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Despite numerous clinical trials, effective disease modifying treatment options for motor neuron disease (MND) remain limited. Motor Neuron Disease – Systematic Multi-Arm Adaptive Randomised Trial (MND- SMART; NCT04302870) is an adaptive platform trial in MND. We aim to develop a systematic and structured framework to identify, evaluate and prioritise candidate drugs for evaluation in MND-SMART using emerging data in different domains and expert opinion. Current incorporated domains are (i) published literature through Repurposing Living Systematic Review-Motor Neuron Disease (ReLiSyR-MND), a machine-learning assisted systematic review evaluating clinical studies of MND and other neurodegenerative diseases, and preclinical MND studies; (ii) in vitro high throughput drug screening; (iii) pathway and network analysis, and (iv) pharmacological, feasibility and clinical trial data by mining drug, chemical and clinical trial registry databases. We compile candidate drugs identified from these domains. Next, we prioritise drugs based on availability in oral formulation, prescription-only medicine status, and evaluation of safety profile by clinical triallists. We further identify, evaluate, and synthesise evidence across the different domains for prioritised drugs and report these using automated workflows as interactive, curated, living evidence summaries. We use these summaries to inform expert panel discussions on drug prioritisation and selection for MND-SMART at trial adaptation epochs.

The latest Triassic was characterised by protracted biotic extinctions concluding in the End-Triassic Extinction (~ 200 Ma) and a global carbon cycle perturbation. The onset of declining diversity is closely related to reducing conditions that spread globally from upper Sevatian (uppermost Norian) to across the Norian-Rhaetian boundary, likely triggered by unusually high volcanic activity. We correlate significant organic carbon cycle perturbations to an increase of CO 2 in the ocean–atmosphere system, likely outgassed by the Angayucham igneous province, the onset of which is indicated by the initiation of a rapid decline in 87 Sr/ 86 Sr and 188 Os/ 187 Os seawater values. A possible causal mechanism involves elevated CO 2 levels causing global warming and accelerating chemical weathering, which increased nutrient discharge to the oceans and greatly increased biological productivity. Higher export production and oxidation of organic matter led to a global O 2 decrease in marine water across the Norian/Rhaetian boundary (NRB). Biotic consequences of dysoxia/anoxia include worldwide extinctions in some fossil groups, such as bivalves, ammonoids, conodonts, radiolarians.

In intensive agriculture areas the use of pesticides can alter soil properties and microbial community structure with the risk of reducing soil quality. In this study the fatty acid methyl esters (FAMEs) evolution has been studied in a factorial lab experiment combining five substrates (a soil, two aged composts and their mixtures) treated with a co-application of three pesticides (azoxystrobin, chlorotoluron and epoxiconazole), with two extraction methods, and two incubation times (0 and 58 days). FAMEs extraction followed the microbial identification system (MIDI) and ester-linked method (EL). The pesticides showed high persistence, as revealed by half-life (t1/2) values ranging from 168 to 298 days, which confirms their recalcitrance to degradation. However, t1/2 values were affected by substrate and compost age down to 8 days for chlorotoluron in S and up to 453 days for epoxiconazole in 12M. Fifty-six FAMEs were detected. Analysis of variance (ANOVA) showed that the EL method detected a higher number of FAMEs and unique FAMEs than the MIDI one, whereas principal component analysis (PCA) highlighted that the monosaturated 18:1ω9c and cyclopropane 19:0ω10c/19ω6 were the most significant FAMEs grouping by extraction method. The cyclopropyl to monoenoic acids ratio evidenced higher stress conditions when pesticides were applied to compost and compost+soil than solely soil, as well as with final time. Overall, FAMEs profiles showed the importance of the extraction method for both substrate and incubation time, the t1/2 values highlighted the effectiveness of solely soil and the less mature compost in reducing the persistence of pesticides.

In intensive agricultural systems runoff is one of the major potential diffuse pollution pathways for pesticides and poses a risk to surface water. Ditches are common in the Po Valley and can potentially provide runoff mitigation for the protection of watercourses. The effectiveness depends on ditch characteristics, so there is an urgent need for site-specific field trials. The use of a fugacity model (multimedia model) can allows recognition of the mitigation main processes. A field experiment was conducted in order to evaluate the mitigation capacity of a typical vegetated ditch, and results were compared with predictions by a fugacity model. To evaluate herbicide mitigation after an extreme runoff, the ditch was flooded with water containing mesotrione, S-metolachlor and terbuthylazine. Two other subsequent floods with uncontaminated water were applied 27 and 82 days later to evaluate herbicides release. Results show that the ditch can immediately reduce runoff concentration of herbicides by at least 50% even in extreme flooding conditions. The half-distances were about 250 m. As a general rule, a runoff of 1 mm from 5 ha is mitigated by 99% in 100 m of vegetated ditch. Herbicides retention in the vegetated ditch was reversible, and the second flood mobilized 0.03-0.2% of the previous one, with a concentration below the drinking water limit of 0.1 μg L(-1). No herbicide was detected in the third flood, because the residual amount in the ditch was too low. Fugacity model results show that specific physical-chemical parameters may be used and a specific soil-sediment-plant compartment included for modelling herbicides behaviour in a vegetated ditch, and confirm that accumulation is low or negligible for herbicides with a half-life of 40 days or less. Shallow vegetated ditches can thus be included in a general agri-environment scheme for the mitigation of pesticides runoff together with wetlands and linear buffer strips. These structures are present in the landscape, and their environmental role can be exploited by proper management.

