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Disseminated intravascular coagulation (DIC) is a syndrome triggered by infectious and noninfectious pathologies characterized by excessive generation of thrombin within the vasculature and widespread proteolytic conversion of fibrinogen. Despite diverse clinical manifestations ranging from thrombo-occlusive damage to bleeding diathesis, DIC etiology commonly involves excessive activation of blood coagulation and overlapping dysregulation of anticoagulants and fibrinolysis. Initiation of blood coagulation follows intravascular expression of tissue factor or activation of the contact pathway in response to pathogen-associated or host-derived, damage-associated molecular patterns. The process is further amplified through inflammatory and immunothrombotic mechanisms. Consumption of anticoagulants and disruption of endothelial homeostasis lower the regulatory control and disseminate microvascular thrombosis. Clinical DIC development in patients is associated with worsening morbidities and increased mortality, regardless of the underlying pathology; therefore, timely recognition of DIC is critical for reducing the pathologic burden. Due to the diversity of triggers and pathogenic mechanisms leading to DIC, diagnosis is based on algorithms that quantify hemostatic imbalance, thrombocytopenia, and fibrinogen conversion. Because current diagnosis primarily assesses overt consumptive coagulopathies, there is a critical need for better recognition of nonovert DIC and/or pre-DIC states. Therapeutic strategies for patients with DIC involve resolution of the eliciting triggers and supportive care for the hemostatic imbalance. Despite medical care, mortality in patients with DIC remains high, and new strategies, tailored to the underlying pathologic mechanisms, are needed.

The assimilation of clear-sky radiance in the European Centre for Medium-Range Weather Forecasts (ECMWF) atmospheric analysis relies on the clear-sky radiances observation operator. Some of these radiances have frequencies that make them sensitive to both the surface and atmosphere. Because the atmospheric and surface analyses are currently not strongly coupled, a specific treatment of the surface is required. The observation operator specifically expects a skin temperature value at the observation location and time as well as the profiles of the atmospheric variables along the viewing path. This skin temperature is added to the control variable and optimised simultaneously with all of the atmospheric variables to produce optimal simulated radiances. We present two approaches to add the skin temperature to the control variable. In the current TOVS Control Variable (TOVSCV) approach, a series of skin temperature values per observation location is added to the control variable. Effectively, in the optimisation process, the skin temperature acts as a sink variable in observation space and is uncoupled from the skin temperature at other locations. In the novel SKin Temperature in the Extended Control Vector (SKTECV) approach, two-dimensional skin temperature fields are added to the control variable. All clear-sky radiances then participate in the optimisation of these two-dimensional fields, and the analysis produces temporally and spatially consistent skin temperature fields. We compare the two approaches over two seasons of 3 months each. Overall, there is a neutral impact of the new approach on the analysis and forecast. Moreover, there is some evidence that the contribution of the subsurface layers should be represented in the new approach for the skin temperature associated with the microwave instruments.

This paper describes a new gas optical depth parameterisation implemented in the most recent release, version 13, of the radiative transfer model RTTOV (Radiative Transfer for TOVS). RTTOV is a fast, one-dimensional radiative transfer model for simulating top-of-atmosphere visible, infrared, and microwave radiances observed by downward-viewing space-borne passive sensors. A key component of the model is the fast parameterisation of absorption by the various gases in the atmosphere. The existing parameterisation in RTTOV has been extended over many years to allow for additional variable gases in RTTOV simulations and to account for solar radiation and better support geostationary sensors by extending the validity to higher zenith angles. However, there are limitations inherent in the current approach which make it difficult to develop it further, for example by adding new variable gases. We describe a new parameterisation that can be applied across the whole spectrum, that allows for a wide range of zenith angles in support of solar radiation and geostationary sensors, and for which it will be easier to add new variable gases in support of user requirements. Comparisons against line-by-line radiative transfer simulations and against observations in the ECMWF operational system yield promising results, suggesting that the new parameterisation generally compares well with the old one in terms of accuracy. Further validation is planned, including testing in operational numerical weather prediction data assimilation systems.

