Integrating petrography, mineralogy and hydrochemistry to constrain the influence and distribution of groundwater contributions to baseflow in poorly productive aquifers: Insights from Gortinlieve catchment, Co. Donegal, NW Ireland

Identifying groundwater contributions to baseflowforms an essential part of surfacewater body characterisation. The Gortinlieve catchment (5 km2) comprises a headwater stream network of the Carrigans River, itself a tributary of the River Foyle, NW Ireland. The bedrock comprises poorly productive metasediments that are characterised by fracture porosity. We present the findings of a multi-disciplinary study that integrates new hydrochemical and mineralogical investigations with existing hydraulic, geophysical and structural data to identify the scales of groundwater flow and the nature of groundwater/bedrock interaction (chemical denudation). At the catchment scale, the development of deep weathering profiles is controlled by NE-SW regional scale fracture zones associated with mountain building during the Grampian orogeny. In-situ chemical denudation of mineral phases is controlled by micro- to meso-scale fractures related to Alpine compression during Palaeocene to Oligocene times. The alteration of primary muscovite, chlorite (clinochlore) and albite along the surfaces of these small-scale fractures has resulted in the precipitation of illite, montmorillonite and illite/montmorillonite clay admixtures. The interconnected but discontinuous nature of these small-scale structures highlights the role of larger scale faults and fissures in the supply and transportation of weathering solutions to/from the sites of mineral weathering. The dissolution of primarily mineral phases releases the major ions Mg, Ca and HCO3 that are shown to subsequently formthe chemical makeup of groundwaters. Borehole groundwater and stream baseflow hydrochemical data are used to constrain the depths of groundwater flow pathways influencing the chemistry of surface waters throughout the stream profile. The results show that it is predominantly the lower part of the catchment, which receives inputs from catchment/regional scale groundwater flow, that is found to contribute to the maintenance of annual baseflow levels. This study identifies the importance
of deep groundwater in maintaining annual baseflow levels in poorly productive bedrock systems.

The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink

PURPOSE: Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.

METHODS: Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.

RESULTS: Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.

CONCLUSIONS: There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Modeling study of woody biomass:Interactions of cellulose, hemicellulose, and lignin

Lignocellulosic biomass pretreatment and the subsequent thermal conversion processes to produce solid, liquid, and gas biofuels are attractive solutions for today's energy challenges. The structural study of the main components in biomass and their macromolecular complexes is an active and ongoing research topic worldwide. The interactions among the three main components, cellulose, hemicellulose, and lignin, are studied in this paper using electronic structure methods, and the study includes examining the hydrogen bond network of cellulose-hemicellulose systems and the covalent bond linkages of hemicellulose-lignin systems. Several methods (semiempirical, Hartree-Fock, and density functional theory) using different basis sets were evaluated. It was shown that theoretical calculations can be used to simulate small model structures representing wood components. By comparing calculation results with experimental data, it was concluded that B3LYP/6-31G is the most suitable basis set to describe the hydrogen bond system and B3LYP/6-31G(d,p) is the most suitable basis set to describe the covalent system of woody biomass. The choice of unit model has a much larger effect on hydrogen bonding within cellulose-hemicellulose system, whereas the model choice has a minimal effect on the covalent linkage in the hemicellulose-lignin system. © 2011 American Chemical Society.

Evaluation of Video Presentation to Deliver Surgical Anatomy Teaching

Title Evaluation of Video Presentation to Deliver Surgical Anatomy Teaching

Authors Walsh I.K., Boohan M., Dorman A.

Objectives To evaluate the efficacy of newly introduced video presentation to deliver Surgical Anatomy teaching to undergraduate medical students.

Design and Setting Qualitative and quantitative study using questionnaires and focus groups, employing students undertaking the perioperative medicine module of the phase 4 undergraduate medical curriculum at Queen’s University Belfast.

