Factors Predicting Early Failure of Etanercept in Rheumatoid Arthritis: An Analysis From the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis) Registry

Objectives: This study aims to investigate the factors associated with early discontinuation (within one year) of etanercept (ETA) in rheumatoid arthritis (RA) patients who began ETA as first biologic disease-modifying antirheumatic drug (bDMARD) and who were entered into the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis; GISEA) registry.Patients and methods: This registry-based cohort study included 477 RA patients (95 males, 382 females; median age 53 years; range 18 to 83 years) who began ETA as first bDMARD. Patient demographics, disease features and drugs were re-evaluated after 12 months. Baseline predictors of ETA discontinuation were estimated by univariate and multivariate analyses using Cox regression model.Results: Seventy patients (14.7%) discontinued ETA during the first year (for inefficacy in 55.8%, adverse events in 28.6%, and other reasons in 6.5%). Concurrent conventional synthetic DMARDs (csDMARDs) were reported in 54.3% of patients, mainly methotrexate (MTX), while 52.4% of subjects took low doses of glucocorticoids. Patients stopping ETA more frequently showed one or more comorbidities, mainly cardiovascular diseases (28.6% vs. 15.7% in patients stopping and continuing ETA, respectively, p=0.009). The presence of comorbidities and a combination therapy with csDMARDs other than MTX were independent factors associated with early discontinuation of ETA at multivariate Cox analysis.Conclusion: Although ETA demonstrated a high persistence in biologic-naive RA patients, about 15% of patients discontinued the treatment within 12 months. The presence of comorbidities and a combination therapy with csDMARDs other than MTX were the main factors for an early withdrawal of the drug

Association of putatively adaptive genetic variation with climatic variables differs between a parasite and its host

Parasitism is a pervasive phenomenon in nature with the relationship between species driving evolution in both parasite and host. Due to their host-dependent lifestyle, parasites may adapt to the abiotic environment in ways that differ from their hosts or from free-living relatives; yet rarely has this been assessed. Here, we test two competing hypotheses related to whether putatively adaptive genetic variation in a specialist mistletoe associates with the same, or different, climatic variables as its host species. We sampled 11 populations of the specialist mistletoe Amyema gibberula var. tatei (n = 154) and 10 populations of its associated host Hakea recurva subsp. recurva (n = 160). Reduced-representation sequencing was used to obtain genome-wide markers and putatively adaptive variation detected using genome scan methods. Climate associations were identified using generalized dissimilarity modelling, and these were mapped geographically to visualize the spatial patterns of genetic composition. Our results supported the hypothesis of parasites and host species responding differently to climatic variables. Temperature was relatively more important in predicting allelic turnover in the specialist mistletoe while precipitation was more important for the host. This suggests that parasitic plants and host species may respond differently to selective pressures, potentially as a result of differing nutrient acquisition strategies. Specifically, mistletoes acquire water from hosts (rather than the abiotic environment), which may provide a buffer to precipitation as a selective pressure. This work deepens and complements the physiological and other ecological studies of adaptation and provides a window into the evolutionary processes that underlie previously observed phenomena. Applying these methods to a comparative study in a host–parasite system has also highlighted factors that affect the study of selection pressure on nonmodel organisms, such as differing adaptation rates and lack of reference genomes

Contrasting patterns of local adaptation along climatic gradients between a sympatric parasitic and autotrophic tree species

Sympatric tree species are subject to similar climatic drivers, posing a question as to whether they display comparable adaptive responses. However, no study has explicitly examined local adaptation of co-occurring parasitic and autotrophic plant species to the abiotic environment. Here we test the hypotheses that a generalist parasitic tree would display a weaker signal of selection and that genomic variation would associate with fewer climatic variables (particularly precipitation) but have similar spatial patterns to a sympatric autotrophic tree species. To test these hypotheses, we collected samples from 17 sites across the range of two tree species, the hemiparasite Nuytsia floribunda (n = 264) and sympatric autotroph Melaleuca rhaphiophylla (n = 272). We obtained 5,531 high-quality genome-wide single nucleotide polymorphisms (SNPs) for M. rhaphiophylla and 6,727 SNPs for N. floribunda using DArTseq genome scan technology. Population differentiation and environmental association approaches were used to identify signals of selection. Generalized dissimilarly modelling was used to detect climatic and spatial patterns of local adaptation across climatic gradients. Overall, 322 SNPs were identified as putatively adaptive for the autotroph, while only 57 SNPs were identified for the parasitic species. We found genomic variation to associate with different sets of bioclimatic variables for each species, with precipitation relatively less important for the parasite. Spatial patterns of predicted adaptive variability were different and indicate that co-occurring species with disparate life history traits may not respond equally to selective pressures (i.e., temperature and precipitation). Together, these findings provide insight into local adaptation of sympatric parasitic and autotrophic tree species to abiotic environments

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Recent trends and variability in river discharge across northern Canada

