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Background In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib. Methods Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial. Results A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients. Conclusions The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 Graphical Abstract A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety .

Airborne hyper-spectral imaging has been proven to be an efficient means to provide new insights for the retrieval of biophysical variables. However, quantitative estimates of unbiased information derived from airborne hyperspectral measurements primarily require a correction of the anisotropic scattering properties of the land surface depicted by the bidirectional reflectance distribution function (BRDF). Hitherto, angular BRDF correction methods rarely combined viewing-illumination geometry and topographic information to achieve a comprehensive understanding and quantification of the BRDF effects. This is in particular the case for forested areas, frequently underlaid by rugged topography. This paper describes a method to correct the BRDF effects of airborne hyperspectral imagery over forested areas overlying rugged topography, referred in the reminder of the paper as rugged topography-BRDF (RT-BRDF) correction. The local viewing and illumination geometry are calculated for each pixel based on the characteristics of the airborne scanner and the local topography, and these two variables are used to adapt the Ross-Thick-Maignan and Li-Transit-Reciprocal kernels in the case of rugged topography. The new BRDF model is fitted to the anisotropy of multi-line airborne hyperspectral data. The number of pixels is set at 35,000 in this study, based on a stratified random sampling method to ensure a comprehensive coverage of the viewing and illumination angles and to minimize the fitting error of the BRDF model for all bands. Based on multi-line airborne hyperspectral data acquired with the Chinese Academy of Forestry’s LiDAR, CCD, and Hyperspectral system (CAF-LiCHy) in the Pu’er region (China), the results applying the RT-BRDF correction are compared with results from current empirical (C, and sun-canopy-sensor (SCS) adds C (SCS+C)) and semi-physical (SCS) topographic correction methods. Both quantitative assessment and visual inspection indicate that RT-BRDF, C, and SCS+C correction methods all reduce the topographic effects. However, the RT-BRDF method appears more efficient in reducing the variability in reflectance of overlapping areas in multiple flight-lines, with the advantage of reducing the BRDF effects caused by the combination of wide field of view (FOV) airborne scanner, rugged topography, and varying solar illumination angle over long flight time. Specifically, the average decrease in coefficient of variation (CV) is 3% and 3.5% for coniferous forest and broadleaved forest, respectively. This improvement is particularly marked in the near infrared (NIR) region (i.e., >750 nm). This finding opens new possible applications of airborne hyperspectral surveys over large areas.

Background Chromatin organizes DNA and regulates its transcriptional activity through epigenetic modifications. Heterochromatic regions of the genome are generally transcriptionally silent, while euchromatin is more prone to transcription. During DNA replication, both genetic information and chromatin modifications must be faithfully passed on to daughter strands. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear. Results We isolate a strong hypomorphic Arabidopsis thaliana mutant of the POL2A catalytic subunit of DNA polymerase epsilon and show that POL2A is required to stabilize heterochromatin silencing genome-wide, likely by preventing replicative stress. We reveal that POL2A inhibits DNA methylation and histone H3 lysine 9 methylation. Hence, the release of heterochromatin silencing in POL2A-deficient mutants paradoxically occurs in a chromatin context of increased levels of these two repressive epigenetic marks. At the nuclear level, the POL2A defect is associated with fragmentation of heterochromatin. Conclusion These results indicate that POL2A is critical to heterochromatin structure and function, and that unhindered replisome progression is required for the faithful propagation of DNA methylation throughout the cell cycle.

Despite recent advances in land surface modeling and remote sensing, estimates of the global water budget are still fairly uncertain. This study aims to evaluate the water budget of the Amazon basin based on several state-of-the-art land surface model (LSM) outputs. Water budget variables (terrestrial water storage TWS, evapotrans-piration ET, surface runoff R, and base flow B) are evaluated at the basin scale using both remote sensing and in situ data. Meteorological forcings at a 3-hourly time step and 18 spatial resolution were used to run 14 LSMs. Precipitation datasets that have been rescaled to match monthly Global Precipitation Climatology Project (GPCP) and Global Precipitation Climatology Centre (GPCC) datasets and the daily Hydrologie du Bassin de l'Amazone (HYBAM) dataset were used to perform three experiments. The Hydrological Modeling and Analysis Platform (HyMAP) river routing scheme was forced with R and B and simulated discharges are compared against observations at 165 gauges. Simulated ET and TWS are compared against FLUXNET and MOD16A2 evapotranspi-ration datasets and Gravity Recovery and Climate Experiment (GRACE) TWS estimates in two subcatchments of main tributaries (Madeira and Negro Rivers). At the basin scale, simulated ET ranges from 2.39 to 3.26 mm day 21 and a low spatial correlation between ET and precipitation indicates that evapotranspiration does not depend on water availability over most of the basin. Results also show that other simulated water budget components vary significantly as a function of both the LSM and precipitation dataset, but simulated TWS generally agrees with GRACE estimates at the basin scale. The best water budget simulations resulted from experiments using HYBAM, mostly explained by a denser rainfall gauge network and the rescaling at a finer temporal scale.