Controversy surrounding the classification of thoracolumbar injuries has given rise to various classification systems over the years, including the most recent AOSpine Thoracolumbar Injury Classification System (ATLICS). This systematic review aims to provide an up-to-date evaluation of the literature, including assessment of a further three studies not analysed in previous reviews. In doing so, this is the first systematic review to include the reliability among non-spine subspecialty professionals and to document the wide variety between reliability across studies, particularly with regard to sub-type classification. Relevant studies were found via a systematic search of PubMed, EBESCO, Cochrane and Web of Science. Data extraction and quality assessment were conducted in line with Cochrane Collaboration guidelines. Twelve articles assessing the reliability of ATLICS were included in this review. The overall inter-observer reliability varied from fair to substantial, but the three additional studies in this review, compared to previous reviews, presented on average only fair reliability. The greatest variation of results was seen in A1 and B3 subtypes. Least reliably classified on average was A4 subtype. This systematic review concludes that ATLICS is reliable for the majority of injuries, but the variability within subtypes suggests the need for further research in assessing the needs of users in order to increase familiarity with ATLICS or perhaps the necessity to include more subtype-specific criteria into the system. Further research is also recommended on the reliability of modifiers, neurological classification and the application of ATLICS in a paediatric context.

The general objective of this study is to explore and identify the perception about Romania as a tourist destination based on travellers’ blogs; we therefore aim to explore and identify the main elements of the image of Romania as a tourist destination based on these blogs. Data were collected manually during May 2021 using the search keywords “travel blogs” and “Romania” on the Google search engine (201 entries). Further, both a word frequency analysis (quantitative), and a content analysis (qualitative) were conducted to ascertain which places are most frequently mentioned in tourists’ travel posts, and the words most often used to describe their experience. The results shown that both destination-specific and primary image attributes are essential to understand visitors’ perceptions through travel blogs. Managerial and practical implications also emerge for tourism managers to improve the destination image of Romania.

The aim of this study is to determine whether there is a benefit of using stereotactic radiosurgery (SRS) versus surgery or conventional external beam radiotherapy (cEBRT) for spinal oligometastatic disease in terms of tumor control, pain control, toxicity and morbidity. This systematic review was conducted by searching electronic databases such as Pubmed, Medline (Ovid) and Oxford Academic using an adapted version of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) checklist. Retrospective and prospective studies were identified and investigated for methods of treatment such as SRS, surgery and radiotherapy of spinal oligometastatic disease. Local Control rates, Overall Survival (OS) rates, Pain Response (PR) and toxicities were extracted to be investigated and compared. A study eligibility criterion was made to ensure that results were valid, statistically significant and relevant to the investigation. One hundred and five articles were relevant to oligometastatic disease with the mention of spinal metastases however 89 of these articles were excluded based on irrelevance to investigation, title, abstract and duplication. Sixteen full text articles were thoroughly screened including 9 of them in the review. For 601 patients the average one year local control rate was 89%, average one year overall survival rate was 88%, evidence of pain relief was present, and some patients suffered low grade toxicities. In conclusion, stereotactic radiosurgery is an excellent modality of treatment of spinal oligometastatic disease as local control rates, overall survival rates, pain response and toxicities indicate improved outcomes in comparison to studies that investigated the same factors with the treatment of surgery or cEBRT. However, there is a lack of data here to make statistically valid claims and require more studies & data to be analyzed and compared.

Background Spinal deformity correction is associated with the risk of intra-operative neurological injury. Surgeon-directed monitoring (SDM) of transcranial motor-evoked potentials (TcMEP) is an option to monitor intra-operative spinal cord function. We report a retrospective analysis of a prospective database to assess the safety of this technique in spinal deformity correction in adolescent patients. Methods Surgeon-directed neuro-monitoring was utilised in 142 consecutive deformity correction surgeries (2012-2017). Surgeons were responsible for electrode placement, intra-operative stimulation, and interpretation of TcMEP data. If waveform disappearance occurred in the lower limb (LL), the surgeon would re-stimulate after excluding technical or anaesthetic factors. Failure to return normal waveforms led to maneuver reversal and reducing distractive force and ensuring subsequent return to baseline. Wake up test and ankle clonus followed by staging surgery was considered if the LL waveforms failed to return indicating potential motor injury. Results Of 142 patients, three cases (2.11%) had a complete visual loss of LL signals that did not resolve with anaesthetic stabilisation, leading to reversed surgical manoeuvre and staged surgery. No cases with permanent neurological dysfunction were recorded. This outcome supports surgeon-directed monitoring as a safe monitoring option, as an alternative to neurophysiologist-led monitoring. It also provides evidence in support of the waveform disappearance criteria as a safe TcMEP warning criterion with a 100% negative predictive value. Conclusions Where there is a lack of availability of trained neurophysiologists, surgeon-directed neuro-monitoring is a safe and reliable method of preventing intra-operative neurological injury amongst adolescent patients undergoing deformity correction.

