal distress was performed to save the baby. Immediately afterwards, video-assisted thoracic surgery with the single-incision approach allowed us to successfully obtain hemostasis and eradication of abnormal vasculature by conducting wedge resection of the pulmonary arteriovenous malformation.Emergency thoracoscopic surgery for a pregnant woman with pulmonary arteriovenous malformation rupture-related hemothorax is safe and feasible. In contrast to transcatheter arterial embolization, video-assisted thoracic surgery could simultaneously achieve hemostasis for prevention of mortality, eradication of abnormal vasculature, and removal of massive thrombi. Pulmonary arteriovenous malformations (PAVMs) are rare vascular abnormalities that allow direct communication between the pulmonary artery and vein, bypassing the capillaries. Most PAVMs are asymptomatic, but occasionally dyspnea may develop owing to a right-to-left shunt. Although hemoptysis and hemothorax are rare complications of PAVM, they can be life-threatening , 2. TherA 31 weeks pregnant 32-year-old Asian woman presented to our emergency department with the chief complaint of sudden-onset dyspnea and backache. Signs of acute respiratory distress, pallor with cold sweats, and hypotension (blood pressure 66/36 mmHg) were noted on arrival. According to her medical record, she had no history of significant systemic disease or medical events. She also denied any recent trauma.3/μl, white blood cell count, 23.37 × 103/μl). Laboratory results also indicated that her renal function, liver function, and levels of serum electrolytes were normal. Hypotension was transiently responsive to fluid resuscitation. A fetal monitor showed variable decelerations, indicating fetal distress. Breath sounds over her right lung field were diminished. Bedside chest ultrasound showed massive right-sided parapneumonic effusion, and thoracentesis yielded bloody fluid. Computed tomography angiography (CTA) of her chest displayed a large right-sided hemothorax with contrast extravasation from an arterial phase-enhanced lesion in the lower lobe of her right lung and mediastinal shifting to the left  was performed via a single incision (5 cm in length), which was located near the mid-axillary line in the seventh intercostal space. After removal of retained thrombus inside the pleural space measuring approximately 1800 mL, a ruptured PAVM was identified in the lower lobe of her right lung Fig. . After aHer postoperative recovery was uneventful. After taking analgesic medication (acetaminophen 500 mg four times a day), only mild wound pain was reported. Examinations of other organs did not identify any additional arteriovenous malformations. She was discharged 1 week later in a stable condition. She is currently healthy 18 months after surgery.PAVMs are rare vascular abnormalities that can cause life-threatening hemothorax when ruptured, especially in a pregnant woman. We present a case of a 31-year-old pregnant Asian woman (31 weeks’ gestation) whose PAVM ruptured, leading to right-sided spontaneous tension hemothorax. To the best of our knowledge, this is the first case using VATS with the single-incision approach instead of transcatheter arterial embolization (TAE) to successfully obtain hemostasis and eradication of abnormal vasculature by conducting wedge resection of the PAVM.PAVMs most commonly occur as a manifestation of hereditary telangiectasia, an autosomal dominant vascular disorder previously known as Osler–Weber–Rendu syndrome . Other cThere are two recommended therapeutic options for the treatment of patients with PAVM: TAE and surgical resection . In cases of massive hemoptysis or hemothorax, surgery is the therapy of choice . TAE is Pregnant women with PAVMs are at risk of PAVM enlargement and rupture, especially in the third trimester . During In two previously reported cases, pregnant women with PAVMs developed spontaneous hemothorax at the 31st  and 36thIn the present case, we performed an emergency cesarean delivery followed by thoracoscopic exploration. The use of VATS exploration allowed us to: (1) clearly identify the ruptured and bleeding PAVM and successfully achieve hemostasis by removing the PAVM via wedge resection of the lung; (2) identify another small PAVM on the surface of the lung that may not otherwise have been identified with computed tomography or angiography; and (3) remove massive thrombi intraoperatively, which greatly reduced the duration of indwelling chest drainage.While angiography can be performed immediately after an emergency cesarean section to diagnose PAVMS and for the embolization of PAVMs, this approach may not always be ideal. First, unless a hybrid operation setting is available, it is likely that the patient will be transferred to an angiography room in an unstable hemodynamic status. Second, retained thrombi in the hemithorax may cause passive pulmonary atelectasis, which may prolong chest tube drainage. Thus, performing thoracoscopic surgery instead of angiography following the patient’s cesarean section may be preferable, since immediate and definitive hemostasis can be achieved, along with thrombi removal to provide excellent lung expansion, as was the case in our patient.Although angiography has been utilized previously to diagnose PAVMs and achieve hemostasis in pregnant women, immediate thoracoscopic surgery following emergency cesarean delivery may be a more appropriate method, as wedge resection of the PAVM to control bleeding and removal of massive thrombi can be performed simultaneously and safely.