Outcome Measures To determine:
(1) if video presentation is effective in delivering surgical anatomy teaching,
(2) student’s learning preferences regarding this teaching method.
Results The questionnaire response rate was 89% (216 of 244 students; female: male ratio 1.25) and 42 students participated in 6 focus groups. Mean questionnaire responses indicated a favourable opinion on quality assurance items, with a mixed response to video presentation as a learning method. 71% of students preferred to receive a lecture in person, rather than via video presentation. There were no statistically significant differences between genders regarding learning preferences in general and regarding video versus live presentation in particular. Exploratory factor analysis demonstrated that favourable responses to video presentation were strongly associated with perceived audiovisual quality and learning preferences (Cronbach’s alpha coefficient 0.77), with 72% of students considering video presentation worthwhile. Positive perception of overall quality was strongly associated with learning preferences as well as more generic quality assurance issues (80% students; alpha coefficient 0.83).
The results were supported by triangulation of the above quantitative data with qualitative data generated by the focus groups. Students further articulated the view that video presentation may be more appropriate and effective in a mixed method setting.

Reference Basu Roy R, McMahon GT. Video-based cases disrupt deep critical thinking in problem-based learning. Med Educ 2012 Apr;46(4):426-435.

Evaluation of Multidisciplinary Delivery of Surgical Anatomy Teaching

Title Evaluation of Multidisciplinary Delivery of Surgical Anatomy Teaching

Authors Walsh I.K., Taylor S.J., Dorman A, Boohan M.

Objectives To evaluate the efficacy of newly introduced multidisciplinary methods to deliver Surgical Anatomy teaching to undergraduate medical students.

Design and Setting Qualitative and quantitative study using questionnaires and focus groups, employing students of the perioperative and emergency medicine (POEM) module of the phase 4 undergraduate medical curriculum at Queen’s University Belfast.

Outcome Measures To determine:
(1) if multidisciplinary teaching is effective in delivering surgical anatomy teaching,
(2) student’s learning preferences regarding this teaching method.
Results The questionnaire response rate was 89% (216 of 244 students; female: male ratio 1.25) and 42 students participated in 6 focus groups. Mean questionnaire responses indicated a favourable opinion on quality assurance items and multidisciplinary teaching. 81% of students agreed that multidisciplinary teaching enhanced learning and 86% felt that this did not adversely affect interaction. A positive contribution towards POEM learning was reported for Radiology (95% of students), Anatomy (93%) and Surgery (78%). The benefits of multidisciplinary teaching were congruent for Anatomy, Radiology and Surgery with 78% of students indicating a perceived favourable association with learning. Multidisciplinary teaching was not associated with diluted interaction, with 62% of students describing interaction as sufficient. 88% of students positively ranked tutor characteristics of enthusiasm and encouragement as being strongly associated with teacher quality. Positive perception of overall quality was strongly associated with learning preferences as well as more generic quality assurance issues (80% students; alpha coefficient 0.83).
The results were supported by triangulation of the above quantitative data with qualitative data generated by the focus groups. Whilst students frequently misunderstood the meaning of “multidisciplinary teaching”, there was an appreciation of the method’s worth; students recognised and valued the relevance of Anatomy, Radiology and Surgery teaching to POEM learning. The importance of vertically integrating Anatomy into all stages of the undergraduate curriculum was especially recognised.

Reference Aarnio M, Nieminen J, Pyorala E, Lindbolm-Ylanne S. Motivating medical students to learn. 2010 Med Teach;32(4):199-204.

Activity and coke formation of nickel and nickel carbide in dry reforming: A deactivation scheme from density functional theory

Dry reforming is a promising reaction to utilise the greenhouse gases CO2 and CH4. Nickel-based catalysts are the most popular catalysts for the reaction, and the coke formation on the catalysts is the main obstacle to the commercialisation of dry reforming. In this study, the whole reaction network of dry reformation on both flat and stepped nickel catalysts (Ni(111) and Ni(211)) as well as nickel carbide (flat: Ni3C(001); stepped: Ni3C(111)) is investigated using density functional theory calculations. The overall reaction energy profiles in the free energy landscape are obtained, and kinetic analyses are utilised to evaluate the activity of the four surfaces. By careful examination of our results, we find the following regarding the activity: (i) flat surfaces are more active than stepped surfaces for the dry reforming and (ii) metallic nickel catalysts are more active than those of nickel carbide, and therefore, the phase transformation from nickel to nickel carbide will reduce the activity. With respect to the coke formation, the following is found: (i) the coke formation probability can be measured by the rate ratio of CH oxidation pathway to C oxidation pathway (r(CH)/r(C)) and the barrier of CO dissociation, (ii) on Ni(111), the coke is unlikely to form, and (iii) the coke formations on the stepped surfaces of both nickel and nickel carbide can readily occur. A deactivation scheme, using which experimental results can be rationalised, is proposed. 

