Advancing impact prediction and hypothesis testing in invasion ecology using a comparative functional response approach

Invasion ecology urgently requires predictive methodologies that can forecast the ecological impacts of existing, emerging and potential invasive species. We argue that many ecologically damaging invaders are characterised by their more efficient use of resources. Consequently, comparison of the classical ‘functional response’ (relationship between resource use and availability) between invasive and trophically analogous native species may allow prediction of invader ecological impact. We review the utility of species trait comparisons and the history and context of the use of functional responses in invasion ecology, then present our framework for the use of comparative functional responses. We show that functional response analyses, by describing the resource use of species over a range of resource availabilities, avoids many pitfalls of ‘snapshot’ assessments of resource use. Our framework demonstrates how comparisons of invader and native functional responses, within and between Type II and III functional responses, allow testing of the likely population-level outcomes of invasions for affected species. Furthermore, we describe how recent studies support the predictive capacity of this method; for example, the invasive ‘bloody red shrimp’ Hemimysis anomala shows higher Type II functional responses than native mysids and this corroborates, and could have predicted, actual invader impacts in the field. The comparative functional response method can also be used to examine differences in the impact of two or more invaders, two or more populations of the same invader, and the abiotic (e.g. temperature) and biotic (e.g. parasitism) context-dependencies of invader impacts. Our framework may also address the previous lack of rigour in testing major hypotheses in invasion ecology, such as the ‘enemy release’ and ‘biotic resistance’ hypotheses, as our approach explicitly considers demographic consequences for impacted resources, such as native and invasive prey species. We also identify potential challenges in the application of comparative functional responses in invasion ecology. These include incorporation of numerical responses, multiple predator effects and trait-mediated indirect interactions, replacement versus non-replacement study designs and the inclusion of functional responses in risk assessment frameworks. In future, the generation of sufficient case studies for a meta-analysis could test the overall hypothesis that comparative functional responses can indeed predict invasive species impacts.

Predator cue studies reveal strong trait-mediated effects in communities despite variation in experimental designs

Nonconsumptive or trait-mediated effects of predators on their prey often outweigh density-mediated interactions where predators consume prey. For instance, predator presence can alter prey behaviour, physiology, morphology and/or development. Despite a burgeoning literature, our ability to identify general patterns in prey behavioural responses may be influenced by the inconsistent methodologies of predator cue experiments used to assess trait-mediated effects. We therefore conducted a meta-analysis to highlight variables (e.g. water type, predator husbandry, exposure time) that may influence invertebrate prey's behavioural responses to fish predator cues. This revealed that changes in prey activity and refuge use were remarkably consistent overall, despite wide differences in experimental methodologies. Our meta-analysis shows that invertebrates altered their behaviour to predator cues of both fish that were fed the focal invertebrate and those that were fed other prey types, which suggests that invertebrates were not responding to specific diet information in the fish cues. Invertebrates also altered their behaviour regardless of predator cue addition regimes and fish satiation levels. Cue intensity and exposure time did not have significant effects on invertebrate behaviour. We also highlight that potentially confounding factors, such as parasitism, were rarely recorded in sufficient detail to assess the magnitude of their effects. By examining the likelihood of detecting trait-mediated effects under large variations in experimental design, our study demonstrates that trait-mediated effects are likely to have pervasive and powerful influences in nature.

A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalysed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods and Results—A genome-wide association study was conducted using 1,830 cases from the UK, New Zealand and Australia with infra-renal aorta diameter =30mm or ruptured AAA and 5,435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1x10-4 were carried through to in silico replication in 1,292 AAA cases and 30,503 controls. One SNP associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1,063 controls from the UK, 507 AAA cases and 199 controls from Denmark and 885 AAA cases and 1,000 controls from New Zealand). Low density lipoprotein receptor (LDLR) rs6511720 A, was significantly associated overall and in three of five individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio 0.76; 95% confidence interval 0.70 to 0.83; P=2.08x10-10).

Conclusions—LDLR rs6511720 is associated with abdominal aortic aneurysm. This finding is consistent with established effects of this variant on coronary artery disease. Shared aetiological pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

In search of common grounds: Stitching the divided landscape of urban parks in Belfast's interface zones

Political and spatial contestation in divided cities contributes to strategies of self-defense that utilize physical and spatial settings to enable the constitution of social boundaries, borders and territories.
Urban parks that are designed to ease division through an open transitional landscape can instead facilitate further segregation through their spatial order and facility layout. This paper investigates the role of the spatial design and material landscape of integrated parks in Belfast interface areas as instruments of engagement or division. It does so by analyzing the spatial organization of the parks’ facilities and the resultant ‘social voids.’ Space, time and distance were found to be effective tools for the negotiation of privacy, the manifestation of power, and the interplay of dominance and self-confidence. In the context of a divided city, strong community-culture tends to reproduce new boundaries and territories within the shared landscape. Through user interviews and spatial analysis, this paper outlines the design principles that influence spatial behavior in the urban parks of contested urban landscapes. It argues that despite granting equal access to shared public facilities, social voids and physical gaps can instill practices of division that deepen territorial barriers, both psychologically and spatially.