Thoracic endovascular repair (TEVAR) is an effective treatment for type B aortic dissection (TBAD). Here, we evaluated the early-midterm effectiveness and safety of TEVAR for treating TBAD patients after renal transplantation. Six patients with TBAD treated with TEVAR after renal transplantation were recruited between February 2012 and December 2016. They were then followed up with clinical examinations and computed tomography angiography (CTA). TEVAR was successfully performed in all patients (100%), and the primary tear sites were well covered by stents with or without coverage of the left subclavian artery. No severe complications occurred in any patient during perioperative period. The one-year survival rate was 100%, one patient died of renal graft failure and heart failure four years after TEVAR; the remaining five patients (83.3%) survived and exhibited no severe complications. Our findings show that TEVAR provides satisfactory short-midterm results for TBAD patients after renal transplantation. Moreover, our experience shows that it need relative longer proximal landing zone to prevent the endoleak and recurrence. However, regular hematodialysis, long-term immunosuppressive therapy, and blood pressure control remain crucial factors to prolong survival. Long-term follow-up studies are needed to evaluate the long-term prognosis in these patients. Aortic dissection (AD) is a catastrophic cardiovascular disease, with a prevalence of 10/100,000 in elderly adults , 3. AD iThoracic endovascular repair (TEVAR) is an effective and minimally invasive treatment compared to open surgery, and is currently widely adopted in treating TBADs. The ultimate goals of TEVAR for TBADs are to cover the entry and re-entry tear site of the dissection and restore normal blood flow in the true lumen , 10-11. TEVAR was successfully performed in all patients, including the coverage of the primary tear site with or without coverage of the left subclavian artery (LSA). The LSA was completely covered in patient 1 and patient 6, and partially covered in patient 3 due to a limited landing zone. We chose the left femoral artery as the operative approach in four patients to prevent the impairment of renal function. In two patients whose renal grafts were not perfused, we delivered the stent graft through the right femoral artery. The mean time of operation was 54.2 minutes (48-64 min), and the mean usage of contrast agent was 73.3 ml (60-90 ml).During postoperative hospitalization, all patients survived without severe complications, including paraplegia, left upper limb ischemia, cardiac or cerebral events and multiple organ failure. While the oxyhemoglobin saturation of patient 3 transiently dropped below 90% on the 3rd day after surgery, the 12th day postoperative CTA showed that the false lumen had already partially thrombosed although pleural effusion was increased. At the 3-month CTA, the pleural effusion disappeared and the false lumen was further narrowed. An increase in pleural effusion was detected in another patient but was absorbed later during follow up. One patient had chest pains after TEVAR that were relieved after 15 days. Patient 2 and patient 4 experienced fever during postoperative hospitalization; this was expected as these two patients received metacortandracin therapy after renal transplantation. The infection was well controlled after antibiotics administration following pharmacy department consultation. Four patients with working renal grafts had mild increase of serum creatinine on 2nd postoperative day; the other two patients received dialysis treatment on 1st postoperative day. Table Follow-up was done by phone calls and outpatient visits after surgery; the general condition, renal function, blood pressure, and CTA surveillance of the patients were evaluated. CTA was performed before discharge, 3 and 6 months after discharge, and then yearly thereafter. Assessment of endoleak, stent graft migration, and the expansion of aortic diameter was performed by CTA. During the 12-48-month follow-up period, no patients had endoleak or stent graft migration. Thrombosis of the proximal false lumen without enlargement was detected by CTA in all patients, while the retrograde blood flow from distal tear site was present in five patients Figure . We alsoThe etiology of AD after renal transplantation is multifactorial. Recently, cardiovascular disease (CVD) was reported in 25% to 53% of patients after renal transplantation . PatientIn the past 40 years, we found eleven cases of AD after renal transplantation, including four type A aortic dissections (TAADs) and seven TBADs -28. RobeTBAD after renal transplantation should be considered a complicated TBAD because these patients have fragile blood vessels, frequently accompanied by hypertension. In addition, the right iliac artery had been bypassed to the renal artery. Damages may occur to the anastomotic stoma when the stent delivery system goes through the right iliac artery to the aorta, resulting in the impairment of renal function. Fortunately, preoperative CTA showed that the majority of the left iliac artery cavity originated from the true lumen in four patients. Therefore, we chose the left side as the operative approach, and the right side in two patients because of renal graft failure. The stent should be delivered through contralateral side in patients with functional renal grafts. Subsequent CTA showed that no renal artery stenosis or thrombosis was present. Although postoperative follow-up results showed that renal function declined in two patients, we believe that it was related with chronic anti-rejection response, stop using anti-rejection medicine (patient 5), nephrotoxicity of long-term use of medication, and hypoperfusion of renal graft caused by iliac artery dissection. All contrast agents have certain nephrotoxicity, but iodixanol is a non-ionized contrast agent that is characterized by isotonicity and is safer for patients with renal transplantation. Reducing the usage is the key to relieve the renal function damage ; adequatIn conclusion, our study shows that thoracic endovascular repair has satisfying short-midterm results for type B aortic dissection after renal transplantation. Besides, we hold that it need relative longer proximal landing zone for preventing the endoleak and recurrence. However, regular hematodialysis, long-term immunosuppressive therapy, and BP control remain crucial factors to prolong survival. Long-term follow-up studies are needed to evaluate the long-term prognosis of thoracic endovascular repair in these patients.This retrospective study was approved by the Ethics Committee of our hospital, and all patients in the study signed consent forms before the operation. The recruited patients presented with TBAD after renal transplantation and received TEVAR from February 2012 to December 2016. There were five male patients and one female patient aged 29 to 62 years old, with an average age of 42.5 years. The etiology of renal failure was varied: three cases resulted from glomerulonephritis, one case resulted from primary nephritic syndrome, and another two cases were due to acute renal failure. Among them, five cases were acute or subacute AD, and one case was chronic AD. Detailed information regarding these six patients is shown in Table All patients received TEVAR in the catheter room under general anesthesia and endotracheal intubation. After intraoperative angiography, we measured the diameters of the proximal and distal landing zones and selected the appropriate stent grafts that were 10%-20% oversized. We delivered the cover stent graft to the aortic arch through the femoral artery to cover the proximal entry tear with or without coverage of the left subclavian artery. The distal side of the aorta was compressed by the false lumen in patient 1 Figure , and thu


