Where do uncertainties reside within environmental risk assessments? Expert opinion on uncertainty distributions for pesticide risks to surface water organisms

A reliable characterisation of uncertainties can aid uncertainty identification during environmental risk assessments (ERAs). However, typologies can be implemented inconsistently, causing uncertainties to go unidentified. We present an approach based on nine structured elicitations, in which subject-matter experts, for pesticide risks to surface water organisms, validate and assess three dimensions of uncertainty: its level (the severity of uncertainty, ranging from determinism to ignorance); nature (whether the uncertainty is epistemic or aleatory); and location (the data source or area in which the uncertainty arises). Risk characterisation contains the highest median levels of uncertainty, associated with estimating, aggregating and evaluating the magnitude of risks. Regarding the locations in which uncertainty is manifest, data uncertainty is dominant in problem formulation, exposure assessment and effects assessment. The comprehensive description of uncertainty described will enable risk analysts to prioritise the required phases, groups of tasks, or individual tasks within a risk analysis according to the highest levels of uncertainty, the potential for uncertainty to be reduced or quantified, or the types of location-based uncertainty, thus aiding uncertainty prioritisation during environmental risk assessments. In turn, it is expected to inform investment in uncertainty reduction or targeted risk management action

Where do uncertainties reside within environmental risk assessments? Testing UnISERA, a guide for uncertainty assessment

A means for identifying and prioritising the treatment of uncertainty (UnISERA) in environmental risk assessments (ERAs) is tested, using three risk domains where ERA is an established requirement and one in which ERA practice is emerging. UnISERA's development draws on 19 expert elicitations across genetically modified higher plants, particulate matter, and agricultural pesticide release and is stress tested here for engineered nanomaterials (ENM). We are concerned with the severity of uncertainty; its nature; and its location across four accepted stages of ERAs. Using an established uncertainty scale, the risk characterisation stage of ERA harbours the highest severity level of uncertainty, associated with estimating, aggregating and evaluating expressions of risk. Combined epistemic and aleatory uncertainty is the dominant nature of uncertainty. The dominant location of uncertainty is associated with data in problem formulation, exposure assessment and effects assessment. Testing UnISERA produced agreements of 55%, 90%, and 80% for the severity level, nature and location dimensions of uncertainty between the combined case studies and the ENM stress test. UnISERA enables environmental risk analysts to prioritise risk assessment phases, groups of tasks, or individual ERA tasks and it can direct them towards established methods for uncertainty treatment

A review of uncertainty in environmental risk: characterising potential natures, locations and levels

Uncertainties, whether due to randomness or human or system errors, are inherent within any decision process. In order to improve the clarity and robustness of risk estimates and risk characterisations, environmental risk assessments (ERAs) should explicitly consider uncertainty. Typologies of uncertainty can help practitioners to understand and identify potential types of uncertainty within ERAs, but these tools are yet to be reviewed in earnest. Here, we have systematically reviewed 30 distinct typologies and the uncertainties they communicate and demonstrate that they: (1) use terminology that is often contradictory; (2) differ in the frequencies and dimensions of uncertainties that they include; (3) do not uniformly use systematic and robust methods to source information; and (4) cannot be applied, on an individual basis, to the domain of ERA. On the basis of these observations, we created a summary typology – consisting of seven locations (areas of occurrence) of uncertainty across five distinct levels (magnitude of uncertainty) – specifically for use with ERAs. This work highlights the potential for confusion, given the many versions of uncertainty typologies which exist for closely related risk domains and, through the summary typology, provides environmental risk analysts with information to form a solid foundation for uncertainty analysis (based on improved understanding) to identify uncertainties within an ERA

