Predicting reference points and associated uncertainty from life histories for risk and status assessment

To assess status of fish populations and the risks of overexploitation, management bodies compare fishing mortality rates and abundance estimates with reference points (RP). Generic, “data-poor” methods for estimating RP are garnering attention because they are faster and cheaper to implement than those based on extensive life history data. Yet data-poor RP are subject to many unquantified uncertainties. Here, we predict fishing mortality RP based on five levels of increasingly comprehensive data, to quantify effects of parameter and structural uncertainty on RP. Level I RP (least data) are estimated solely from species' maximum size and generic life history relationships, while level V RP (most data) are estimated from population-specific growth and maturity data. By estimating RP at all five data levels, for each of 12 North Sea populations, we demonstrate marked changes in the median RP values, and to a lesser extent uncertainty, when growth parameters come from data rather than life history relationships. As a simple rule, halving the median level I RP gives almost 90% probability that a level V median RP is not exceeded. RP and uncertainty were substantially affected by assumed gear selectivity; plausible changes in selectivity had a greater effect on RP than adding level V data. Calculations of RP using data for successive individual years from 1984 to 2014 showed that the median RP based on data for any given year would often fall outside the range of uncertainty for RP based on data from earlier or later years. This highlighted the benefits of frequent RP updates when suitable data are available. Our approach provides a quantitative method to inform risk-based management and decisions about acceptable targets for data collection and quality. Ultimately, however, the utility and extent of adoption of data-poor methods for estimating RP will depend on the risk aversion of managers

Evaluation and management implications of uncertainty in a multispecies size-structured model of population and community responses to fishing

1. Implementation of an ecosystem approach to fisheries requires advice on trade-offs among fished species and between fisheries yields and biodiversity or food web properties. However, the lack of explicit representation, analysis and consideration of uncertainty in most multispecies models has limited their application in analyses that could support management advice. 2. We assessed the consequences of parameter uncertainty by developing 78 125 multispecies size-structured fish community models, with all combinations of parameters drawn from ranges that spanned parameter values estimated from data and literature. This unfiltered ensemble was reduced to 188 plausible models, the filtered ensemble (FE), by screening outputs against fish abundance data and ecological principles such as requiring species' persistence. 3. Effects of parameter uncertainty on estimates of single-species management reference points for fishing mortality (FMSY, fishing mortality rate providing MSY, the maximum sustainable yield) and biomass (BMSY, biomass at MSY) were evaluated by calculating probability distributions of estimated reference points with the FE. There was a 50% probability that multispecies FMSY could be estimated to within ±25% of its actual value, and a 50% probability that BMSY could be estimated to within ±40% of its actual value. 4. Signal-to-noise ratio was assessed for four community indicators when mortality rates were reduced from current rates to FMSY. The slope of the community size spectrum showed the greatest signal-to-noise ratio, indicating that it would be the most responsive indicator to the change in fishing mortality F. Further, the power of an ongoing international monitoring survey to detect predicted responses of size spectrum slope was higher than for other size-based metrics. 5. Synthesis and applications: Application of the ensemble model approach allows explicit representation of parameter uncertainty and supports advice and management by (i) providing uncertainty intervals for management reference points, (ii) estimating working values of reference points that achieve a defined reduction in risk of not breaching the true reference point, (iii) estimating the responsiveness of population, community, food web and biodiversity indicators to changes in F, (iv) assessing the performance of indicators and monitoring programmes and (v) identifying priorities for data collection and changes to model structure to reduce uncertainty

The response of a protandrous species to exploitation, and the implications for management : a case study with patellid limpets

A zygote production model for the patellid limpet Patella vulgata has been developed to examine the effect of exploitation on the reproductive output of a protandrous (male to female sequential) hermaphrodite. Patellid limpets are broadcast spawners which can have specific implications for the effect of exploitation on reproductive output, due to sperm limitation. The combined zygote production model was made of three component sub-models; a population fecundity model, a gamete dispersal model, and a fertilisation model. The model makes explicit account of sperm limitation, and is based upon data collected through field and laboratory investigations conducted as part of this thesis. The model was used to examine the relationship between egg and zygote production, and spawning stock biomass (SSB) and fishery yield for a range of P. vulgata populations across a wave exposure gradient. The effect of different management strategies, minimum landing size or marine protected areas, on the relationship between reproductive output and yield was also examined. Protandry lead to a decoupling between SSB and zygote production as the populations were exposed to the simulated fishery. There was a five-fold variation in zygote production per unit area across a wave exposure gradient. Comparison of different management strategies indicates that the fishery yield could vary by up to three-fold depending on the management strategy used, whilst still protecting the same level of population reproductive output. The genetic population structure of the Azorean Patella candei population was also examined to determine the scale of larval dispersal to allow the management recommendations of the zygote production model to be examined in a wider ecological context. Due to evidence of a recent population bottleneck in the Azorean P. candei population no firm conclusions could be drawn from this study as to the scale of larval dispersal.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies

Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients

Decline in Antigenicity of Tumor Markers by Storage Time Using Pathology Sections Cut From Tissue Microarrays.