Inflammatory skin disorders that cause serious deterioration of the quality of life have become one of the major public concerns. Despite their significance, there is no fundamental cure to date. Mesenchymal stem cells (MSCs) possess unique immunomodulatory properties which make them a promising tool for the treatment of various inflammatory diseases. Our recent preclinical and clinical studies have shown that MSCs can be successfully used for the treatment of atopic dermatitis (AD), one of the major inflammatory skin diseases. This observation along with similar reports from other groups revealed the efficacy and underlying mechanisms of MSCs in inflammatory dermatosis. In addition, it has been proposed that cell priming or gene transduction can be novel strategies for the development of next-generation high-efficacy MSCs for treating inflammatory skin diseases. We discuss here existing evidence that demonstrates the regulatory properties of MSCs on immune responses under inflammatory conditions. Inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis are considered major public issues with increasing prevalence due to the rapid industrialization of modern society ,2. TheseSince the first identification of MSCs from bone marrow (BM) as precursor cells of osteogenic lineage in 1970 , a subseAlthough it is somewhat conflicting whether MSCs are immunoprivileged or immunoevasive, MSCs are typically regarded to have hypo-immunogenicity because of their low expression level in major histocompatibility complex (MHC) class I molecules, and lack of MHC class II and co-stimulatory molecules, including CD80, CD86, and CD40, which enables MSCs to be safely used for allogeneic environment without potential risks for immune rejection ,32. FurtMSCs have been revealed to possess distinct immunomodulatory properties which induce immune tolerance in diverse inflammatory conditions . Since tBased on in vitro results that BMSCs inhibit the proliferation of T lymphocytes  and in vMSC-mediated immunomodulation has also been examined in various inflammatory skin conditions especially unresponsive to conventional therapy. In the field of dermatology, the vast majority of studies used IV administration of allogeneic BMSCs as the primary regimen to investigate immunomodulatory effects on cutaneous inflammation. Indeed, a number of clinical data support the therapeutic efficacy and safety of IV injected BMSCs in both acute and chronic GvHD with skin manifestations , skin syDermatosis is considered to have a great importance in terms of public health owing to the high prevalence and chronicity despite the non-fatal nature of the diseases. In addition, skin symptoms frequently cause disfiguration, disability, and complications with inconvenience, which can result in considerable physiopsychological burdens on patients. While MSCs therapy in dermatology was initiated as a concept of cell replacement remedy for skin defects and wound healing, accumulating evidence has recently suggested that MSC-mediated immunomodulation can be usefully applicable to the treatment of inflammatory skin conditions. In fact, the beneficial results have been observed in various preclinical models of inflammatory skin diseases, including AD, psoriasis, and scleroderma as well as autoimmune disorders that affect the skin, including GvHD and SLE . Based o+ helper T (Th) cell and CD8+ cytotoxic T lymphocyte (CTL), both of which can differentiate into different effector subsets upon antigen-specific activation by antigen-presenting cells (APCs). Naïve Th precursor cells can differentiate into Th1, Th2 and Th17 subsets in response to the certain cytokine milieu. CD8+ precursor cells can also develop as different subtypes similar to Th cell counterparts. Moreover, regulatory T (Treg) cells that suppress the activation of effector cells are concomitantly generated to maintain immune homeostasis.GvHD is a debilitating complication that might frequently develop after allogeneic BM or hematopoietic stem cell transplantation (HSCT). It is estimated that the incidence of GvHD is approximately 80% of patients with human leukocyte antigen (HLA)-mismatched GvHD and less frequently up to 50% even in HLA-matched GvHD. This disease can be classified into two forms, acute and chronic GvHD, depending on the time of onset and disease severity. The most commonly affected organs by acute GvHD are skin, liver and gastrointestinal tract, whereas manifestations by chronic GvHD can appear anywhere . In acut+ and CD8+ T cells and NK cells. Therefore, Th1-mediated CTLs have initially been regarded as major effector cells in acute GvHD, but several recent studies have reported an involvement of Th2 cells and IL-22-producing CD4+ T cells. By contrast, chronic GvHD has traditionally thought to be closely linked with Th2-cell responses. More recently, various studies have suggested that Th1, Th17 and Treg cells as well as B cells might contribute to the development of the disease [The diverse T cell responses play a critical role in the development of cutaneous GvHD. Recent experimental results using animal models have revealed that the pathomechanism of acute GvHD largely consists of three sequential phases. Activated host APCs under HSCT condition result in the activation, proliferation and migration of immunocompetent T cells transferred from the donor, subsequently substantial tissue damages occur mainly by CD4 disease .Classically, early studies showed that MSCs can effectively inhibit the proliferation and differentiation of T lymphocytes through various mechanisms, including induction of cell cycle arrest , direct Lupus erythematosus (LE) is a multifarious immune-mediated disease with a broad spectrum of clinical presentations provoked by impairment of self-tolerance and autoimmunity. Clinical manifestations of the disease may affect multiple tissues and organs, including the renal, neural, cardiovascular, musculoskeletal and cutaneous system with varying degrees of severity . AlthougFas mutated MRL/lpr and NZB/W F1 mice have been widely used as experimental animal models of SLE to explore the therapeutic potential of MSCs. Indeed, IV administration of allogeneic MSCs efficiently improved multiorgan dysfunction in both MRL/lpr mice [0/G1 phase without the induction of apoptosis [lpr mice ,67 and Nlpr mice . Althougpoptosis  and supppoptosis  or solubpoptosis . In addipoptosis , whereaspoptosis  , platelet-derived growth factor (PDGF), TGF-β and IL-4, induce fibroblast activation and extracellular matrix compound (ECM) deposition . ParticuAlthough several studies have shown the marked therapeutic potential of BMSCs and UC-MSCs in bleomycin-induced rodent SSc models, these results have been limited only to anti-fibrotic effects against the lung fibrosis and injuries but not the systemic manifestations including cutaneous scleroderma ,122,123.Although none of these models perfectly reproduces the human disease condition, in vitro and in vivo results afford a sufficient basis for the clinical benefit of MSC transplantation in patients with SSc. The first clinical case report by Christopeit et al. represented that systemic delivery of haploidentical allogeneic BMSCs significantly improved the skin symptoms in a patient with severe generalized SSc . The secPsoriasis is a common chronic autoimmune disease manifesting mainly in the skin and joint, or both, which affects approximately 2%–4% of the worldwide population ,125. AloThe pathogenesis of psoriasis is represented by DCs and T cell-mediated immune responses with complex cellular networks including macrophages, keratinocytes and neutrophilic granulocytes. Particularly, Th1 and Th17 subsets are widely considered the primary effector cells in psoriasis . In the There have been several attempts to apply allogeneic or autologous HSCT to patients with severe psoriasis and comorbidities over the last two decades. However, HSCT has been reported to have a greater risk of developing secondary autoimmune diseases, such as thyroiditis, myasthenia gravis, ulcerative colitis and insulin-dependent diabetes mellitus ,136,137.According to the NIH ClinicalTrials.gov database, the only clinical trial (NCT02491658) is currently underway using UC-MSCs for patients with moderate-to-severe psoriasis vulgaris. Based on early