The rainfall over West Africa has been characterized by extreme variability in the last half-century, with prolonged droughts resulting in humanitarian crises. There is, therefore, an urgent need to better understand and predict the West African monsoon (WAM), because social stability in this region depends to a large degree on water resources. The economies are primarily agrarian, and there are issues related to food security and health. In particular, there is a need to better understand land–atmosphere and hydrological processes over West Africa because of their potential feedbacks with the WAM. This is being addressed through a multiscale modeling approach using an ensemble of land surface models that rely on dedicated satellite-based forcing and land surface parameter products, and data from the African Multidisciplinary Monsoon Analysis (AMMA) observational field campaigns. The AMMA land surface model (LSM) Intercomparison Project (ALMIP) offline, multimodel simulations comprise the equivalent of a multimodel reanalysis product. They currently represent the best estimate of the land surface processes over West Africa from 2004 to 2007. An overview of model intercomparison and evaluation is presented. The far-reaching goal of this effort is to obtain better understanding and prediction of the WAM and the feedbacks with the surface. This can be used to improve water management and agricultural practices over this region.

Aim: Seasonally dry tropical forest (SDTF) of the Caribbean Islands (primarily West Indies) is floristically distinct from Neotropical SDTF in Central and South America. We evaluate whether tree species composition was associated with climatic gradients or geographical distance. Turnover (dissimilarity) in species composition of different islands or among more distant sites would suggest communities structured by speciation and dispersal limitations. A nested pattern would be consistent with a steep resource gradient. Correlation of species composition with climatic variation would suggest communities structured by broad‐scale environmental filtering.Location: The West Indies (The Bahamas, Cuba, Hispaniola, Jamaica, Puerto Rico, US Virgin Islands, Guadeloupe, Martinique, St. Lucia), Providencia (Colombia), south Florida (USA) and Florida Keys (USA).Taxon: Seed plants—woody taxa (primarily trees).Methods: We compiled 572 plots from 23 surveys conducted between 1969 and 2016. Hierarchical clustering of species in plots, and indicator species analysis for the resulting groups of sites, identified geographical patterns of turnover in species composition. Nonparametric analysis of variance, applied to principal components of bioclimatic variables, determined the degree of covariation in climate with location. Nestedness versus turnover in species composition was evaluated using beta diversity partitioning. Generalized dissimilarity modelling partitioned the effect of climate versus geographical distance on species composition.Results: Despite a set of commonly occurring species, SDTF tree community composition was distinct among islands and was characterized by spatial turnover on climatic gradients that covaried with geographical gradients. Greater Antillean islands were characterized by endemic indicator species. Northern subtropical areas supported distinct, rather than nested, SDTF communities in spite of low levels of endemism.Main conclusions: The SDTF species composition was correlated with climatic variation. SDTF on large Greater Antillean islands (Hispaniola, Jamaica and Cuba) was characterized by endemic species, consistent with their geological history and the biogeography of plant lineages. These results suggest that both environmental filtering and speciation shape Caribbean SDTF tree communities.