Sectioning a whole tissue microarrray (TMA block) and storing the sections maximizes the number of sections obtained, but may impair the antigenicity of the stored sections. We have investigated the impact of TMA section storage on antigenicity. First, we reexamined existing TMA data to determine whether antigenicity in stored sections changes over time. Component scores for each marker, based on cellular compartment of staining and score-type, were evaluated separately. Residual components scores adjusted for grade, tumor size, and node positivity, were regressed on the number of days storage to evaluate the effect of storage time. Storage time ranged from 2 to 1897 days, and the mean change in antigenicity per year ranged from -0.88 (95% confidence interval, -1.11 to -0.65) to 0.035 (95% confidence interval, 0.016-0.054). Further analysis showed no significant improvement in the fit of survival models if storage time adjusted scores were included in the models rather than unadjusted scores. We then compared 3 ways of processing TMA sections after cutting-immediate staining, staining after 1 year, and staining after 1 year coated in wax-on the immunohistochemistry results for: progesterone receptor, a routinely used, robust antibody, and MKI67, which is generally considered less robust. The progesterone receptor scores for stored sections were similar to those for unstored sections, whereas the MKI67 scores for stored sections were substantially different to those for unstored sections. Wax coating made little difference to the results. Biomarker antigenicity shows a small decline over time that is unlikely to have an important effect on studies of prognostic biomarkers.We acknowledge the SEARCH team, the National Cancer Registration Service Eastern Office and Information Centre, the Histopathology Core Facility at the CRUK Cambridge Research Institute for immunohistochemical staining and digital image acquisition and the Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust. This work was funded through a programme grant from Cancer Research UK (C490/A10119, C490/A10124 and C490/A16561) and funding from the NIHR Biomedical Research Centre.This is the final version of the article. It was first published by Lippincott Williams & Wilkins at http://dx.doi.org/10.1097/PAI.000000000000017

Inclusion of multiple high‐risk histopathological criteria improves the prediction of adjuvant chemotherapy efficacy in lung adenocarcinoma

AIMS: The decision to consider adjuvant chemotherapy (AC) for non-small cell lung cancer is currently governed by clinical stage. This study aims to assess other routinely collected pathological variables related to metastasis and survival for their ability to predict the efficacy of AC in lung adenocarcinoma. METHODS AND RESULTS: A retrospective single-centre series of 620 resected lung non-mucinous adenocarcinoma cases from 2005-2015 was used. Digital images of all slides were subjected to central review, and data on tumour histopathology, AC treatment and patient survival were compiled. A statistical case matching approach was used to counter selection bias. Several high-risk pathological criteria predict both pathological nodal involvement and early death: positive vascular invasion status (VI+) (HR=2.10 P<0.001), positive visceral pleural invasion status (VPI+) (HR=2.16 P<0.001), and solid/micropapillary-predominant WHO tumour type (SPA/MPPA) (HR=3.29 P<0.001). Crucially, these criteria also identify patient groups benefiting from AC (VI+ HR=0.69 P=0.167, VPI+ HR=0.44 P=0.004, SPA/MPPA HR=0.36 P=0.006). Cases showing VI+/VPI+/SPA/MPPA histology in the absence of AC stage criteria were common (170 of 620 total), and 8 had actually received AC. This group showed much better outcomes than equivalent untreated cases in matched analysis (3-year OS 100.0% vs 31.3%). Inclusion of patients with VI+/VPI+/SPA/MPPA histology would increase AC-eligible patients from 51.0% to 84.0% of non-mucinous tumours in our cohort. CONCLUSIONS: Our data provide preliminary evidence that the consideration of AC in patients with additional high-risk pathological indicators may significantly improve outcomes in operable lung adenocarcinoma, and that AC may be currently underused

Characterisation of microRNA expression in post-natal mouse mammary gland development.

BACKGROUND: The differential expression pattern of microRNAs (miRNAs) during mammary gland development might provide insights into their role in regulating the homeostasis of the mammary epithelium. Our aim was to analyse these regulatory functions by deriving a comprehensive tissue-specific combined miRNA and mRNA expression profile of post-natal mouse mammary gland development.We measured the expression of 318 individual murine miRNAs by bead-based flow-cytometric profiling of whole mouse mammary glands throughout a 16-point developmental time course, including juvenile, puberty, mature virgin, gestation, lactation, and involution stages. In parallel whole-genome mRNA expression data were obtained. RESULTS: One third (n = 102) of all murine miRNAs analysed were detected during mammary gland development. MicroRNAs were represented in seven temporally co-expressed clusters, which were enriched for both miRNAs belonging to the same family and breast cancer-associated miRNAs. Global miRNA and mRNA expression was significantly reduced during lactation and the early stages of involution after weaning. For most detected miRNA families we did not observe systematic changes in the expression of predicted targets. For miRNA families whose targets did show changes, we observed inverse patterns of miRNA and target expression. The data sets are made publicly available and the combined expression profiles represent an important community resource for mammary gland biology research. CONCLUSION: MicroRNAs were expressed in likely co-regulated clusters during mammary gland development. Breast cancer-associated miRNAs were significantly enriched in these clusters. The mechanism and functional consequences of this miRNA co-regulation provide new avenues for research into mammary gland biology and generate candidates for functional validation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Can monophagous specialists mediate host plant choices in generalist planthoppers (Hemiptera: Delphacidae)?

A preference experiment was set up with two planthopper species (Hemiptera: Delphacidae) to test the influence of competition on host plant choice. The delphacid Javesella pellucida was chosen as a generalist and the rarer Ribautodelphax imitans as a monophagous specialist, which feeds on the grass, tall fescue Schedonorus arundinaceus. In the absence of the specialist, the generalist showed a marked preference for tall fescue. In some experiments, however, the introduction of the specialist resulted in a shift of preference to an alternative plant if the specialist was established prior to the introduction of the generalist. This experiment supports the hypothesis that specialist herbivores can potentially alter the host plant choices of generalists, which may lead to differing host plant use patterns in insect communities

Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial