Ecological risk assessments to guide decision-making: Methodology matters

Ecological risk assessment is often applied to guide the decision-making process that underpins ecosystem-based management and prioritisation of risk factors for management. Several studies have recently used ecological risk assessment approaches to identify risk factors of greatest concern, but rarely are the underlying methodological decisions discussed in terms of the effect that those decisions have on the outcome of the assessment and ultimately, how that affects prioritisation of risk factors for management. This study therefore evaluates the effect of methodological decisions involving (1) the choice and definition of risk factors, and (2) the calculation of risk scores, providing, where possible, recommendations on what should be the most appropriate methodologies. The definition of risk factors is often determined by the policy context and could result in the comparison of one broadly defined risk meta-factor (e.g. Food Production) with corresponding specific risk factors defined more narrowly (i.e. Oil and Gas production or Offshore Wind). Depending on the method to calculate risk this may result in a systematic bias prioritising any risk meta-factor. For the calculation of individual impact chain risk scores we compared weighted scores with ordinal scores, where the former allows more flexibility to represent the qualitative categories that determine risk and provided results better supported by scientific evidence. A consideration of different risk assessment applications in EBM showed there is no one-size-fits-all solution to this as these methodological decisions need to be considered in concert and the preferred methodology may depend on the context in which the risk assessment is applied. The outcome of the risk assessment should always be accompanied by an explicit consideration of these methodological issues and description of the resulting methodological choices

A Unique Automation Platform for Measuring Low Level Radioactivity in Metabolite Identification Studies

Generation and interpretation of biotransformation data on drugs, i.e. identification of physiologically relevant metabolites, defining metabolic pathways and elucidation of metabolite structures, have become increasingly important to the drug development process. Profiling using 14C or 3H radiolabel is defined as the chromatographic separation and quantification of drug-related material in a given biological sample derived from an in vitro, preclinical in vivo or clinical study. Metabolite profiling is a very time intensive activity, particularly for preclinical in vivo or clinical studies which have defined limitations on radiation burden and exposure levels. A clear gap exists for certain studies which do not require specialized high volume automation technologies, yet these studies would still clearly benefit from automation. Use of radiolabeled compounds in preclinical and clinical ADME studies, specifically for metabolite profiling and identification are a very good example. The current lack of automation for measuring low level radioactivity in metabolite profiling requires substantial capacity, personal attention and resources from laboratory scientists. To help address these challenges and improve efficiency, we have innovated, developed and implemented a novel and flexible automation platform that integrates a robotic plate handling platform, HPLC or UPLC system, mass spectrometer and an automated fraction collector

Evaluation of ecosystem-based marine management strategies based on risk assessment

Abstract This study presents a comprehensive and generic framework that provides a typology for the identification and selection of consistently defined ecosystem-based management measures and allows a coherent evaluation of these measures based on their performance to achieve policy objectives. The performance is expressed in terms of their reduction of risk of an adverse impact on the marine ecosystem. This typology consists of two interlinked aspects of a measure, i.e. the “Focus” and the “Type”. The “Focus” is determined by the part of the impact chain (Driver–Pressure–State) the measure is supposed to mitigate or counteract. The “Type” represents the physical measure itself in terms of how it affects the impact chain directly; we distinguish Spatio-temporal distribution controls, Input and Output controls, Remediation and Restoration measures. The performance of these measures in terms of their reduction in risk of adverse impacts was assessed based on an explicit consideration of three time horizons: past, present and future. Application of the framework in an integrated management strategy evaluation of a suite of measures, shows that depending on the time horizon, different measures perform best. “Past” points to measures targeting persistent pressures (e.g. marine litter) from past activities. “Present” favors measures targeting a driver (e.g. fisheries) that has a high likelihood of causing adverse impacts. “Future” involves impacts that both have a high likelihood of an adverse impact, as well as a long time to return to pre-impacted condition after the implementation of appropriate management, e.g. those caused by permanent infrastructure or persistent pressures such as marine litter or specific types of pollution

Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an open-label pharmacokinetic cohort study