results of this clinical study, both patients infused with UC-MSCs remained relapse free of psoriasis for four to five years . An addiAD, also referred to as atopic eczema, is a representative inflammatory dermatopathy that features eczematous skin lesions with nasty pruritus, resulting from abnormal allergic immune responses against certain types of antigen, so-called “allergens”. It is estimated that AD affects approximately up to 20% of children  and 10% Dermatophagoides farinae (Df)-induced murine AD by inhibiting MC degranulation. Particularly, local SC injection of MSCs exhibited more remarkable therapeutic potential in AD mice compared with IV administration. PGE2 and TGF-β1 secreted by hUCB-MSCs are responsible for the suppression of MC degranulation and FcεRI expression, respectively [Despite the development and application of intensive treatments including biologic targeted therapies like dupilumab (anti-interleukin (IL)-4 receptor), AD cannot be cured completely at present. Therefore, several studies have examined the therapeutic effects of MSCs against AD-like symptoms in experimental animal models. Na et al. demonstrated that IV injected syngeneic and allogeneic BM-derived clonal MSCs (cMSCs) can attenuate the severity of ovalbumin (OVA)-induced murine AD by reducing the infiltration of immune cells and IL-4 expression in the skin lesions and down-regulating the serum IgE level. Inhibition of T cell function via direct cell contact and nitric oxide (NO) production as well as suppression of IgE production through inhibition of class switch DNA recombination (CSR) were proposed as principal mechanisms of cMSCs . Consideectively . Since Mectively . Althoug7 cells)-treated group exhibited a 50% reduction in the Eczema Area and Severity Index (EASI50) without any noteworthy side effects. This is so far the only and first-in-class clinical study demonstrating efficacy and safety of allogeneic MSC therapy for patients with AD. However, further clinical studies with more patients and placebo group as well as mechanistic investigations verifying the mechanisms of crosstalk between MSCs and disease-related immune cells would make up the current lack of knowledge in this field.Later on, the therapeutic efficacy of hUCB-MSCs was consistently confirmed by clinical trials (phase I/IIa) with moderate-to-severe AD patients . The sin+ and CD8+ effector cells as well as Treg cells. When sensitized individuals are re-exposured to the same allergen, sensitized effector T cells homing from dLNs secrete a variety of cytokines and chemokines, resulting in tissue damages and recruitment of other immune cells to the skin lesion. This phase is called the elicitation or challenge phase of ACD. MCs present in the ACD skin have been reported to participate in amplifying immune responses of elicitation phase through the secretion of TNF-α and IL-8 [Repeated contact with specific allergens or irritants can cause epidermal inflammation and subsequent symptoms including a localized rash, which is defined as contact dermatitis. It is one of the most common dermatoses in human with a socioeconomic significance due to the intimate correlation between its prevalence and occupational attribute ,156. Theand IL-8 .+ T cells, Th17 and MCs in skin lesions, and the increased Treg population at the dLNs and the contact area. GMSC-mediated suppressive effects on DCs and MCs were mediated by PGE2-dependent mechanisms [The hapten-induced murine CHS has been used as a preclinical model for human ACD. As haptens are not immunogenic by themselves but able to elicit immune responses only when binding to a protein, they have been frequently used as the most suitable allergen substitute to reproduce human disease. Lim and colleagues reported that IV infused BMSCs alleviated the murine CHS through the NO-mediated induction of activated T cell apoptosis in the dLNs . In addichanisms . Similarchanisms .MSC-based cell therapy has been spotlighted as a promising approach for the treatment of inflammatory skin disorders, and relevant clinical trials are ongoing. We have highlighted the current knowledge about the interaction between MSCs and immune responses in inflammatory microenvironment of various dermatoses. Overall, MSCs seem to specifically target immune-competent cells in disease progression to attenuate their responses to inflammatory triggers. MSCs use a wide range of anti-inflammatory cytokines that suppress excessive immune responses and protect adjacent tissues. The interesting point is that the immunoregulatory activity seems to be critically altered by the microenvironmental milieu that MSCs encounter after their infusion . Indeed,Another advantage of MSCs as therapeutics is their homing effect after in vivo administration. Indeed, several studies have demonstrated that MSCs can engraft into inflammatory lesions where they might exert immunomodulatory effects ,159. HowMore recently, researchers have tried to establish highly efficient MSCs due to their slightly limited therapeutic efficacy in clinical trials. Although satisfactory results have been observed in most of the phase I trials, MSCs have been shown only moderate efficacy in further phases per se. Therefore, novel strategies to facilitate the therapeutic benefits of MSCs are extremely required. The main potential drawback of MSC therapy is their “hit-and-run” mechanism , thereby


With increasing use of cardiac fluoroscopic intervention, the incidence of fluoroscopy-induced radiation ulcer is increasing. Radiation ulcer is difficult to manage and currently there are no treatment guidelines. To identify the optimal treatment approaches for managing cardiac fluoroscopy-induced radiation ulcers, we retrospectively reviewed medical records of 13 patients with fluoroscopy-induced radiation ulcers receiving surgical interventions and following up in our hospital from 2012 to 2015. Conventional wound care and hyperbaric oxygen therapy were of little therapeutic benefit. Twelve patients received reconstruction with advancement flap or split thick skin graft. One-stage radical excision of radiation damaged area in eight cases with immediate reconstruction led to better outcomes than conservative excisions in four cases. Radical surgical excision to remove all the radiation damaged tissues in combination with immediate reconstruction appears to offer the optimal treatment results for cardiac fluoroscopy-induced radiation ulcers. Adequate excision of the damaged areas in both vertical (to the muscular fascia) and horizontal (beyond the sclerotic areas) dimension is pivotal to achieve good treatment outcomes. Although guidelines for a safe radiation use during interventional procedures have been proposed1256789101112The managements for skin damages resulting from radiotherapy and those from cardiac catheterization are very different. This is because the radiation beams used in these two settings are different in term of physics characteristics, energy levels, biological reactions and depth-dose distribution. Radiotherapy for cancer uses either beta ions or high-level energy photons at the energy level of mega-electron volts (MeV) or mega-volts (MV), while the radiation source for fluoroscopy is X-rays with a low energy level between 40 and 140 kilo-volts (KV). When a high-level radiation photon beam enters the body, it loses only little energy in the skin and subcutaneous tissue and deposits most of its energy at the deeper area , whereasThis retrospective study complied with the guidelines of the Declaration of Helsinki and was approved by the Medical Ethics Committee of Kaohsiung Veterans General Hospital, a tertiary referral center in southern Taiwan, with institutional Review Board approval (No. VGHKS15-CT3-08).By reviewing medical records from 2012 to 2015 in our hospital, thirteen cases with radiation ulcers were identified. All these 13 patients required surgical interventions to treat their cardiac fluoroscopic related ulcers. Their demographic data, procedures received, skin changes, surgical interventions, treatment outcomes and the