Spectroscopic Observations of SN 2012fr: A Luminous Normal Type Ia Supernova with Early High Velocity Features and Late Velocity Plateau

We present 65 optical spectra of the Type Ia supernova SN 2012fr, of which 33 were obtained before maximum light. At early times SN 2012fr shows clear evidence of a high-velocity feature (HVF) in the Si II 6355 line which can be cleanly decoupled from the lower velocity "photospheric" component. This Si II 6355 HVF fades by phase -5; subsequently, the photospheric component exhibits a very narrow velocity width and remains at a nearly constant velocity of v~12,000 km/s until at least 5 weeks after maximum brightness. The Ca II infrared (IR) triplet exhibits similar evidence for both a photospheric component at v~12,000 km/s with narrow line width and long velocity plateau, as well as a high-velocity component beginning at v~31,000 km/s two weeks before maximum. SN 2012fr resides on the border between the "shallow silicon" and "core-normal" subclasses in the Branch et al. (2009) classification scheme, and on the border between normal and "high-velocity" SNe Ia in the Wang et al. (2009a) system. Though it is a clear member of the "low velocity gradient" (LVG; Benetii et al., 2005) group of SNe Ia and exhibits a very slow light-curve decline, it shows key dissimilarities with the overluminous SN 1991T or SN 1999aa subclasses of SNe Ia. SN 2012fr represents a well-observed SN Ia at the luminous end of the normal SN Ia distribution, and a key transitional event between nominal spectroscopic subclasses of SNe Ia.

Defining Target Volumes for Stereotactic Ablative Radiotherapy of Early-stage Lung Tumours:A Comparison of Three-dimensional F-fluorodeoxyglucose Positron Emission Tomography and Four-dimensional Computed Tomography

Aims: High local control rates are achieved in stage I lung cancer using stereotactic ablative radiotherapy. Target delineation is commonly based on four-dimensional computed tomography (CT) scans. Target volumes defined by positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional') F-fluorodeoxyglucose (F-FDG) PET/CT. Materials and methods: For 16 stage I non-small cell lung cancer tumours, six approaches for deriving PET target volumes were evaluated: manual contouring, standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV (35%SUV), 41% of SUV (41%SUV) and two different source to background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum intensity projection (MIP ITV). Volumetric and positional correlation was assessed using the Dice similarity coefficient (DSC). Results: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV = 0.63, 41%SUV = 0.57. SBR-1 = 0.52, SBR-2 = 0.49. PET-based target volumes were smaller than corresponding MIP ITVs. Conclusions: Conventional three-dimensional F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use (MIP ITV). Caution is required in using three-dimensional PET for motion encompassing target volume delineation. © 2012 The Royal College of Radiologists.

Transgressing Contemporary Boundaries:The Narrator as True Custodian of Cultural Knowledge in Ulster Society

Historically in Gaelic culture, the bard was greatly valued and admired as an important and integral part of society. Travelled, schooled and specifically trained in their art, the bard helped ensure identity and reassurance for Gaelic families by grounding them both temporarily and spatially into their landscape. Entrusted with the duty and responsibility of recording place and event, the bards worked without writing and by transgressing man-made boundaries, travelled throughout the land weaving their histories into the very fabric of society.

Now no longer with us, we find ourselves without the distinguished chronicler to undertake this duty. Yet the responsibility of the Gaelic bard is one still shared by all artists today; to facilitate memory and identity, whether good or bad. Many Ulster writers, by happenstance and geography have found themselves located in a place of painful histories. An immediate difficulty for those local writers becomes manifest by being intrinsically implicated into those histories – whilst having first-hand knowledge and comprehension beyond that of the outsider, the local writer is automatically damned by association and relationship, thereby tarnishing their voice in comparison to the perceived impartiality of others.
Some writers however have successfully sought ways to escape this limitation and have worked in ways that can transgress the restrictions of prejudgement. John Hewitt, by purposely becoming a self-imposed tourist was able to distance himself to write impartially about the past, recognising that ’the place without its ghosts is a barren place.’1 In ‘The Colony’,2 tradition, peoples and mapping of the land are all narrated by Hewitt in a similar way to the Gaelic bardic topographic poems of Sean O'Dubhagain and Giolla Na Naomh O'Huidhrin3 in compiling a rich cultural atlas.

Similarly the Belfast poet and novelist Ciaran Carson also writes and records the city from an intermediary position; that of translator. Mediating between reader and aisling,4 Carson himself takes the reader on a journey into name, meaning, time and place, focusing primarily on the city of Belfast, familiar in name but impenetrable in depth to most.

Furthermore, this once-forgotten tradition to chronicle is now being continued by the new breed of Irish crime writers where the likes of Brian McGilloway, Stuart Neville and Adrian McKinty can, by way of the crime novel, accurately record contemporary society. Thus, ghost estates, listed buildings, archaeological digs, street and city have all provided setting and subject matter for recent novels. Moreover by choosing the ‘outsider from within’ as their chief protagonist, whether detective or criminal, each author is able to transgress the boundaries of prejudice and preconception that hinder genuine understanding and knowledge.