Contains fulltext : 97636.pdf (publisher's version ) (Open Access)BACKGROUND: This study in patients with rheumatoid arthritis (RA) treated with infliximab describes prospectively the course of (anti)infliximab levels within an infusioncycle to assess at what moment patients develop low/no infliximab trough levels and/or detectable anti-infliximab levels. METHODS: Infliximab treated RA patients were included in this descriptive open-label cohort study. During one infusioncycle (anti-)infliximab levels were assessed just before and one hour after infusion, and subsequently at 50%, 75% and at the end of the infusioncycle (pre-infusion). RESULTS: 27 patients were included. The median infliximab levels decreased from 77.0 mg/l (p25-p75: 65-89) one hour after the infusion to pre-infusion levels of 0.0 mg/l (p25-p75: 0.0-3.1). In 7 (26%) patients pre-infusion anti-infliximab antibodies were detected; these antibodies were already present halfway through the infusioncycle in 5 of the 7 individuals. Patients with detectable pre-infusion anti-infliximab antibodies have significantly more often low/no infliximab levels (< 1 mg/l) halfway trough the infusioncycle (in 5/7 patients) compared to patients without detectable pre-infusion anti-infliximab antibodies (0/20 patients, p < 0.001). CONCLUSIONS: Most anti-infliximab forming patients have detectable anti-infliximab antibodies halfway through an infusioncycle, which implies that these patients are exposed to nontherapeutical infliximab levels during more than halve of their infusion cycle. As none of the patients without anti-infliximab antibodies had no/low-infliximab levels halfway through the infusioncycle, the presence of pre-infusion anti-infliximab antibodies seems a sensitive and specific predictor for no/low infliximab-levels

Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification

BACKGROUND: Decisions concerning malaria treatment depend on species identification causing disease. Microscopy is most frequently used, but at low parasitaemia (<20 parasites/μl) the technique becomes less sensitive and time consuming. Rapid diagnostic tests based on Plasmodium antigen detection do often not allow for species discrimination as microscopy does, but also become insensitive at <100 parasites/μl. METHODS: This paper reports the development of a sensitive and specific real-time Quantitative Nucleic Acid Sequence Based Amplification (real-time QT-NASBA) assays, based on the small-subunit 18S rRNA gene, to identify the four human Plasmodium species. RESULTS: The lower detection limit of the assay is 100 – 1000 molecules in vitro RNA for all species, which corresponds to 0.01 – 0.1 parasite per diagnostic sample (i.e. 50 μl of processed blood). The real-time QT-NASBA was further evaluated using 79 clinical samples from malaria patients: i.e. 11 Plasmodium. falciparum, 37 Plasmodium vivax, seven Plasmodium malariae, four Plasmodium ovale and 20 mixed infections. The initial diagnosis of 69 out of the 79 samples was confirmed with the developed real-time QT-NASBA. Re-analysis of seven available original slides resolved five mismatches. Three of those were initially identified as P. malariae mono-infection, but after re-reading the slides P. falciparum was found, confirming the real-time QT-NASBA result. The other two slides were of poor quality not allowing true species identification. The remaining five discordant results could not be explained by microscopy, but may be due to extreme low numbers of parasites present in the samples. In addition, 12 Plasmodium berghei isolates from mice and 20 blood samples from healthy donors did not show any reaction in the assay. CONCLUSION: Real-time QT-NASBA is a very sensitive and specific technique with a detection limit of 0.1 Plasmodium parasite per diagnostic sample (50 μl of blood) and can be used for the detection, identification and quantitative measurement of low parasitaemia of Plasmodium species, thus making it an effective tool for diagnostic purposes and useful for epidemiological and drug studies

An exposure-effect approach for evaluating ecosystem-wide risks from human activities

Ecosystem-based management (EBM) is promoted as the solution for sustainable use. An ecosystem-wide assessment methodology is therefore required. In this paper, we present an approach to assess the risk to ecosystem components from human activities common to marine and coastal ecosystems. We build on: (i) a linkage framework that describes how human activities can impact the ecosystem through pressures, and (ii) a qualitative expert judgement assessment of impact chains describing the exposure and sensitivity of ecological components to those activities. Using case study examples applied at European regional sea scale, we evaluate the risk of an adverse ecological impact from current human activities to a suite of ecological components and, once impacted, the time required for recovery to pre-impact conditions should those activities subside. Grouping impact chains by sectors, pressure type, or ecological components enabled impact risks and recovery times to be identified, supporting resource managers in their efforts to prioritize threats for management, identify most at-risk components, and generate time frames for ecosystem recovery