associated complications were recorded and analyzed .All of the 13 cases were male, and their mean age was 58.5 ± 12.4 years (range: 43 to 81 years). Eight of them had diabetes mellitus; but none of these diabetic cases had history of diabetic ulcers in limbs. None of these 13 cases had autoimmune disease or peripheral arterial occlusive disease. Twelve patients received percutaneous coronary interventions for coronary artery disease, and one patient underwent electrophysiological ablation for a refractory supraventricular accessory pathway. Notably, fluoroscopic interventions were performed at least three times in all patients. The estimated accumulative peak skin dose is 19.1 ± 5.3 Grays  and 24.7 ± 7.1 Gy  . The radAll cases had non-healing ulcers, which often worsened with conventional wound care, for at least 3 months. Five cases received hyperbaric oxygen therapy before surgery but no therapeutic effects were noted. One case received vacuum-assisted wound closure and hyperbaric oxygen therapy after repetitive conservative debridement. Although his wound became smaller, it failed to heal even after following up for 1 year. Like other cardiac diseases patients, repetitive anesthesia and wound debridement increase the risk of cardiac attack in these patients. One of our patients indeed developed unstable angina during debridement and need further cardiac fluoroscopic interventions to control his cardiac ischemia.We categorized our patients into three groups according to their treatment modalities : Group AThe first five cases (case 1 to case 5) underwent three to five sessions of conservative debridement , aiming Patients in this group (case 6 to case 10), the debridement (excision) margins were extended laterally to the outer zone (exceeding the white sclerotic area) of damaged skin and vertically deep to the muscular fascia layer  and 4. RPatients in this group (case 11 to 13) received radical excision (the same excision method as group B) and immediate coverage with split thickness skin graft . All thrThe aims of treating radiation ulcers include preventing infection, controlling pain, closing wounds and preventing malignancy. When planning an operation, clinicians should bear in mind that the zone of radiation injury is larger than the area exhibiting clinical symptoms and signs, and inadequate excision inevitably leads to treatment failure. In addition, the residual radiation damaged tissue may increase the risk of subsequent radiation-related malignancies.As a general rule, the severity of radiation injury increases with accumulated exposure dose i.e. if the exposed dose is less than a threshold, the radiation dermatitis is typically not clinically detectable but once the accumulated exposure dose exceeds the threshold, radiation dermatitis occurs. To recover from the injury, the damaged tissues need stem cells either from radiated area or adjacent tissues. If enough number of stem cells still present, the lesion will usually respond to the conventional wound care. On the other hand, when a radiation ulcer appears, the adjacent tissues tend to suffer severe radiation damage as well. As a result, these tissues not only have limit ability to facilitate lesion site’s recovery but also impose further stresses on healing processes. Therefore, complete removal of these severely damaged tissues is the cornerstone of radiation ulcers managements. From our experience, this principle applies to all the radiation ulcers treatments, irrespective of the accumulated exposure dose.Another possible cause of radiation ulcer is radiation vasculopathyCardiac fluoroscopic procedures adopt the radiation energy levels at about 100 kV. Thus, most of the fluoroscopy-induced radiation damages are located within the superficial layers of skin and their severity decrease steadily down to deeper area . A typicTo achieve primary wound healing, reconstructive methods are usually necessary. However, it is not known whether a vascularized flap is better than a simple skin grafting in bringing wound healing in these patients15In the management of fluoroscopy-induced chronic radiation ulcers, one-stage radical excision with immediate wound reconstruction showed the best result in our study. It alleviates patients’ suffering and the risk of repetitive anesthesia. Adequate excision of the radiation damaged areas including the vertical  and the horizontal (beyond the sclerotic and telangiectasia area) dimensions is the key to achieve good treatment outcomes.This study focuses on the most severe radiation injuries (radiation ulcers), thus our findings can not be applied to the management of radiation dermatitis. Although the underlying diseases of these patients were diverse, none of them had history of diabetic ulcer, or peripheral arterial occlusive disease or autoimmune disease.How to cite this article: Wei, K.-C. et al. Management of fluoroscopy-induced radiation ulcer: One-stage radical excision and immediate reconstruction. Sci. Rep.6, 35875; doi: 10.1038/srep35875 (2016).


Readmission prevention is a marker of patientcare quality and requires comprehensive, early discharge planning for safehospital transitions. Effectively performed, this process supports patientsatisfaction, efficient resource utilization, and care integration. This studydeveloped/tested the utility of a predictive early discharge risk assessmentwith 366 elective orthopedic/cardiovascular surgery patients. Qualityimprovement cycles were undertaken for the design and to inform analytic plan.An 8-item questionnaire, which includes patient self-reported health, wasintegrated into care managers’ telephonic pre-admission assessments duringa 12-month period.2 = .334) and length-of-stay . Independent variables of“lives-alone” and “self-rated health” were statisticallysignificant for increased readmission odds, as was “self-ratedhealth” for increased length-of-stay. Quality measures, patient experienceand increased rates of discharges-to-home further supported the benefit ofembedding these questions into the pro-active planning process.Regression models found the questionnaire to be predictiveof readmission (p ≤ .005; Radvanceof elective admissions, it can facilitate pro-active discharge planningessential for producing quality outcomes and addressing new reimbursementmethodologies for continuum-based episodes of care.The pilot discharge risk assessment was predictive ofreadmission risk and length-of-stay for elective orthopedic/cardiovascularpatients. Given the usability of the questionnaire in  Whereas a surgical hospitalization can be categorized as a discrete medical episode,there are crucial pre-hospitalization, inpatient, and post-hospitalizationtransition points that require integration and communication across care settingsand clinical providers. These may serve to influence the overall quality and safetyof patient care and rehabilitative outcomes, including readmission. This pilotquality improvement study was conducted to facilitate an improved process forpatient risk assessment and early discharge planning in order to: 1) inform andintegrate care across the pre-, inpatient, and post-hospital settings 2) improvepatient experience and outcomes, and 3) engage patients/their caregivers in thepatient care planning process. Specifically, our pilot developed and tested theutility of an early discharge risk assessment questionnaire applicable to pro-activepre-admission discharge planning for elective orthopedic/cardiovascular surgerypatients. Furthermore, in addition to its potential for improving quality patientoutcomes, the pro-active approach to discharge planning piloted in this study isimmediately relevant to new reimbursement models emerging in the U.S. Medicaremarket that require enhanced coordination and efficiency across the continuum ofcarePrevention of hospital readmission is increasingly viewed as a marker of patient carequality, and identified by health plans as a key component of value-basedreimbursement methodology, including new models for U.S. Medicare reimbursementunder a comprehensive care payment