Looking in turn at the Gaelic bard, the twentieth century Ulster poet and the new breed of Irish crime writer, the authors will outline the real value of the narrator, by being able to act as cultural transgressor beyond the seeming and alleged as the true chronicler in society, and then with specific reference to city and countryside in Ireland, as a valuable custodian of knowledge in architecture and place.

Keywords
Architecture, Crime Fiction, Cultural Atlas, Place, Poetry.

1 From ‘The Bloody Brae’, a one act play written by John Hewitt in the 1930’s.
2 Hewitt, J. (1968) published in Collected Poems 1932-67. London:McGibbon & Kee.
3 Lengthy and detailed medieval Gaelic poems composed in the fourteenth and fifteenth centuries first edited by John O'Donovan in 1862 for the Irish Archaeological and Celtic Society in Dublin.
4 The aisling is the Irish song or poem genre when the poet is visited by their muse in a daydream or dream-vision state.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Treatments for macular oedema following central retinal vein occlusion: systematic review

Objectives: To review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO).

Data sources: MEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013).

Study eligibility criteria, participants and interventions: RCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions.

Study appraisal and synthesis methods: 2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies.

Results: 8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40–60% gaining ≥15 letters on active drugs, compared to 12–28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias.

Limitations: All studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO.

Conclusions and implications of key findings: Bevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify ‘responders’ is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.

Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography.:PETCT versus 4DCT for SABR in Early Stage NSCLC

AIMS: High local control rates are achieved in stage I lung cancer using
stereotactic ablative radiotherapy. Target delineation is commonly based on
four-dimensional computed tomography (CT) scans. Target volumes defined by
positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional')
(18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT.

MATERIALS AND METHODS: For 16 stage I non-small cell lung cancer tumours, six
approaches for deriving PET target volumes were evaluated: manual contouring,
standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV
(35%SUV(MAX)), 41% of SUV(MAX) (41%SUV(MAX)) and two different source to
background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum
intensity projection (MIP(MOD) ITV). Volumetric and positional correlation was
assessed using the Dice similarity coefficient (DSC).

RESULTS: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP(MOD) ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV(MAX) = 0.63, 41%SUV(MAX) = 0.57. SBR-1 = 0.52, SBR-2 =0.49. PET-based target volumes were smaller than corresponding MIP ITVs.

CONCLUSIONS: Conventional three-dimensional (18)F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use
(MIP(MOD) ITV). Caution is required in using three-dimensional PET for motion
encompassing target volume delineation.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Towards groundwater security in coastal East Africa: initiating a regional research network and integrated hydrogeologic, climatic & socio-economic observatories in coastal aquifers of the Comoros Islands, Kenya and Tanzania

African coastal regions are expected to experience the highest rates of population growth in coming decades. Fresh groundwater resources in the coastal zone of East Africa (EA) are highly vulnerable to seawater intrusion. Increasing water demand is leading to unsustainable and ill-planned well drilling and abstraction. Wells supplying domestic, industrial and agricultural needs are or have become, in many areas, too saline for use. Climate change, including weather changes and sea level rise, is expected to exacerbate this problem. The multiplicity of physical, demographic and socio-economic driving factors makes this a very challenging issue for management. At present the state and probable evolution of coastal aquifers in EA are not well documented. The UPGro project 'Towards groundwater security in coastal East Africa' brings together teams from Kenya, Tanzania, Comoros Islands and Europe to address this knowledge gap. An integrative multidisciplinary approach, combining the expertise of hydrogeologists, hydrologists and social scientists, is investigating selected sites along the coastal zone in each country. Hydrogeologic observatories have been established in different geologic and climatic settings representative of the coastal EA region, where focussed research will identify the current status of groundwater and identify future threats based on projected demographic and climate change scenarios. Researchers are also engaging with end users as well as local community and stakeholder groups in each area in order to understanding the issues most affecting the communities and searching sustainable strategies for addressing these.

Endothelial progenitor cells in diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of visual impairment worldwide. Patients with DR may irreversibly lose sight as a result of the development of diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR); retinal blood vessel dysfunction and degeneration plays an essential role in their pathogenesis. Although new treatments have been recently introduced for DME, including intravitreal vascular endothelial growth factor inhibitors (anti-VEGFs) and steroids, a high proportion of patients (~40-50%) do not respond to these therapies. Furthermore, for people with PDR, laser photocoagulation remains a mainstay therapy despite this being an inherently destructive procedure. Endothelial progenitor cells (EPCs) are a low-frequency population of circulating cells known to be recruited to sites of vessel damage and tissue ischemia where they promote vascular healing and re-perfusion. A growing body of evidence suggests that the number and function of EPCs are altered in patients with varying degrees of diabetes duration, metabolic control, and in the presence or absence of DR. Although there are no clear-cut outcomes from these clinical studies, there is mounting evidence that some EPC sub-types may be involved in the pathogenesis of DR and may also serve as biomarkers for disease progression and stratification. Moreover, some EPC sub-types have considerable potential as therapeutic modalities for DME and PDR in the context of cell therapy. This study presents basic clinical concepts of DR and combines this with a general insight on EPCs and their relation to future directions in understanding and treating this important diabetic complication.