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota, the implications of these responses need to be determined.

Territorial development and rural tourism are linked. Rural tourism involves tourists in rural areas who are attracted by the distinctive character of the landscape, recreation such as local and food resources, and the potential for spiritual, environmental, and cultural growth. The aim of the present paper is to investigate the economic, sustainable, and social role of tourism in the development of the rural area of Mărginimea Sibiului in Romania. It highlights the role of local entrepreneurs in developing new practices and sustainable approaches. Drawing on the literature review on the topic of sustainable rural tourism, this paper uses the case study as a methodological approach. We have developed consistent desk research relying on the processing of official governmental data and of national statistics, supported by analytical strategies involving induction and deduction. The main findings lead towards the conclusion that Mărginimea Sibiului has managed to gain both national and international notoriety while developing coherently, capitalizing on its natural and cultural heritage, and providing services in successful agritourist boarding houses and rural guesthouses, which have continuously developed both numerically and in terms of comfort levels. Because more than two thirds of the initially established lodgings in the early 2000s continue to function today, these facilities have proven to be sustainable and attractive businesses.

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.

This paper describes a new gas optical depth parameterisation implemented in the most recent release, version 13, of the radiative transfer model RTTOV (Radiative Transfer for TOVS). RTTOV is a fast, one-dimensional radiative transfer model for simulating top-of-atmosphere visible, infrared and microwave radiances observed by downward-viewing space-borne passive sensors. A key component of the model is the fast parameterisation of absorption by the various gases in the atmosphere. The existing parameterisation in RTTOV has been extended over many years to allow for additional variable gases in RTTOV simulations and to account for solar radiation and better support geostationary sensors by extending the validity to higher zenith angles. However, there are limitations inherent in the current approach which make it difficult to develop it further, for example by adding new variable gases. We describe a new parameterisation that can be applied across the whole spectrum, allows for a wide range of zenith angles in support of solar radiation and geostationary sensors, and for which it will be easier to add new variable gases in support of user requirements. Comparisons against line-by-line radiative transfer simulations, and against observations in the ECMWF operational system yield promising results, suggesting that the new parameterisation generally compares well with the old one in terms of accuracy. Further validation is planned, including testing in operational numerical weather prediction data assimilation systems.

Background During sepsis, gram‐negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)‐anchored receptor CD14 transferring LPS to the Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD‐2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy. Objectives We investigated the effect of CD14 blockade on sepsis‐induced coagulopathy, inflammation, organ dysfunction, and mortality. Methods We used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti‐CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli. Results Following anti‐CD14 treatment, two animals reached the 7‐day end‐point survivor criteria, while three animals had a significantly prolonged survival as compared to the non‐treated animals that developed multiple organ failure and died within 30 hours. Anti‐CD14 reduced the activation of coagulation through inhibition of tissue factor‐dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b‐9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti‐CD14 reduced neutrophil activation, cell death, LPS levels, and pro‐inflammatory cytokines (tumor necrosis factor, interleukin (IL)‐6, IL‐1β, IL‐8, interferon gamma, monocyte chemoattractant protein‐1), more significantly in the survivors than non‐surviving animals. Conclusions Our results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti‐CD14 treatment in E coli sepsis.