The challenges of harmonising anti-doping policy implementation

The policy-implementation gap conceptualises how policy intentions and outcomes often differ due to a failure to consider the realities of implementation. The World Anti-Doping Agency (WADA) directs Olympic anti-doping policy, seeking to harmonise anti-doping policy globally; however, the realisation of consistent implementation has proven challenging. A major cause of inconsistent policy implementation is inter-signatory variation, but the mechanisms of variation are poorly understood. WADA provides an excellent example to explore why policy gaps occur in international sport governance. Consequently, we aimed to analyse the different types of inter-signatory variation in anti-doping policy and identify practical solutions to address inter-signatory variation in anti-doping. Data were collected from the Regional Anti-Doping Programme (RADO), a group of organisations tasked with increasing the capacity of NADOs globally. Semi-structured interviews were conducted with 22 RADO staff and board members who were sampled as key informants to discuss how inter-signatory variation affects anti-doping policy compliance. Following reflexive thematic analysis, we identified four thematic categories explaining inter-signatory variation in anti-doping implementation: (1) socio-geographic, (2) political, (3) organisational, and (4) human resources. Based on our analysis, we theorise why the policy-implementation gap occurs and provide recommendations to improve anti-doping policy implementation

Risk stratification for arrhythmic death in an emergency department cohort: a new method of nonlinear PD2i analysis of the ECG

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) >7%. Brief digital ECGs (>1000 heartbeats, ∼15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk >24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment

Prospects for progress on health inequalities in England in the post-primary care trust era : professional views on challenges, risks and opportunities

Background - Addressing health inequalities remains a prominent policy objective of the current UK government, but current NHS reforms involve a significant shift in roles and responsibilities. Clinicians are now placed at the heart of healthcare commissioning through which significant inequalities in access, uptake and impact of healthcare services must be addressed. Questions arise as to whether these new arrangements will help or hinder progress on health inequalities. This paper explores the perspectives of experienced healthcare professionals working within the commissioning arena; many of whom are likely to remain key actors in this unfolding scenario. Methods - Semi-structured interviews were conducted with 42 professionals involved with health and social care commissioning at national and local levels. These included representatives from the Department of Health, Primary Care Trusts, Strategic Health Authorities, Local Authorities, and third sector organisations. Results - In general, respondents lamented the lack of progress on health inequalities during the PCT commissioning era, where strong policy had not resulted in measurable improvements. However, there was concern that GP-led commissioning will fare little better, particularly in a time of reduced spending. Specific concerns centred on: reduced commitment to a health inequalities agenda; inadequate skills and loss of expertise; and weakened partnership working and engagement. There were more mixed opinions as to whether GP commissioners would be better able than their predecessors to challenge large provider trusts and shift spend towards prevention and early intervention, and whether GPs’ clinical experience would support commissioning action on inequalities. Though largely pessimistic, respondents highlighted some opportunities, including the potential for greater accountability of healthcare commissioners to the public and more influential needs assessments via emergent Health & Wellbeing Boards. Conclusions - There is doubt about the ability of GP commissioners to take clearer action on health inequalities than PCTs have historically achieved. Key actors expect the contribution from commissioning to address health inequalities to become even more piecemeal in the new arrangements, as it will be dependent upon the interest and agency of particular individuals within the new commissioning groups to engage and influence a wider range of stakeholders.</p

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

HIV outbreaks among people who inject drugs in Europe, North America and Israel

During 2011–16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors : a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium

Treatment with chemotherapy, radiotherapy, or surgery that involves reproductive organs can cause impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male pubertal, adolescent, and young adult cancer survivors. Guidelines for surveillance and management of potential adverse effects could improve cancer survivors' health and quality of life. Surveillance recommendations vary considerably, causing uncertainty about optimum screening practices. This clinical practice guideline recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium, developed using evidence-based methodology, critically synthesises surveillance recommendations for gonadotoxicity in male childhood, adolescent, and young adult (CAYA) cancer survivors. The recommendations were developed by an international multidisciplinary panel including 25 experts in relevant medical specialties, using a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. The guidelines reveal the paucity of high-quality evidence, highlighting the need for further targeted research.Peer reviewe