model123436789101112Unfortunately, currently available risk assessment models and tools are not readilyapplicable to a general medical/surgical population 15161718.151617171920212221202317691516One meta-analysis, in particular, identified 26 unique models for readmission riskassessment . Many mo172021Undoubtedly, continued work to improve performance in this area is required todevelop better, not only more comprehensive approaches to risk assessment, but toimprove the discharge planning process as well. In fact, Allaudeen et al 2011)discuss the need for a systematic and consistent discharge process using risk factordata for targeting quality improving efforts [11discusThis quality improvement pilot was conducted by the Care Management Department atNYU Langone Medical Center (NYULMC), a major academic medical center in New YorkCity. NYULMC is a 1000+ bed multi-hospital system that provides tertiary andquaternary services to a diverse urban population. The patient target populationfor this initiative was 366 adult patients, aged 25 and above, electing to haveorthopedic hip or knee replacement surgery or cardiac valve surgery. These arehigh-volume surgical populations for our medical center.Excluded from this study were pediatric patients and non-elective emergent/urgentpatients. No patients were eliminated from this study based on their performanceon the risk questionnaire; the entire pool of available, electively admittedsurgical hip and knee patients were therefore included in this evaluation.With guidance from the NYU School of Medicine IRB, this initiative falls withinthe domain of quality improvement and not considered human subjects research. Itwas not a randomized, controlled trial. Thus, the project did not require IRBreview and meets our institution’s standards for ethical adherence inresearch.The study was designed to answer the following specific research questions: 1)Can a brief questionnaire be developed to identify early readmission riskfactors for more effective discharge planning; 2) Is there a statisticallysignificant relationship between patient’s self-rating of health andreadmission risk for elective surgical patients; and 3) Can these questions beused to identify risk for readmission and increased hospital stay prior toadmission or early in the hospital stay?A continuous quality process improvement approach192123262829303132333435362126The eight risk assessment questions were integrated into the care managerpre-admission discharge planning assessment process which was conductedtelephonically for patients one-to-four weeks prior to elective admission fororthopedic and cardiac surgeries scheduled during 2013–2014. Names of patientsassigned to the surgery pre-admission clinic registration for hip, knee, or cardiacvalve replacement were forwarded to the nurse care managers responsible for thesepatient groups. Patients were contacted by the care managers within 72 hours of thepatient name being added to the schedule. This could occur anytime betweenone-to-four weeks prior to surgery as determined by the surgeon in collaborationwith the patient. Care managers contacted patients via phone to conduct thescreening assessment, discuss what to expect during hospitalization, review methodsfor active patient/family participation and how to prepare for surgery, establishexpectations for hospital length-of-stay, and prepare a mutually agreed upon planfor care goals and for discharge from the hospital.Readmission and hospital length-of-stay outcomes were retrospectively evaluated inrelationship to the patient discharge risk questionnaire responses. Regressionanalyses were performed using SPSS version 23 to analyze data and an alpha level of.05 was set for all statistical tests. Stepwise logistic regression analysis wasperformed to determine which independent variable predicted likelihood ofreadmission within 30 days of discharge. Multivariate regression analysis wasperformed to examine predictive power of the questions vis-à-vis hospitalutilization (proxy utilization measure = length of stay). Transformation of thelength of stay (LOS) dependent variable was required for the regression analysis; LN(LOS) was used to adjust for the non-normal distribution in hospital length of staydata in order to conform to the assumptions of the regression model. For purposes ofresults discussion in this paper, LOS refers to the transformed variable of LN(LOS).Stepwise models examined the following independent variables: demographic variables and health insurance type; clinical variable(orthopedic or cardiac surgery); plus social/functional variables .Quality process measures were also retrospectively evaluated for (i) patientexperience with the transition of care and discharge as reported through theHospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patientexperience surveyThe majority of patients (89%) were elective orthopedic; 11% were electivecardiac. Payers included Medicare , Medicaid (5%), and commercial plans (42%). A majority (59%) ofpatients were female with 41% of the patients being male. 44% of the patientswere age 65 and older with the mean age being 65, median and modal age being 66.The average hospital length of stay for the study patients was 3.59 days. The overall 30-day readmissionrate for all patients in the pilot was 3.8% .2 = .334)and explained 33.4 percent of the variance in the outcome measure (i.e.readmission among study population). While cardiac patients, as expected due totheir clinical complexity, had over 11.0 times greater odds of being readmitted,the analysis (Model Five) demonstrated that when controlling for this and allother variables in the equation, patients who live alone have nearly a 5.0 timesgreater odds of readmission (p ≤ .05) and patients who have poor/fairself-rated health have approximately an 18.0 times greater odds of readmission(p ≤ .001).The stepwise logistic regression model Table  was predModel Four, with its statistically significant contributions for “livesalone” and “self-rated health” (two out of eight riskscreening questions) accounts for over 30% of the variance. Model Fiveincorporates the remaining 6 out of 8 risk screening questions. As can be seenfrom the results in Table 2 =.314) and revealed that poor/fair self-rated health was a significant predictorof increased length of stay . The stepwise regression modelexplains 31.4 percent of the variance in length of stay. The independentvariable of self-rated health was highly predictive of increased length of stay(p ≤ .05).The multiple regression model Table was predOther measures of effectiveness included (i) patient experience with caretransitions and discharge, (ii) care manager accuracy in predicting best optionfor patient discharge pre-admission compared to patient’s actual dischargedisposition, (iii) the percentage of patient’s able to be dischargeddirectly home compared to an interim skilled nursing or rehabilitation facility.Specific findings related to these measures are: Examples of these associatedmeasures of program effectiveness exhibited positive results as follows:th percentile to the 60th percentile for anoverall increase of 20% between the time of the start of the pilot in2013 compared to the experience scores received after the conclusion ofthe pilot in 2014 (p > .05 at p = .068). For the same time period,patient satisfaction with discharge increased from the 88thpercentile to the 95th percentile, for an overall increase ofgreater than 7% (p < .05 at p = .013).Elective orthopedic hip and knee surgery patient experience scores forsatisfaction with the care transition process increased from the50Percentage of knee replacement patients being discharged directly tohome, rather than to skilled nursing or acute rehabilitation care,increased from 42% (pre-pilot) to 60% after the conclusion of thepilot.Percentage of pre-admission discharge plans that matched the actualdischarge disposition increased from 62% (pre-pilot) to 82% after theconclusion of the pilot for knee replacement patients.This study of a discharge risk questionnaire and early planning process