This work examines the projected image of Romania as an emerging tourism destination. Computed content-analysis was applied to the photos, text and video materials promoted online in Romania&rsquo, s last international tourism campaign. The conceptual framework used corresponds to intrinsic values (play, aesthetics, ethics and spirituality), from Holbrook&rsquo, s typology of value. Being more difficult to apprehend and therefore studied less, intrinsic values allow a more sophisticated approach to value creation. The purpose here is to identify the main attributes that are promoted about Romania by destination marketing organizations. The content analysis of text (last international promotion campaign Explore the Carpathian Garden) and visual data (27 photos from the official Facebook webpage and 7 TV videos) allow to depict an experiential view of Romania&rsquo, s image: natural resources (coded as aesthetics with 29% of references), epistemic value of discovery (play 25.8%), authentic and historical traditions (ethics 25.8%) and wellness and therapeutic activities (spirituality, 19.3%). Destination marketing organizations have the potential to develop some distinctive aspects such as authenticity (as an ethical value dimension) and play (as an active, self-oriented value). Findings also highlight that a complimentary approach using textual and visual data might be a suitable option to research destination brand image.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting primarily premature infants. The disease is characterized by intestinal inflammation and leucocyte infiltration, often progressing to necrosis, perforation, systemic inflammatory response and death. Neutrophil extracellular traps (NETs), denoting nuclear DNA, histone and antimicrobial protein release, have been suggested to play a role in NEC. This study aimed to determine the role of NETs in NEC and explore the effect of chloramidine, a NET inhibitor, on a murine NEC‐like intestinal injury model. Blood and intestinal tissues were collected from infants diagnosed with ≥ Stage II NEC, and levels of nucleosomes and NETs, respectively, were compared with those of case‐matched controls. In mice, NEC was induced with dithizone/Klebsiella, and mice in the treatment group received 40 mg/kg chloramidine. Bacterial load, intestinal histology, plasma myeloperoxidase and cytokine levels, and immunofluorescent staining were compared with controls. Nucleosomes were significantly elevated in both human and mouse NEC plasma, whereas NET staining was only present in NEC tissue in both species. Chloramidine treatment increased systemic inflammation, bacterial load, organ injury and mortality in murine NEC. Taken together, our findings suggest that NETs are critical in the innate immune defence during NEC in preventing systemic bacteraemia.

The analyse of land-use change has a meaningful importance in scholars research. Hence, the influence of the urbanisation beneath the conditions that lead to the increase of tourism activity in urban areas it is connected with the extinction of the land-use space. Given the fact that the development of urbanisation leads to tourism development, this paper aims to shape a model of urban growth for the city of Iaşi which emphasises the spatio-temporal growth of the city with impact on tourism growth. The data used was Corine Land Cover (CLC) for 2000 and 2006 years. The type of land use, the areas and the relationship of the driving factors were identified for further analysis. The methodology included Geographic Information System (GIS) spatial analysis and statistic functions of it. In order to obtain the model of urban growth which sustains the hypothesis that the urban increase leads to tourism development, an urban growth simulation was made through Pyhton language programming by cellular automata (CA) method.

Background Sepsis triggers dysfunction of coagulation and fibrinolytic systems leading to disseminated intravascular coagulation (DIC) that contributes to organ failure and death. Fondaparinux (FPX) is a synthetic pentasaccharide that binds to antithrombin (AT) and selectively inhibits factor (F) Xa and other upstream coagulation proteases but not thrombin (T). Objectives We used a baboon model of lethal Escherichia coli sepsis to investigate the effects of FPX treatment on DIC, organ function, and outcome. Methods Two experimental groups were studied: (a) E. coli challenge (n = 4); and (b) E coli plus FPX (n = 4). Bacteremia was modeled by intravenous infusion of pathogen (1-2 × 1010 CFU/kg). Fondaparinux (0.08 mg/kg) was administered subcutaneously, 3 h prior to and 8 h after bacteria infusion. Results Bacteremia rapidly increased plasma levels of inhibitory complexes of AT with coagulation proteases. Activation markers of both intrinsic (FXIa-AT), and extrinsic (FVIIa-AT) pathways were significantly reduced in FPX-treated animals. Factor Xa-AT and TAT complexes were maximal at 4 to 8 h post challenge and reduced >50% in FPX-treated animals. Fibrinogen consumption, fibrin generation and degradation, neutrophil and complement activation, and cytokine production were strongly induced by sepsis. All parameters were significantly reduced, while platelet count was unchanged by the treatment. Fondaparinux infusion attenuated organ dysfunction, prolonged survival, and saved two of four challenged animals (log-rank Mantel-Cox test, P = .0067). Conclusion Our data indicate that FPX-mediated inhibition of coagulation prevents sepsis coagulopathy; protects against excessive complement activation, inflammation, and organ dysfunction; and provides survival benefit in E. coli sepsis.