This study presents an analysis of the observed inter-annual variability and inter-decadal trends in river discharge across northern Canada for 1964–2013. The 42 rivers chosen for this study span a combined gauged area of 5.26  ×  10⁶ km² and are selected based on data availability and quality, gauged area and record length. Inter-annual variability in river discharge is greatest for the eastern Arctic Ocean (coefficient of variation, CV  =  16 %) due to the Caniapiscau River diversion into the La Grande Rivière system for enhanced hydropower production. Variability is lowest for the study area as a whole (CV  =  7 %). Based on the Mann–Kendall test (MKT), no significant (<i>p</i> &gt; 0.05) trend in annual discharge from 1964 to 2013 is observed in the Bering Sea, western Arctic Ocean, western Hudson and James Bay, and Labrador Sea; for northern Canada as a whole, however, a statistically significant (<i>p</i> &lt; 0.05) decline of 102.8 km³ 25 yr⁻¹ in discharge occurs over the first half of the study period followed by a statistically significant (<i>p</i> &lt; 0.05) increase of 208.8 km³ 25 yr⁻¹ in the latter half. Increasing (decreasing) trends in river discharge to the eastern Hudson and James Bay (eastern Arctic Ocean) are largely explained by the Caniapiscau diversion to the La Grande Rivière system. Strong regional variations in seasonal trends of river discharge are observed, with overall winter (summer) flows increasing (decreasing, with the exception of the most recent decade) partly due to flow regulation and storage for enhanced hydropower production along the Hudson and James Bay, the eastern Arctic Ocean and Labrador Sea. Flow regulation also suppresses the natural variability of river discharge, particularly during cold seasons

Evidence for local climate adaptation in early-life traits of Tasmanian populations of Eucalyptus pauciflora

Understanding the genetic basis of adaptation to contemporary environments is fundamental to predicting the evolutionary responses of tree species to future climates. Using seedlings grown in a glasshouse from 275 open-pollinated families collected from 37 Tasmanian populations, we studied quantitative genetic variation and adaptation in Eucalyptus pauciflora, a species that is widespread in Tasmania and the alpine regions of mainland Australia. Most traits exhibited significant quantitative genetic variation both within and between populations. While there was little association of the trait-derived Mahalanobis distance among populations with geographic distance or divergence in putatively neutral markers (F ST ), there was strong evidence of climate adaptation for several genetically independent, functional traits associated with ontogenetic maturation, biomass allocation, and biotic interactions. This evidence comprised the following: (i) significantly more differentiation among populations (Q ST) than expected through drift (F ST ); (ii) little association of pairwise population divergence due to drift (F ST ) and trait divergence (Q ST); and (iii) strong correlations of functional traits with Q ST > F ST with potential environmental drivers of population divergence. Correlates with population divergence in quantitative traits include altitude and associated climatic factors, especially maximum temperature of the warmest period and moisture indices. It is argued that small changes in climate, such as a long-term 1 °C increase in the maximum temperature of the warmest period, are likely to affect the adaptation of local populations of the species. However, since there appears to be significant quantitative genetic variation within populations for many key adaptive traits, we argue that populations are likely to maintain significant evolutionary potential

How REDD+ and FLEGT-VPA Processes are Contributing Towards SFM in Indonesia-The Specialists' Viewpoint

In an effort to reverse the trend of deforestation and forest degradation, several international initiatives have been attempted. Though promoted in different political arenas, Forest Law Enforcement, Governance and Trade (FLEGT)-Voluntary Partnership Agreement (VPA), and Reducing Emissions from Deforestation and forest Degradation in developing countries (REDD+) share overlapping objectives of conservation of tropical forests. We explore specialists' viewpoint on FLEGT-VPA and REDD+ processes in Indonesia with reference to their contribution towards Sustainable Forest Management (SFM). The study shows that FLEGT-VPA and REDD+ regimes contribute towards SFM. While FLEGT-VPA improves enabling condition for SFM through governance reform, improved harvesting practices, and timber legality assurance system, REDD+ supports SFM through institutional strengthening, reforming policies and frameworks, mobilizing new and additional financial resources and increasing social and ecological resilience. We identified opportunities to achieve synergies between REDD+ and FLEGT-VPA by harmonizing their processes, tools, methodologies, technical assistance, capacity-building and funding mechanisms.</p

A segregated assessment of total carbon stocks by the mode of origin and ecological functions of forests: implication on restoration potential

In depth understanding of variation of biomass and carbon pools in different forest ecosystems is crucial for monitoring, reporting and verification of forest carbon stocks in the context of forest landscape restoration (FLR). The study compares carbon stocks from five carbon pools by the mode of origin (natural vs planted forests) and ecological functions (Special use, Protection and Production forests) of the forests. An intensive forest carbon inventory was conducted in six communes of Dinh Hoa district, Vietnam. Soil organic carbon (SOC) was found to be the largest carbon pool. Mean SOC densities were not significantly different between natural forests and planted forests, but were significantly different among different forest types classified based on ecological functions. When considering the total of all carbon pools, mean carbon densities were neither significantly different between natural and planted forests, nor among Special use, Protection and Production forests. Our study provides evidence that different FLR interventions may provide equivalent potentials for increasing forest carbon stocks. We link FLR with the United Nations Framework Convention on Climate Change (UNFCCC) initiative Reducing Emissions from Deforestation and Forest Degradation in developing countries (REDD+) to highlight synergies between processes of regaining ecological functionality, enhancement of human well-being across deforested or degraded forest landscapes, and contribution to the enhancement of forest carbon stocks