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Introduction: Ongoing monitoring of cohort demographic variation is an essential part of quality assurance in medical education assessments, yet the methods employed to explore possible underlying causes of demographic variation in performance are limited. Focussing on properties of the vignette text in single-best-answer multiple-choice questions (MCQs), we explore here the viability of conducting analyses of text properties and their relationship to candidate performance. We suggest that such analyses could become routine parts of assessment evaluation and provide an additional, equality-based measure of an assessment's quality and fairness., Methods: We describe how a corpus of vignettes can be compiled, followed by examples of using Microsoft Word's native readability statistics calculator and the koRpus text analysis package for the R statistical analysis environment for estimating the following properties of the question text: Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (Grade), word count, sentence count, and average words per sentence (WpS). We then provide examples of how these properties can be combined with equality and diversity variables, and the process automated to provide ongoing monitoring., Conclusions: Given the monitoring of demographic differences in assessment for assurance of equality, the ability to easily include textual analysis of question vignettes provides a useful tool for exploring possible causes of demographic variations in performance where they occur. It also provides another means of evaluating assessment quality and fairness with respect to demographic characteristics. Microsoft Word provides data comparable to the specialized koRpus package, suggesting routine use of word processing software for writing items and assessing their properties is viable with minimal burden, but that automation for ongoing monitoring also provides an additional means of standardizing MCQ assessment items, and eliminating or controlling textual variables as a possible contributor to differential attainment between subgroups.

Aims: To investigate the impact of progress testing on the learning experiences of undergraduate students in three programs namely, medicine, dentistry and dental therapy., Methods: Participants were invited to respond to an online questionnaire to share their perceptions and experiences of progress testing. Responses were recorded anonymously, but data on their program, year of study, age, gender, and ethnicity were also captured on a voluntary basis., Results: A total of 167 participants completed the questionnaire yielding a response rate of 27.2% (n = 167). These included 96 BMBS students (27.4%), 56 BDS students (24.7%), and 15 BScDTH students (39.5%). A 3 -Program (BMBS, BDS, BScDTH) by 8-Topic (A-H) mixed analysis of variance (ANOVA) was conducted on the questionnaire responses. This revealed statistically significant main effects of Program and Topic, as well as a statistically significant interaction between the two (i.e. the pattern of topic differences was different across programs)., Conclusions: Undergraduate students in medicine, dentistry, and dental therapy and hygiene regarded PT as a useful assessment to support their learning needs. However, in comparison to students in dentistry and dental therapy and hygiene, the perceptions of medical students were less positive in several aspects of PT.

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [ 64 Cu]CuCl 2 PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [ 64 Cu]CuCl 2 was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [ 64 Cu]CuCl 2 retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Aims: To evaluate the self-perceived preparedness to practice of final year dental undergraduate students in three dental institutions., Methods: Dental undergraduate students in their final year from three dental institutions in Pakistan were invited to participate in an online study to assess self-perceived preparedness using a validated preparedness assessment scale., Results: In total, 134 students responded to the questionnaire yielding a response rate of 72%. Students felt adequately prepared to carry out several clinical procedures including clinical assessment, fillings, tooth extractions and communication skills. However, perceived preparedness was low in the students' ability to undertake intraoral radiographs, treatment planning, crowns, multirooted endodontics, research skills, referral for suspected oral cancer and raising concerns regarding inappropriate behaviour of colleagues., Conclusions: This is the first study which investigates the self-perceived preparedness of final year undergraduate dental students in Pakistan. The results show that the self-perceived preparedness of final year students was satisfactory for a range of clinical and affective skills. However, several areas of weaknesses were identified which underscore the need for additional training and consolidation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gain-of-function (GOF) mutations in PIK3CD , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors., (© 2018 Avery et al.)

