Acidity promotes degradation of multi-species environmental DNA in lotic mesocosms

Accurate quantification of biodiversity is fundamental to understanding ecosystem function and for environmental assessment. Molecular methods using environmental DNA (eDNA) offer a non-invasive, rapid, and cost-effective alternative to traditional biodiversity assessments, which require high levels of expertise. While eDNA analyses are increasingly being utilized, there remains considerable uncertainty regarding the dynamics of multispecies eDNA, especially in variable systems such as rivers. Here, we utilize four sets of upland stream mesocosms, across an acid–base gradient, to assess the temporal and environmental degradation of multispecies eDNA. Sampling included water column and biofilm sampling over time with eDNA quantified using qPCR. Our findings show that the persistence of lotic multispecies eDNA, sampled from water and biofilm, decays to non-detectable levels within 2 days and that acidic environments accelerate the degradation process. Collectively, the results provide the basis for a predictive framework for the relationship between lotic eDNA degradation dynamics in spatio-temporally dynamic river ecosystems

Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy

BACKGROUND: Patients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments. OBJECTIVES: To develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies. METHODS: The risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C-statistic, the calibration slope and the calibration in the large. RESULTS: Overall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism-corrected C-statistic of 0·64 [95% confidence interval (CI) 0·60-0·69], calibration in the large of 0·02 (95% CI -0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70-1·07), while external validation performance was poor, with C-statistic 0·52 (95% CI 0·42-0·62), calibration in the large 0·06 (95% CI -0·25 to 0·37) and calibration slope 0·36 (95% CI -0·24 to 0·97). CONCLUSIONS: We present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision-making process

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial

Background Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. Objectives To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. Methods We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2–16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg–1 daily) or MTX (0.4 mg kg–1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. Results In total, 103 participants were randomized (May 2016–February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD –5.69, 97.5% confidence interval (CI) –10.81 to –0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23–5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13–0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42–6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. Conclusions Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation

Modelling multiple metal toxic effects in the field – evaluation of the Toxicity Binding Model (TBM)

Summary • Understanding metal and proton toxicity under field conditions requires consideration of the complex nature of chemicals in mixtures. Here, we demonstrate a novel method for relating the stream and river water concentrations of cationic species to a field ecological variable. The model WHAM-FTOX postulates that non-specific binding sites on or in aquatic macroinvertebrates can be represented by the functional groups of natural organic matter (humic acid), as described by the Windermere Humic Aqueous Model (WHAM6). • Using quantile regression on published data from over 400 sites across three continents, complex water chemistries were condensed into a single linear function that relates the combined toxicities of metals and H+ to the species richness of Ephemeroptera, Trichoptera and Plecoptera. The toxicity function (FTOX) is the sum of the products of the bound concentration and a toxicity coefficient (M), for each metal or the proton. A lower threshold of FTOX is defined, below which toxic effects are absent, and an upper threshold above which organisms are absent. • The available field data, from waters affected by acid deposition and abandoned mines, permitted the derivation of parameters for four cations, with values of M following the sequence Cu > Zn > Al > H+. For waters affected mainly by H+ and Al, FTOX shows a steady decline with increasing pH, crossing the lower threshold near to pH 7. Competition effects mean that toxicity due to Cu and Zn is most significant between pH 6 and pH 8. • It should be clearly recognised that our results do not deny the environmental toxicity of heavy metals other than Cu and Zn (e.g. Ni, Cd, Hg, Pb) – it is simply that their toxicities are not expressed at the study sites used in this work. • WHAM-FTOX is a plausible model describing the toxicity of mixtures of metals and protons, based on chemical speciation concepts, and as such is a significant forward step. The results are consistent with mixture dose-response relationships in the field, supporting and extending previous conclusions based on a much smaller data set. • Calculations with the parameterised model for different streamwater discharges suggest that in some streams, changes in the concentration of the important competing cation Ca can at least sometimes compensate for changes in heavy metal concentration. However, in systems that are only acidified (not impacted by heavy metals) low pH conditions brought about by high discharge are substantially more toxic than low-discharge conditions. • The analysis presented here is incomplete, limited by the available published data, and further research is clearly desirable. This could include further field work, laboratory work, or the analysis of existing toxicity data. With respect to field studies, it would be especially helpful to work on systems with fewer unknown factors, or with well-known factors, so there is less reliance on quantile regression. • Several applications of the model can be envisaged. Scientifically WHAM-FTOX provides a conceptual and quantitative framework within which to evaluate mixture toxicity effects, the contributions of individual components, and the role played by “protective” cationic metals such as Mg and Ca. The model provides a means to estimate and predict actual toxicity effects in the field, as well as site-specific Environmental Quality Standards. It could be useful to guide remediation activities, including cost-benefits, which might be especially valuable for abandoned mines