Background: The peer review process has been questioned as it may fail to allow the publication of high-quality articles. This study aimed to evaluate the accuracy in identifying inadequate reporting in RCT reports by early career researchers (ECRs) using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process.Methods: We performed a cross-sectional diagnostic study of 119 manuscripts, from BMC series medical journals, BMJ, BMJ Open, and Annals of Emergency Medicine reporting the results of two-arm parallel-group RCTs. One hundred and nineteen ECRs who had never reviewed an RCT manuscript were recruited from December 2017 to January 2018. Each ECR assessed one manuscript. To assess accuracy in identifying inadequate reporting, we used two tests: (1) ECRs assessing a manuscript using the COBPeer tool (after completing an online training module) and (2) the usual peer-review process. The reference standard was the assessment of the manuscript by two systematic reviewers. Inadequate reporting was defined as incomplete reporting or a switch in primary outcome and considered nine domains: the eight most important CONSORT domains and a switch in primary outcome(s). The primary outcome was the mean number of domains accurately classified (scale from 0 to 9).Results: The mean (SD) number of domains (0 to 9) accurately classified per manuscript was 6.39 (1.49) for ECRs using COBPeer versus 5.03 (1.84) for the journal's usual peer-review process, with a mean difference [95% CI] of 1.36 [0.88-1.84] (p < 0.001). Concerning secondary outcomes, the sensitivity of ECRs using COBPeer versus the usual peer-review process in detecting incompletely reported CONSORT items was 86% [95% CI 82-89] versus 20% [16-24] and in identifying a switch in primary outcome 61% [44-77] versus 11% [3-26]. The specificity of ECRs using COBPeer versus the usual process to detect incompletely reported CONSORT domains was 61% [57-65] versus 77% [74-81] and to identify a switch in primary outcome 77% [67-86] versus 98% [92-100].Conclusions: Trained ECRs using the COBPeer tool were more likely to detect inadequate reporting in RCTs than the usual peer review processes used by journals. Implementing a two-step peer-review process could help improve the quality of reporting.

virtualspecies is a freely available package for R designed to generate virtual species distributions, a procedure increasingly used in ecology to improve species distribution models. This package combines the existing methodological approaches with the objective of generating virtual species distributions with increased ecological realism. The package includes 1) generating the probability of occurrence of a virtual species from a spatial set of environmental conditions (i.e. environmental suitability), with two different approaches; 2) converting the environmental suitability into presence–absence with a probabilistic approach; 3) introducing dispersal limitations in the realised virtual species distributions and 4) sampling occurrences with different biases in the sampling procedure. The package was designed to be extremely flexible, to allow users to simulate their own defined species–environment relationships, as well as to provide a fine control over every simulation parameter. The package also includes a function to generate random virtual species distributions. We provide a simple example in this paper showing how increasing ecological realism of the virtual species impacts the predictive performance of species distribution models. We expect that this new package will be valuable to researchers willing to test techniques and protocols of species distribution models as well as various biogeographical hypotheses.

Novel fibers containing different ratios of PVA and d-limonene were fabricated using electrospinning for antibacterial active packaging applications. The PVA/d-limonene fibers were thoroughly characterized using a scanning electron microscope, fourier-transform infrared spectrometry, thermal gravimetry, differential scanning calorimetry, tensile tests, and oxygen permeability tests. The results of these analyses showed that the highest tensile strength and elongation at break values of 3.87 ± 0.25 MPa and 55.62 ± 2.93%, respectively, were achieved for a PVA/d-limonene ratio of 7:3 (v/v) and an ultrasonication time of 15 min during processing. This material also showed the lowest oxygen permeation and the best degradability and bacteriostatic properties of all samples.

The Red List Categories and the accompanying five criteria developed by the International Union for Conservation of Nature (IUCN) provide an authoritative and comprehensive methodology to assess the conservation status of organisms. Red List criterion B, which principally uses distribution data, is the most widely used to assess conservation status, particularly of plant species. No software package has previously been available to perform large‐scale multispecies calculations of the three main criterion B parameters [extent of occurrence (EOO), area of occupancy (AOO) and an estimate of the number of locations] and provide preliminary conservation assessments using an automated batch process. We developed ConR, a dedicated R package, as a rapid and efficient tool to conduct large numbers of preliminary assessments, thereby facilitating complete Red List assessment. ConR (1) calculates key geographic range parameters (AOO and EOO) and estimates the number of locations sensu IUCN needed for an assessment under criterion B; (2) uses this information in a batch process to generate preliminary assessments of multiple species; (3) summarize the parameters and preliminary assessments in a spreadsheet; and (4) provides a visualization of the results by generating maps suitable for the submission of full assessments to the IUCN Red List. ConR can be used for any living organism for which reliable georeferenced distribution data are available. As distributional data for taxa become increasingly available via large open access datasets, ConR provides a novel, timely tool to guide and accelerate the work of the conservation and taxonomic communities by enabling practitioners to conduct preliminary assessments simultaneously for hundreds or even thousands of species in an efficient and time‐saving way. We developed ConR, a dedicated R package, as a rapid and efficient tool to conduct large numbers of preliminary assessments, thereby facilitating complete Red List assessment. As distributional data for taxa become increasingly available via large open access datasets, ConR provides a novel, timely tool to guide and accelerate the work of the conservation and taxonomic communities by enabling practitioners to conduct preliminary assessments simultaneously for multiple species in an efficient and time‐saving way.