Context: Discrimination and harassment create a hostile environment with deleterious effects on student well-being and education. In this study, we aimed to: (i) measure prevalences and types of discrimination and harassment in one UK medical school, and (ii) understand how and why students report them., Methods: The study used a mixed-methods design. A medical school population survey of 1318 students was carried out in March 2014. Students were asked whether they had experienced, witnessed or reported discrimination or harassment and were given space for free-text comments. Two focus group sessions were conducted to elicit information on types of harassment and the factors that influenced reporting. Proportions were analysed using the Wilson score method and associations tested using chi-squared and regression analyses. Qualitative data were subjected to framework analysis. Degrees of convergence between data were analysed., Results: A total of 259 (19.7%) students responded to the survey. Most participants had experienced (63.3%, 95% confidence interval [CI]: 57.3-69.0) or witnessed (56.4%, 95% CI: 50.3-62.3) at least one type of discrimination or harassment. Stereotyping was the form most commonly witnessed (43.2%, 95% CI: 37.4-49.3). In the qualitative data, reports of inappropriate joking and invasion of personal space were common. Black and minority ethnic students had witnessed and religious students had experienced a greater lack of provision (χ 2  = 4.73, p = 0.03 and χ 2  = 4.38, p = 0.04, respectively). Non-heterosexual students had experienced greater joking (χ 2  = 3.99, p = 0.04). Students with disabilities had experienced more stereotyping (χ 2  = 13.5, p < 0.01). Female students and students in clinical years had 2.6 (95% CI: 1.3-5.3) and 3.6 (95% CI: 1.9-7.0) greater odds, respectively, of experiencing or witnessing any type of discrimination or harassment. Seven of 140 survey respondents had reported incidents (5.0%, 95% CI: 2.4-10.0). Reporting was perceived as ineffective and as potentially victimising of the reporter., Conclusions: Harassment and discrimination are prevalent in this sample and associated with gender, ethnicity, sexuality, disability and year group. Reporting is rare and perceived as ineffective. These findings have informed local developments, future strategies and the development of a national prevention policy., (© 2018 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Progress testing provides a longitudinal assessment of the development and sustainability of students' knowledge at regular intervals over the duration of an educational program. Comparisons of performance on successive tests are used to monitor growth in knowledge. The aim of this study was to evaluate the effects of progress testing in an undergraduate program for dental therapy and hygiene (DTH) students in the United Kingdom as the main tool for academic assessment. Data were collected for progress tests of all 38 DTH students from 2015 to 2017. Each test consisted of 100 single best answer multiple-choice items with accompanying vignette. The students chose their answer from five options. A score of 1 was awarded for a correct answer, -0.25 for an incorrect answer, and 0 for don't know (DK). Three cohorts of DTH students were included in the study, and seven progress tests were conducted over a period of three years. Analysis of performance showed growth in knowledge across successive years, with the largest increase in knowledge in the transition from Year 1 to Year 2 and concomitant reduction in incorrect and DK responses. This was a pioneering study to report the establishment and use of progress testing among undergraduate DTH students. Notwithstanding the challenges involved, the study found merit in further exploring the use of progress testing for students in the DTH program.

Objectives: Coronary angiography can be stressful for patients and anxiety-caused physiological responses during the procedure increase the risk of dysrhythmia, coronary artery spasms and rupture. This study therefore aimed to investigate the effects of peer, video and combined peer-and-video training on anxiety among patients undergoing coronary angiography., Methods: This single-blinded randomised controlled clinical trial was conducted at two large educational hospitals in Iran between April and July 2016. A total of 120 adult patients undergoing coronary angiography were recruited. Using a block randomisation method, participants were assigned to one of four groups, with those in the control group receiving no training and those in the three intervention groups receiving either peer-facilitated training, video-based training or a combination of both. A Persian-language validated version of the State-Trait Anxiety Inventory was used to measure pre- and post-intervention anxiety., Results: There were no statistically significant differences in mean pre-intervention anxiety scores between the four groups (F = 0.31; P = 0.81). In contrast, there was a significant reduction in post-intervention anxiety among all three intervention groups compared to the control group (F = 27.71; P <0.01); however, there was no significant difference in anxiety level in terms of the type of intervention used., Conclusion: Peer, video and combined peer-and-video education were equally effective in reducing angiography-related patient anxiety. Such techniques are recommended to reduce anxiety amongst patients undergoing coronary angiography in hospitals in Iran., Competing Interests: CONFLICT OF INTEREST The authors declare no conflict of interest.