Independent position correction on tumor and lymph nodes; consequences for bladder cancer irradiation with two combined IMRT plans

Abstract Background The application of lipiodol injections as markers around bladder tumors combined with the use of CBCT for image guidance enables daily on-line position correction based on the position of the bladder tumor. However, this might introduce the risk of underdosing the pelvic lymph nodes. In this study several correction strategies were compared. Methods For this study set-up errors and tumor displacements for ten complete treatments were generated; both were based on the data of 10 bladder cancer patients. Besides, two IMRT plans were made for 20 patients, one for the elective field and a boost plan for the tumor. For each patient 10 complete treatments were simulated. For each treatment the dose was calculated without position correction (option 1), correction on bony anatomy (option 2), on tumor only (option 3) and separately on bone for the elective field (option 4). For each method we analyzed the D99% for the tumor, bladder and lymph nodes and the V95% for the small intestines, rectum, healthy part of the bladder and femoral heads. Results CTV coverage was significantly lower with options 1 and 2. With option 3 the tumor coverage was not significantly different from the treatment plan. The ΔD99% (D99%, option n - D99%, treatment plan) for option 4 was small, but significant. For the lymph nodes the results from option 1 differed not significantly from the treatment plan. The median ΔD99% of the other options were small, but significant. ΔD99% for PTVbladder was small for options 1, 2 and 4, but decreased up to -8.5 Gy when option 3 was applied. Option 4 is the only method where the difference with the treatment plan never exceeds 2 Gy. The V95% for the rectum, femoral heads and small intestines was small in the treatment plan and this remained so after applying the correction options, indicating that no additional hot spots occurred. Conclusions Applying independent position correction on bone for the elective field and on tumor for the boost separately gives on average the best target coverage, without introducing additional hot spots in the healthy tissue.</p

The effect of on-line position correction on the dose distribution in focal radiotherapy for bladder cancer

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to determine the dosimetric effect of on-line position correction for bladder tumor irradiation and to find methods to predict and handle this effect.</p> <p>Methods</p> <p>For 25 patients with unifocal bladder cancer intensity modulated radiotherapy (IMRT) with 5 beams was planned. The requirement for each plan was that 99% of the target volume received 95% of the prescribed dose. Tumor displacements from -2.0 cm to 2.0 cm in each dimension were simulated, using 0.5 cm increments, resulting in 729 simulations per patient. We assumed that on-line correction for the tumor was applied perfectly. We determined the correlation between the change in D_99%and the change in path length, which is defined here as the distance from the skin to the isocenter for each beam. In addition the margin needed to avoid underdosage was determined and the probability that an underdosage occurs in a real treatment was calculated.</p> <p>Results</p> <p>Adjustments for tumor displacement with perfect on-line position correction resulted in an altered dose distribution. The altered fraction dose to the target varied from 91.9% to 100.4% of the prescribed dose. The mean D_99%(± SD) was 95.8% ± 1.0%. There was a modest linear correlation between the difference in D_99%and the change in path length of the beams after correction (R²= 0.590). The median probability that a systematic underdosage occurs in a real treatment was 0.23% (range: 0 - 24.5%). A margin of 2 mm reduced that probability to < 0.001% in all patients.</p> <p>Conclusion</p> <p>On-line position correction does result in an altered target coverage, due to changes in average path length after position correction. An extra margin can be added to prevent underdosage.</p

Osteopenia: A Diagnostic and Therapeutic Challenge

We discussed whether we are able to select a subgroup of patients with osteopenia having a high fracture risk, in which anti-osteoporotic drug treatment can be advocated. We concluded that in individuals in whom, based on clinical risk factors, a dual-energy x-ray absorptiometry (DXA) was performed in which osteopenia was diagnosed, anti-osteoporotic treatment should be prescribed in those patients with prevalent vertebral fractures, and in patients chronically using glucocorticoids, in a dosage of 7.5 mg per day or more. Although recent developments with regard to high-resolution imaging techniques (eg, peripheral quantitative computed tomography) seem to be promising, until now they do not provide substantial more reliable information than DXA in the prediction of fractures. We think that more data are urgently needed, since safe and effective drugs are available, but there is uncertainty to which patients with osteopenia these drugs should be prescribed