In this paper, we review the use of satellite-based remote sensing in combination with in situ data to inform Earth surface modelling. This involves verification and optimization methods that can handle both random and systematic errors and result in effective model improvement for both surface monitoring and prediction applications. The reasons for diverse remote sensing data and products include (i) their complementary areal and temporal coverage, (ii) their diverse and covariant information content, and (iii) their ability to complement in situ observations, which are often sparse and only locally representative. To improve our understanding of the complex behavior of the Earth system at the surface and sub-surface, we need large volumes of data from high-resolution modelling and remote sensing, since the Earth surface exhibits a high degree of heterogeneity and discontinuities in space and time. The spatial and temporal variability of the biosphere, hydrosphere, cryosphere and anthroposphere calls for an increased use of Earth observation (EO) data attaining volumes previously considered prohibitive. We review data availability and discuss recent examples where satellite remote sensing is used to infer observable surface quantities directly or indirectly, with particular emphasis on key parameters necessary for weather and climate prediction. Coordinated high-resolution remote-sensing and modelling/assimilation capabilities for the Earth surface are required to support an international application-focused effort.

Background The physiological function of ADTRP (androgen‐dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low‐pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE ‐cadherin and claudin‐5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell‐based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low‐density lipoprotein receptor‐related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/β‐catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )‐9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp −/− pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt‐pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt‐regulated genes that control vascular stability and integrity.

This paper gives an update of the RTTOV (Radiative Transfer for TOVS) fast radiative transfer model, which is widely used in the satellite retrieval and data assimilation communities. RTTOV is a fast radiative transfer model for simulating top-of-atmosphere radiances from passive visible, infrared and microwave downward-viewing satellite radiometers. In addition to the forward model, it also optionally computes the tangent linear, adjoint and Jacobian matrix providing changes in radiances for profile variable perturbations assuming a linear relationship about a given atmospheric state. This makes it a useful tool for developing physical retrievals from satellite radiances, for direct radiance assimilation in NWP models, for simulating future instruments, and for training or teaching with a graphical user interface. An overview of the RTTOV model is given, highlighting the updates and increased capability of the latest versions, and it gives some examples of its current performance when compared with more accurate line-by-line radiative transfer models and a few selected observations. The improvement over the original version of the model released in 1999 is demonstrated.

Source at https://doi.org/10.1073/pnas.1706818114. Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coli-induced “oxidative burst,” as well as leukocyte activation, without affecting host phagocytosis of E. coli. RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death.

Sepsis concurrently activates both coagulation and complement systems. Although complement activation by bacteria is well documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine whether generation of coagulation proteases in vivo can activate the complement cascade in 2 highly coagulopathic models. We compared temporal changes in activation biomarkers of coagulation (thrombin-antithrombin [TAT]), fibrinolysis (plasmin-antiplasmin [PAP]), and complement (C3b, C5a, C5b-9) in baboons infused with factor Xa (FXa) and phospholipids (FXa/phosphatidylcholine-phosphatidylserine [PCPS]) vs LD100 Escherichia coli We found that, albeit with different timing, both FXa/PCPS and E coli infusion led to robust thrombin and plasmin generation. Conversely, only E coli challenge activated the complement system, reaching a maximum at 2 hours postchallenge during the peaks of lipopolysaccharide and bacteremia but not of TAT and PAP. Despite inducing a strong burst of thrombin and plasmin, FXa/PCPS infusion did not produce measurable levels of complement activation in vivo. Similarly, ex vivo incubation of baboon serum with thrombin, plasmin, or FXa did not show noticeable complement cleavage unless supraphysiologic amounts of enzymes were used. Our results suggest that in vivo-generated thrombin and plasmin do not directly activate the complement in nonhuman primates.

A novel multilevel threshold segmentation method for color satellite images based on Masi entropy is proposed in this paper. Lévy multiverse optimization algorithm (LMVO) has a strong advantage over the traditional multiverse optimization algorithm (MVO) in finding the optimal solution for the segmentation in the three channels of an RGB image. As the work advancement introduces a Lévy multiverse optimization algorithm which uses tournament selection instead of roulette wheel selection, and updates some formulas in the algorithm with mutation factor. Then, the proposal is called TLMVO, and another advantage is that the population diversity of the algorithm in the latest iterations is maintained. The Masi entropy is used as an application and combined with the improved TLMVO algorithm for satellite color image segmentation. Masi entropy combines the additivity of Renyi entropy and the non-extensibility of Tsallis entropy. By increasing the number of thesholds, the quality of segmenttion becomes better, then the dimensionality of the problem also increases. Fitness function value, average CPU running time, Peak Signal-to-Noise Ratio (PSNR), Structural Similarity Index (SSIM) and Feature Similarity Index (FSIM) were used to evaluate the segmentation results. Further statistical evaluation was given by Wilcoxon’s rank sum test and Friedman test. The experimental results show that the TLMVO algorithm has wide adaptability to high-dimensional optimization problems, and has obvious advantages in objective function value, image quality detection, convergence performance and robustness.

