Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all ...collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
Abstract A non-neutral model (NNM) of the axial plasma discharge in a Hall thruster, including full electron inertia, is presented. In the finite-volume formulation, two types of sheath boundary ...conditions previously used in the literature are tested and proven to behave practically identically in this model. Both normal and reversed (i.e. electron repelling and attracting, respectively) anode sheaths are admitted. This model is compared with the quasineutral model developed in a previous work, which includes only azimuthal electron inertia and normal anode sheaths. Both models agree excellently within the parametric region where steady-state solutions with a normal anode sheath exist. The NNM shows the absence of steady-state solutions with a reversed anode sheath. Nonetheless, a reversed sheath can appear during the transient to a steady-state solution with a normal sheath and the periodic transition from a normal to a reversed sheath can be observed in the presence of breathing-mode oscillations. In other cases, the reversed sheath leads to the discharge shut-off. Full electron inertia is always important in the presence of a reversed sheath. The parametric threshold of the wall accommodation parameter from a stationary solution to a breathing mode one differs slightly between the non-neutral and the quasi-neutral model.
Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through ...changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (
,
a and
) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1 : RNA2 : RNA3 : RNA4 ratios, depending on the infected host species and organ.
Today the use of spaceborne Very High Resolution (VHR) optical sensors for automatic 3D information extraction is increasing in the scientific and civil communities. The 3D Optical Metrology (3DOM) ...unit of the Bruno Kessler Foundation (FBK) in Trento (Italy) has collected VHR satellite imagery, as well as aerial and terrestrial data over Trento for creating a complete testfield for investigations on image radiometry, geometric accuracy, automatic digital surface model (DSM) generation, 2D/3D feature extraction, city modelling and data fusion. This paper addresses the radiometric and the geometric aspects of the VHR spaceborne imagery included in the Trento testfield and their potential for 3D information extraction. The dataset consist of two stereo-pairs acquired by WorldView-2 and by GeoEye-1 in panchromatic and multispectral mode, and a triplet from Pléiades-1A. For reference and validation, a DSM from airborne LiDAR acquisition is used. The paper gives details on the project, dataset characteristics and achieved results.
Essentials
Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently.
DOAC specific measurements were performed at trough in patients with atrial fibrillation.
Patients who ...developed thromboembolic events showed lower DOAC plasma levels.
This study supports the concept of measuring DOAC levels at steady state.
Summary
Background
Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C‐trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry.
Methods
DOAC‐specific measurements (diluted thrombin time or anti‐activated factor II calibrated for dabigatran; anti‐activated FX calibrated for rivaroxaban or apixaban) at C‐trough were performed locally at steady state within 15–25 days after the start of treatment. For each DOAC, the interval of C‐trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow‐up were recorded.
Results
Thromboembolic events (1.8%) occurred in 10 patients who had baseline C‐trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C‐trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2DS2‐VASc score than that of the total patient population: 5.3 (95% confidence interval CI 4.3–6.3 versus 3.0 (95% CI 2.9–3.1).
Conclusion
In this study cohort, thrombotic complications occurred only in DOAC‐treated AF patients who had very low C‐trough levels, with a relatively high CHA2DS2‐VASc score. Larger studies are warranted to confirm these preliminary observations.
Aim: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods: We ...carried out a patient‐level meta‐analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan‐Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results: The 5‐year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5‐year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5‐year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1‐fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8‐fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.
Abstract
One-dimensional axial models of a Hall thruster give a good qualitative picture of the main physical phenomena in the discharge with small computational effort. Time-dependent models, in ...particular, are widely used for the analysis of low-frequency axial oscillations (i.e. the breathing mode). The standard time-dependent three-fluid model found in the literature is here enhanced by extending the physical domain beyond the cathodic surface into the far plume, and improving the modeling of some physical phenomena. A suite of five models is presented in this work with an increasing complexity of added physics; the most complete version accounting for ion and neutral energy evolution equations along with the partial inclusion of electron inertia. The added physics has a non negligible impact on both the dynamics of the breathing mode and the time-averaged response of the plasma. In particular, it is found that the onset of the instability is sensitive to both the level of modeled physics and the operational parameters. In some cases, the strong breathing mode oscillations can result in a weak plasma attachment to the anode, leading to the collapse of the normal anode sheath and to the subsequent failure of the model.
Background: In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence.
Objectives: We aimed to ...develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies.
Methods: One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism‐corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis.
Results: Abnormal D‐dimer after stopping anticoagulation, age < 50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D‐dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area = 0.71). The annualized recurrence risk was 3.1% (95% confidence interval CI, 2.3–3.9) for a score ≤ 1, 6.4% (95% CI, 4.8–7.9) for a score = 2 and 12.3% (95% CI, 9.9–14.7) for a score ≥ 3. By considering at low recurrence risk those patients with a score ≤ 1, life‐long anticoagulation might be avoided in about half of patients with unprovoked VTE.
Conclusions: The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months.
Summary
Introduction
D‐dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event ...of venous thromboembolism (VTE).
Methods
Commercial D‐dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10.
Results
In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age‐adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event.
Conclusion
The results confirm the usefulness of the cutoff levels used in DULCIS.
Essentials
The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism.
We assessed the ACCP bleeding risk score in an inception‐cohort of patients receiving AC.
...53% were categorized at high‐risk, but their bleeding rate was low during long‐term AC.
ACCP score had low predictive value for bleeding.
Summary
Background
The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE).
Methods
We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long‐term anticoagulation (1522 treated with vitamin K antagonists VKAs and the remaining with direct oral anticoagulants DOACs) belonging to the Italian START2 Register.
Results
More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low‐risk category. For 3130 years (median 12 interquartile range 6, 24 months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high‐ and low‐risk categories, respectively). The c‐statistic of the ACCP score was 0.55 (0.48–0.63), 0.50 (0.42–0.58) and 0.56 (0.48–0.64) in low‐, moderate‐ and high‐risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 1.3–4.7), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively).
Conclusion
The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.
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