Increasing Prevalence of Myopia in Europe and the Impact of Education

PURPOSE: To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend.

DESIGN: Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E(3)) Consortium.

PARTICIPANTS: The E(3) Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years.

METHODS: Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent ≤-0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment.

MAIN OUTCOME MEASURES: Variation in age-specific myopia prevalence for differing years of birth and educational level.

RESULTS: There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6-18.1) to 23.5% (95% CI, 23.2-23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0-25.8), 29.1% (CI, 28.8-29.5), and 36.6% (CI, 36.1-37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio-2.43 (CI, 1.26-4.17) and 2.62 (CI, 1.31-5.00), respectively-whereas individuals born in the 1960s and completing higher education had approximately 4 times the reference risk: a prevalence ratio of 3.76 (CI, 2.21-6.57).

CONCLUSIONS: Myopia is becoming more common in Europe; although education levels have increased and are associated with myopia, higher education seems to be an additive rather than explanatory factor. Increasing levels of myopia carry significant clinical and economic implications, with more people at risk of the sight-threatening complications associated with high myopia.

SWAT-1: The effectiveness of a 'site visit' intervention on recruitment rates in a multi-centre randomised trial

Background: Recruitment rates in multi-centre randomised trials often fall below target recruitment rates, causing problems for study outcomes. The Studies Within A Trial (SWAT) Programme, established by the All-Ireland Hub for Trials Methodology Research in collaboration with the Medical Research Council Network of Hubs in the United Kingdom and others, is developing methods for evaluating aspects of trial methodology through the conduct of research within research. A recently published design for a SWAT-1 provides a protocol for evaluating the effect of a site visit by the principal investigator on recruitment in multi-centre trials.

Methods: Using the SWAT-1 design, the effect of a site visit, with the sole purpose of discussing trial recruitment, on recruitment rates in a large multicentre trial in the Republic of Ireland was evaluated. A controlled before and after intervention comparison was used, where the date of the site visit provides the time point for the intervention, and for the comparison to control sites. Site A received the intervention. Site B and Site C acted as the controls. Z-scores for proportions were calculated to determine within site recruitment differences. Odds ratios and 95% confidence intervals were calculated to determine between site recruitment differences.

Results: Recruitment rates were increased in Site A post-intervention (17% and 14% percentage point increases at 1 and 3 months, respectively). No differences in recruitment occurred in Site B or in Site C. Comparing between site differences, at 3 months post-intervention, a statistically significant difference was detected in favour of higher recruitment in Site A (34% versus 25%; odds ratio 1.57, 95% confidence interval 1.09 to 2.26).

Conclusions: This is the first reported example of a study in the SWAT programme.. It provides evidence that a site visit, combined with a scheduled meeting, increases recruitment in a clinical trial. Using this example, other researchers might be encouraged to consider conducting a similar study, allowing the findings of future SWAT-1s to be compared and combined, so that higher level evidence on the effect of a site visit by the principal investigator can be obtained.

Fasciola hepatica:the effect of the microfilament inhibitor cytochalasin B on the ultrastructure of the adult fluke