Contamination of the environment by glyphosate (GLP) and its metabolite aminomethylphosphonic acid (AMPA) is still of major concern worldwide due to specific interactions among these molecules and soil and water. Two monitoring sites were established in the Prosecco wine production area (Conegliano and Valdobbiadene) in northeastern Italy, which has been included in UNESCO’s World Heritage List since 2019. The study aims to increase the knowledge about GLP dynamics in this area where it has been intensively used by farmers and the potential risk for groundwater pollution is still debated. Each site was equipped with two soil-water monitoring stations consisting of multisensor soil probes and suction cups at three soil depths (10, 30, and 70 cm). Soil and water were sampled for 10 and 6 months, respectively, and analyzed for GLP and AMPA concentrations, for a total of 242 samples to describe their vertical movement and dissipation dynamics. Soil properties, in particular, the different forms of Fe and Al oxide contents, and Freundlich adsorption coefficients were quantified along the soil profile. First attempts showed that glyphosate dissipation time was 36 ± 8 days in Conegliano and Valdobbiadene soils and fully completed in both after 6 months. In contrast, AMPA dissipation dynamic —first described by an original equation—was longer than that of GLP and fully dissipated after almost 300 days. GLP showed a strong binding affinity with clay and Fe and Al chelated to soil organic matter, which likely acted as cation bridges and in turn led to low GLP mobility. GLP and AMPA were mostly detected after heavy rainfall events at 70 cm depth, likely bypassing the porous matrix of the intermediate layers.

A soil and an organic biomix (soil/vine branch/garden compost 20/40/40) were used in this lab experiment to evaluate adsorption and degradation parameters for three pesticides (chlorpyrifos, metalaxyl and cymoxanil) used in a vineyard. Adsorption in the biomix material was higher than in the soil for the three pesticides and chlorpyrifos was the most adsorbed pesticide. The role of the organic carbon is essential for enhancing the adsortion of the three pesticides, especially for the most apolar chlorpyrifos. Degradation was generally faster in the biomix material than in the soil although the process was slower in the case of chlorpyrifos if compared with the other two chemicals, due to a more toxic effect of this pesticide on soil microflora and a larger adsorption of this pesticide on the organic biomix that reduces its availability for dissipation. Amendment with cheap and available organic wastes or a grass-covered management of soil in the vineyard could reduce the impact of pesticides in the vineyard ecosystem and contribute to the sustainable management of chemicals in the environment.

Pesticides play a significant role in agriculture, but their leaching into soil and water poses serious environmental risks. This study examines pesticide contamination in surface and groundwater in northern Tunisia, specifically in Kef governorate, involving a survey of 140 farmers to gather data on agricultural practices and pesticide use. Twenty-four pesticides were monitored and utilized within the Pesticide Environmental Risk Indicator (PERI) model to evaluate environmental risk scores for each substance. Soil and water samples were analyzed using a multi-residue method and liquid chromatography–tandem mass spectrometry. Results showed that 50% of the pesticides assessed had an Environmental Risk Score of 5 or higher. Contamination was identified in water and soil, with 18 and 15 pesticide residues, respectively. Notable concentrations included 7.8 µg/L of linuron and flupyradifurone in water and 1718.4 µg/kg of linuron in soil. Commonly detected substances included the insecticide acetamiprid and fungicides like cyflufenamid and penconazole in water, while soil contamination was linked to fungicides metalaxyl and metalaxyl-m, as well as herbicides linuron and s-metolachlor. Factors such as proximity to treated water points and poor packaging management were discussed as risks. The findings emphasize the need for better monitoring and sustainable agricultural practices to mitigate contamination.

In alpine environments, colonies of snow vole (Chionomys nivalis Martins) cause strong pedoturbation, which may affect humification process and soil organic matter (SOM) cycling, with repercussions on the hormone‐like activity of organics. We investigated the effect of snow vole pedoturbation on the chemical and spectroscopic features of soil organic fractions, and the potential hormone‐like activity of humic and fulvic acids (HA, FA). The study site was located on the high‐mountain environment of the Majella massif (central Italy). Pedoturbated and regular soils were morphologically described and characterized for pH and content of total organic carbon, total extractable carbon, HA, and FA. Both HA and FA were extracted and investigated using attenuated total reflectance/Fourier transform infrared (ATR/FTIR), nuclear magnetic resonance with high‐resolution magic angle spinning (HRMAS‐NMR), and 1H‐13C heteronuclear single quantum coherence (HSQC). HA and FA were also tested for their auxin‐like and gibberellin‐like activities. Results provide evidences that bioturbated and regular soils contain a poorly decomposed SOM, but HA and FA with a well‐defined molecular structure. The HA and FA from both bioturbated and regular soils show a hormone‐like activity with a different allocation along the soil profile. In the regular soil, the highest auxin‐like activity was shown by HA and FA from Oe1 horizon, while gibberellin‐like activity was expressed by FA from Oe2 horizon. Burrowing activity determines a redistribution of organics throughout the profile with a relatively high auxin‐like activity in the FA from straw tunnel wall (STW) and gibberellin‐like activity in the HA from vole feces (VF). The relative high presence of carboxylic acids, amides, proteins, and amino acids in the FA from STW and the aromatic moieties in the HA from VF put evidences for their different behavior. The fact that snow vole activity has modified the chemical and biological properties of SOM in these soils otherwise considered governed only by low temperature has important ecological implications such as the preservation of soil fertility and vegetal biodiversity. Bioturbated and regular soils contain a poorly decomposed SOM, but HA and FA with a well defined molecular structure. Burrowing activity determines a redistribution of organics throughout the profile with a relatively high auxin‐like activity in the FA from straw tunnel wall (STW) and gibberellin‐like activity in the HA from vole faeces VF. The relative high presence of carboxylic acids, amides, proteins and aminoacids in the FA from STW and the aromatic moieties in the HA from VF put evidences for their different behavior.

ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.MethodsWe conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.ResultsFrom the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.