waspiloted on a specific orthopedic and cardiac surgery population. Thegeneralizability of its findings to the broader patient population is thereforelimited. In addition, although our study examined a sample of 366 patients, thelow rate of readmission occurrences, while certainly desirable from a clinicalperspective, necessitates caution in interpreting these findings. Thediscriminatory power of the discharge risk questionnaire, tested on a populationwith a relatively low number of outcome events , couldnot be examined. Further application of the risk questionnaire to a larger andmore diverse sample would enhance generalizability and allow for more advancedanalysis of the psychometric  and analytic  properties of the questionnaire.With regard to a potential source of confound, it should be acknowledged that thequestionnaire’s implementation could itself have influenced the outcome itwas aiming to predict. In this way, the questionnaire’s administration atpre-admission may have contributed to the patient’s course of treatment,discharge, and readmission. Indeed, this should have been expected and desiredgiven that the primary goal of the clinical staff was to optimize patient care.This systematic bias, however, would have served to weaken, not strengthen,observed relationships between questionnaire responses and outcome measuresbecause clinical intervention would have compensated for any anticipated need ofthe patient. Consequently, any relationship that emerged as statisticallysignificant can be viewed as especially robust given that the direction ofcontamination bias would have “stacked the deck” against it.As mentioned, future studies with a larger and more diverse patient populationwill be required to further elucidate the utility of this questionnaire. Giventhe timeframe and scope of this pilot quality improvement study, however, itsstatistically significant findings and its pre-admission discharge processnonetheless provide a useful starting point for care transitions redesignefforts for hospitals.Three primary lessons can be gleaned from this pilot study: 1) Early evaluation ofpatient utilization and readmission risk is possible and has the potential to impactthe quality and safety, and cost of patient care transitions: 2) Engagement of theclinician  is required for a comprehensive, effectiveworkflow to improve patient care planning and transition management; and 3) Directpatient input regarding self-rated health is a key variable in assessing patientrisk for extended utilization and readmission risk. Each of these three points isdiscussed in more detail below.To address the first point, in this pilot study, the discharge risk assessmentquestionnaire was administered in advance of hospital admission. Such pre-admissiondischarge risk assessment is a novel approach allowing clinicians to engage patientsand their caregivers at the earliest possible point in the care trajectory fortargeted discharge planning. This is highly important in order to quickly identifyand help to mitigate factors which may place surgical patients at risk for adverseoutcomes including re-admissions. Results demonstrated that the questionnaire holdspromise in predicting elective surgical patients with higher hospital utilizationand readmission risk. The benefits of early assessment are evident for both the caremanager and patient in allowing them to collaborate in planning for morepatient-centered discharges and aligning expectations for care planning and goalsetting, which may positively impact patient satisfaction, safety, and overallexperience.While a risk assessment questionnaire that can be initiated at the patient’searliest point of entry into the healthcare system may positively improve dischargeand care transition planning, it single-handedly, will not transform the quality ofcare transitions nor reduce readmissions. Nor can it be developed in isolation ofthe clinicians who carry out this essential work. This is the second importantlesson of our pilot study: the need to centrally involve the clinical nurse caremanager in the development process for both the risk questionnaire and theassociated discharge planning workflow. The partnership of nurse care managers wasof vital importance to this pilot initiative. The final risk questionnaire anddischarge planning model was clinically driven by our team of care managers,producing a questionnaire and approach that increased care manager ownership in, andfollow-through with, the process. As reported by the care managers, the availabilityof an easy-to-use discharge risk screening questionnaire was an effective method tofacilitate patient engagement, initiate further discussion related to patient goalsand preferences, and could be applied in real time to prepare the patient indeveloping an appropriate plan for safe discharge and care transition.Given that patients do not experience their care needs as discrete episodes , a comprehensive care management/transitionalcare effort is required which employs skilled clinical care managers to conducteffective preadmission planning, careful communication and coordination throughoutthe inpatient stay, and diligent discharge planning follow-through,inter-agency/provider interface, and patient outreach in the immediate post-acutecare days. Inclusion of clinicians, from the very start of the process, is criticalto overall success of the initiative and ultimately to the successful transition ofpatients across the healthcare continuum.Thirdly, and possibly the most important finding, the study demonstrates thatdirectly soliciting the patient’s rating of his/her health is a key predictorassociated with risk of re-hospitalization and utilization of hospital resources.While clinical, utilization, and demographic variables are common to high riskassessment, patient self-reported variables are not as common. The implication isclear: Patient input is important in assessing risk and in the discharge planningprocess. This pilot demonstrated that patients can be reliable sources ofinformation about their own health and their self-assessments can help to predictoutcomes. In our study, patient self-assessment of health and living alone werestatistically significant risk factors that may be considered “early warningsignals” of those patients with highest risk of readmissions or longerhospital utilization. Other variables, such as depression, functional status,previous admission history, etc., while expected to yield statistically relevantfindings based on previous results documented in the literature, did not. This maybe due to the mitigating effect of the care manager’s role in pre-admissionplanning and the level of patient engagement. It may also be related to sample size,or lack of generalizability of previous research findings to our specific surgicalpopulation. These non-statistically significant variables, however, did contributeto the overall positive findings of our model, and remain useful in providinginformation necessary for effective discharge planning and overall carecoordination/care transition processes.This unique pre-admission risk questionnaire was found to be predictive ofreadmission risk and increased length of stay in a pilot quality improvement studywith two elective surgical populations. Embedded into an early discharge planningprocess which incorporated mutually agreed upon patient-clinical goals, relatedfindings also support the questionnaire’s utility in improving patientsatisfaction with discharge and improvements in the percentage of patients able tobe discharged directly home, rather than discharged to nursing facilities followingsurgery.Given the flexibility of this questionnaire to be administered in advance of anelective surgery admission, it has the potential to support pro-active dischargeplanning decision making and early intervention to address patient needs in advanceof hospitalization and surgery. Such efforts are relevant not only to improved carequality, but to delivery of effective, integrated care transitions critical undernew healthcare delivery and reimbursement models.