The effect of the microfilament inhibitor cytochalasin B (10 and 100 micrograms/ml) on the ultrastructure of adult Fasciola hepatica was determined in vitro by scanning and transmission electron microscopy (SEM, TEM) using both intact flukes and tissue-slice material. SEM revealed that initial swelling of the tegument led to surface blebbing and limited areas of sloughing after 24 h treatment at 100 micrograms/ml. In the tegumental syncytium, basal accumulations of secretory bodies (especially T2s) were evident in the earlier time periods but declined with longer incubations, until few secretory bodies remained in the syncytium overall. Blebbing of the apical plasma membrane and occasional areas of breakdown and sloughing of the tegument were observed over longer periods of treatment at 100 micrograms/ml. In the tegumental cell bodies, the Golgi complexes gradually decreased in size and activity, and few secretory bodies were produced. In the later time periods, the cells assumed abnormal shapes, the cytoplasm shrinking in towards the nucleus. In the vitelline follicles, a random dispersion of shell protein globules was evident within the intermediate-type cells, rather than their being organized into distinct shell globule clusters. Disruption of this process was more severe at the higher concentration of 100 micrograms/ml and again was more evident in tissue-slice material. In the latter, after prolonged (12 h) exposure to cytochalasin B, the intermediate and mature vitelline cells were filled with loosely packed and expanded shell globule clusters, containing few shell protein globules. The mature vitelline cells continued to lay down "yolk" globules and glycogen deposits. Disruption of the network of processes from the nurse cells was evident at the higher concentration of cytochalasin. Spaces began to appear between the vitelline cells and grew larger with progressively longer incubation periods, and the cells themselves assumed abnormal shapes. A number of binucleate stem cells were observed in tissue-slice material at the longest incubation period (12 h).

Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.

This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.

General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.

Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.

Prokineticin ligands and receptors are expressed in the human fetal ovary and regulate germ cell expression of COX2

CONTEXT: Fetal ovarian development and primordial follicle formation underpin future female fertility. Prokineticin (PROK) ligands regulate cell survival, proliferation and angiogenesis in adult reproductive tissues including the ovary. However, their expression and function during fetal ovarian development remains unclear.

OBJECTIVE: To investigate expression and localization of the PROK ligands, receptors and their downstream transcriptional targets in the human fetal ovary.

SETTING: This study was conducted at the University of Edinburgh.

PARTICIPANTS: Ovaries were collected from 37 morphologically normal human fetuses.

DESIGN AND MAIN OUTCOME MEASURES: mRNA and protein expression of PROK ligands and receptors was determined in human fetal ovaries using qRT-PCR, immunoblotting and immunohistochemistry. Functional studies were performed using a human germ tumour cell line (TCam-2) stably transfected with PROKR1.

RESULTS: Expression of PROK1 and PROKR1 was significantly higher in mid-gestation ovaries (17-20 weeks) than at earlier gestations (8-11 and 14-16 weeks). PROK2 significantly increased across the gestations examined. PROKR2 expression remained unchanged. PROK ligand and receptor proteins were predominantly localised to germ cells (including oocytes within primordial follicles) and endothelial cells, indicating these cell types to be the targets of PROK signalling in the human fetal ovary. PROK1 treatment of a germ cell line stably-expressing PROKR1 resulted in ERK phosphorylation, and elevated COX2 expression.

CONCLUSIONS: Developmental changes in expression and regulation of COX2 and pERK by PROK1 suggest that PROK ligands may be novel regulators of germ cell development in the human fetal ovary, interacting within a network of growth and survival factors prior to primordial follicle formation.

The utility of animal models in developing immunosuppressive agents

The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R׳s: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies.

Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis

Clathrin-mediated endocytosis involves the assembly of a network of proteins that select cargo, modify membrane shape and drive invagination, vesicle scission and uncoating. This network is initially assembled around adaptor protein (AP) appendage domains, which are protein interaction hubs. Using crystallography, we show that FxDxF and WVxF peptide motifs from synaptojanin bind to distinct subdomains on alpha-appendages, called 'top' and 'side' sites. Appendages use both these sites to interact with their binding partners in vitro and in vivo. Occupation of both sites simultaneously results in high-affinity reversible interactions with lone appendages (e.g. eps15 and epsin1). Proteins with multiple copies of only one type of motif bind multiple appendages and so will aid adaptor clustering. These clustered alpha(appendage)-hubs have altered properties where they can sample many different binding partners, which in turn can interact with each other and indirectly with clathrin. In the final coated vesicle, most appendage binding partners are absent and thus the functional status of the appendage domain as an interaction hub is temporal and transitory giving directionality to vesicle assembly.