Summary. Background: The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. Objective: To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. Methods: Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. Results: The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA−/− and Plg−/− mice, which are unable to generate plasmin. Conclusion: The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications.

Observing system experiments (OSEs) are commonly used to quantify the impact of different observation types on forecasts produced by a specific numerical weather prediction system. Recently, methods based on degree of freedom for signal (DFS) have been implemented to diagnose the impact of observations on the analyses. In this paper, the DFS is used as a diagnostic to estimate the amount of information brought by subsets of observations in the context of OSEs. This study is interested in the evaluation of the North American observing networks applied to OSEs performed at the Meteorological Service of Canada for the period of January and February 2007. The relative values of the main observing networks over North America derived from DFS calculations are compared with those from OSEs in which aircraft or radiosonde data have been removed. The results show that removing some observation types from the assimilation system influences the effective weight of the remaining assimilated observations, which may have an increased impact to compensate for the removal of other observations. The response of the remaining observations when a given set of observations is denied is illustrated comparing DFS calculations with the observations’ impact estimated from OSEs.

One of the objectives of data assimilation is to produce initial conditions that will improve the quality of forecasts. Studies on singular vectors and sensitivity studies have shown that small changes to the initial conditions can sometimes lead to exponential error growth. This has motivated research to include flow-dependent structures within the assimilation that would have the characteristics to correctly predict the growth or decay of meteorological systems. This relates to the characterization of precursors to atmospheric instability. In this paper, the observability of such structures by observations is discussed. Several studies have shown that deploying observations over regions where changes in the initial conditions may impact the forecast the most do not lead to the expected benefit. In this paper, it is shown that given the small magnitude of the signal to be detected, it is important to take into account the accuracy of the observations. If the signal-to-noise ratio is too low, observations cannot detect and characterize precursors to forecast error growth. From that perspective, the assimilation only has the possibility to extract information about evolved structures of error growth. Experiments with a simple one-dimensional variational data assimilation (1D-Var) system are presented and, then, an adapted three-dimensional variational data assimilation (3D-Var) system with different sensitivity structure functions is used. The results have been obtained by adapting the variational assimilation system of Environment Canada.

The degrees of freedom for signal (DFS) is used in data assimilation applications to measure the self-sensitivity of analysis to different observation types. This paper describes a practical method to estimate the DFS of observations from a posteriori statistics. The method does not require the consistency of the error statistics in the analysis system and it is shown that the observational impact on analyses can be estimated from observation departures with respect to analysis or the forecast. This method is first introduced to investigate the impact of a complete set, or subsets, of observations on the analysis for idealized one-dimensional variational data assimilation (1D-Var) analysis experiments and then applied in the framework of the three dimensional (3D)- and four-dimensional (4D)-Var schemes developed at Environment Canada.

Cell exposed tissue factor (TF) is generally in a low procoagulant ("cryptic") state, and requires an activation step (decryption) to exhibit its full procoagulant potential. Recent data suggest that TF decryption may be regulated by the redox environment through the oxidoreductase activity of protein disulfide isomerase (PDI). In this article we review PDI contribution to different models of TF decryption, namely the disulfide switch model and the phosphatidylserine dynamics, and hypothesize on PDI contribution to TF self-association and association with lipid domains. Experimental evidence debate the disulfide switch model of TF decryption and its regulation by PDI. More recently we showed that PDI oxidoreductase activity regulates the phosphatidylserine equilibrium at the plasma membrane. Interestingly, PDI reductase activity could maintain TF in the reduced monomeric form, while also maintaining low exposure of PS, both states correlated with low procoagulant function. In contrast, PDI inhibition or oxidants may promote the adverse effects with a net increase in coagulation. The relative contribution of disulfide isomerization and PS exposure needs to be further analyzed to understand the redox control of TF procoagulant function. For the moment however TF regulation remains cryptic.