Moreover, finely ground feed is known to trigger the development of ulcers and other pathologies of PN while coarsely ground feed protects from such lesions. The interactions between grinding fineness and DON contamination of feed were not examined so far. Therefore, both finely and coarsely ground feeds were tested either in the absence or presence of a DON contaminated wheat on growth performance and health of rearing piglets, including stomach integrity. DON contamination significantly reduced feed intake and serum albumin concentration with this effect being more pronounced after feeding the coarsely ground feed. Albeit at a higher level, albumin concentration was also reduced after feeding the finely ground and uncontaminated feed. Finely ground and DON-contaminated feed caused a significantly more pronounced lymphoplasmacytic infiltration both of PN and pars glandularis, partly paralleled by lymph follicle formation and detritus filled foveolae and tubes suggesting a local immune response probably triggered by epithelial lesions. It is concluded that DON contamination of feed exacerbates the adverse effects of finely ground feed on stomach mucosal integrity.The common feed contaminant deoxynivalenol (DON) was reported to influence the morphology of the  Fusarium-infected cereal grains. Under practical feeding conditions, most prominent toxic effects of DON include a decrease in feed intake causing a reduced live weight gain and contributing to the DON-associated immune-modulation -2,5-diphenyl-tetrazolium bromide (MTT) as described elsewhere [For lsewhere ,41. The pars nonglandularis and pars glandularis of the stomachs were fixed in a 10% formaldehyde solution buffered with CaCO3 for at least 24 h and embedded in paraffin. Tissues were then sectioned at a thickness of 5 µm and stained with hematoxylin and eosin (H & E) for histological examination. Tissue samples of The tissue sections were visually graded according to the occurrence of lymphoplasmacytic infiltration  blind to the treatments. Scores are reported as cumulative scores of two evaluated slides. For technical reasons, the samples of group CON-coarse were lost. Therefore, only groups CON-fine, FUS-coarse and FUS-fine were evaluated.Fusarium-toxin contaminated wheat, FUS) and structure, resulting from different sieve widths of the hammer mill used for feedstuff grinding, (Str)  and the interactions between CT and Str as fixed factors. Chyme characteristics  were analyzed according to a complete two by two by two 3-factorial design ANOVA with the intestinal segment  and the corresponding interactions as additional fixed factors. A “Repeated” statement was applied to account for possible dependencies of a specific parameter measured both in jejunum and caecum of the same animal. Performance parameters, clinical-chemical serum characteristics, results of the cell culture tests and organ weights were evaluated according to a complete two by two 2-factorial design of analysis of variance (ANOVA) with cereal type (CT) . Tukey test was used for De-DON concentrations in serum and histological lesion scores were not normally distributed and were evaluated by the non-parametric Mann–Whitney U test. Corresponding results were presented as medians and ranges (minimum–maximum).Finally, to visualize the relationships between the large number of variables in a two-dimensional space, a principal component analysis (PCA) based on correlations was performed additionally. The relationships between serum DON and albumin concentration were further examined by linear regressions and slope comparisons.All statistics were performed using STATISTICA 12.0 .


Long non-coding RNAs (lncRNAs) regulate critical cellular processes and their dysregulation contributes to multiple diseases. Although only a few lncRNAs have defined mechanisms, many of these characterized lncRNAs interact with transcription factors to regulate gene expression, suggesting a common mechanism of action. Identifying RNA-bound transcription factors is especially challenging due to inefficient RNA immunoprecipitation and low abundance of many transcription factors. Here we describe a highly sensitive, user-friendly, and inexpensive technique called RATA (RNA-associated transcription factor array), which utilizes a MS2-aptamer pulldown strategy coupled with transcription factor activation arrays for identification of transcription factors associated with a nuclear RNA of interest. RATA requires only ~5 million cells and standard molecular biology reagents for multiplexed identification of up to 96 transcription factors in 2–3 d. Thus, RATA offers significant advantages over other technologies for analysis of RNA-transcription factor interactions. Dysregulation of lncRNAs has recently been linked to multiple human diseases, especially cancer . While tin vitro transcribed, biotinylated RNA with cell lysate significantly increases efficiency of RNA purification . ASLNCR1 interactors (Brn3a and AR) [Because our methodology requires overexpression of the tagged RNA of interest, there are important potential caveats to consider when using this approach. First, inclusion of an RNA tag may affect secondary structure of the RNA, and therefore may also affect interactions with partner proteins. If possible, phenotypic or gene expression changes should be quantified following overexpression of either the untagged or tagged RNA to determine if the tag interferes with normal functionality of the RNA (Step 1.2.1). Ideal placement of the RNA tag may need to be determined empirically. Second, overexpression of RNA may increase/induce non-specific binding with proteins that do not interact with the RNA under physiological conditions. Thus, candidate RNA-transcription factor interactions identified through RATA should be validated through orthogonal assays. For example, RIP assays, in which an RNA binding protein of interest is immunoprecipitated and associated RNAs are identified through RT-qPCR, may be used to confirm if a candidate transcription factor interactor identified through RATA maintains its interaction with endogenous RNAs . Indeed, and AR) .® based assays capable of quantifying 40 transcription factors in up to 96 samples  in a single plate. The wide variety of transcription factor arrays available enables great flexibility in assay design. The selection of a transcription factor array depends on the RNA being studied and the type of information desired. For example, if a scientist is interested in testing the hypothesis that a lncRNA binds to transcription factors, Signosis’ Array I or II, which contain 48 or 96 of the most well-studied transcription factor, respectively (many of which have been shown to bind to lncRNAs), may be suitable. Alternatively, if the lncRNA in question is expressed exclusively in cancer and implicated in tumorigenesis, Signosis’ Cancer Stem Cell Array (containing 4 sets of 23 transcription factor specific probes) may be appropriate. For a more comprehensive analysis of associated transcription factors, scientists may choose to screen multiple arrays, or use the 345 probe Panomics Combo Array. It may also be helpful to consider which transcription factors are expressed in the cell line being tested; however, the arrays are very sensitive and are capable of detecting transcription factors even when they are not detected via western blotting.While RATA is limited to the identification of transcription factors included in the arrays, there are multiple versions of commercially available transcription factor activation arrays compatible with this technique. Signosis offers 12 different arrays, each including various combinations of over 150 unique transcription factors. Panomics offers 5 different transcription factor activation arrays , with their largest array (Combo Array) able to quantify 345 transcription factors in a single assay. Collectively, the Panomics and Signosis Arrays cover over 400 unique transcription factor in varying combinations. Importantly, these transcription factors represent the most biologically relevant and well-characterized transcription factors, covering approximately 25% of the 1672 currently identified human transcription factors . AdditioThis report details a novel protocol for the efficient and low cost identification of transcription factors associated with an RNA of interest, including lncRNAs. We have designed an exclusively nuclear MS2 fusion protein and optimized conditions to enable highly efficient isolation of ribonucleoprotein complexes. This easily implemented protocol will enable scientists from a range of fields to more efficiently and comprehensively investigate the role that RNAs play in modulating transcription factor activity and regulating gene expression.Table 2.Potential problems and troubleshooting suggestions are listed in