Aims: The aim of this research was to evaluate the impact of early clinical exposure on the learning experiences of undergraduate dental students., Methods: This study was based on mixed methods. The first phase involved administering a purposely designed questionnaire consisting of 16 items, grouped into three subscales. The second phase of the research was conducted using qualitative semi-structured interviews to explore the perceptions and experiences of stakeholders regarding early clinical exposure., Results: In total, 134 undergraduate dental students and eight clinical supervisors responded to the questionnaire and reported positive perceptions regarding the learning experiences, professional relationship and learning environment. Qualitative interviews were conducted with 12 participants, and early clinical exposure was perceived to be useful in providing a context to theoretical learning and development of interpersonal skills. Curriculum overload and further need for consolidation were highlighted as the main challenges., Conclusions: This study provided insights into the clinical training model in an undergraduate dental programme and highlights the benefits and challenges of early clinical exposure in the study population. The study served as a vehicle for engagement with a range of stakeholders using a mixed methods approach to inform further development of the training model., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The development of shark vertebrae and the possible drivers of inter- and intra-specific differences in vertebral structure are poorly understood. Shark vertebrae are used to examine life-history traits related to trophic ecology, movement patterns, and the management of fisheries; a better understanding of their development would be beneficial to many fields of research that rely on these calcified structures. This study used Scanning X-ray Fluorescence Microscopy to observe zinc distribution within vertebrae of ten shark species from five different orders. Zinc was mostly localised within the intermedialis and was generally detected at levels an order of magnitude lower in the corpus calcareum. In most species, zinc concentrations were higher pre-birth mark, indicating a high rate of pre-natal zinc deposition. These results suggest there are inter-specific differences in elemental deposition within vertebrae. Since the deposition of zinc is physiologically-driven, these differences suggest that the processes of growth and deposition are potentially different in the intermedialis and corpus calcareum, and that caution should be taken when extrapolating information such as annual growth bands from one structure to the other. Together these results suggest that the high inter-specific variation in vertebral zinc deposition and associated physiologies may explain the varying effectiveness of ageing methodologies applied to elasmobranch vertebrae.

Dental students are assessed using a range of methods in their final-year examinations. The aim of this study was to explore the correlations and predictive value of final-year dental students' performance on knowledge-based and clinical assessments. Examination data related to applied dental knowledge (ADK), exit case presentation (CP), and integrated structured clinical examination (ISCE) assessments for five consecutive cohorts of final-year students at one U.K. dental school from 2011-12 to 2015-16 were collated. The relationships between the scores produced by each assessment were investigated to explore the relative contributions of each to the understanding of students' abilities across the domains. The study utilized data from all 304 students: 147 (48.4%) females and 157 (51.6%) males. Significant positive correlations were found between ISCE and ADK performance (r(391)=0.42, p<0.001) as well as between ISCE and CP (r(391)=0.44, p<0.001). In addition, both ADK performance and CP performance were significant predictors (at p<0.001) of ISCE performance. This study provides important information about the relationship between these students' performance across knowledge (ADK) and clinical (ISCE and CP) domains and highlights their predictive value. Further research is required to establish if these findings can be generalized and to explore the correlations between performance of dental students before and after graduation.

Aims: To compare the academic performance of graduate-entry and direct school leavers in an undergraduate dental programme., Methods: This study examined the results of students in applied dental knowledge (ADK) progress tests conducted during two academic years. A mixed model analysis of variance (ANOVA) was conducted to compare the performance of graduate-entry and direct school leavers. ADK was treated as a repeated measures variable, and the outcome variable of interest was percentage score on the ADK., Results: The results show statistically significant main effects for ADK [F (1,113) = 61.58, P < 0.001, η 2 p = 0.35], Cohort [F (1,113) = 88.57, P < 0.001, η 2 p = 0.44] and Entry [F (1,113) = 11.31, P = 0.001, η 2 p = 0.09]. That is, students do better on each subsequent test (main effect of ADK), students in later years of the programme perform better than those in earlier years (main effect of cohort), and graduate-entry students outperform direct school leavers., Conclusions: This is the first study to explore the differences in the academic performance of graduate-entry and direct school leavers in an undergraduate dental programme. The results show that the academic performance of graduate students was better than the direct school leavers in years 2 and 3. Further research is required to compare the performance of students longitudinally across the entire duration of undergraduate dental programmes and evaluate whether this difference persists throughout., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This article was migrated. The article was marked as recommended. The Angoff standard setting method depends fundamentally on the conceptualisation of an anchor statement. The precise wording and consequent interpretation of anchor statements varies in practice. Emphasis is often placed on standard setting judges' perceptions of difficulty for a candidate subgroup. The current review focusses on the meaning of anchor statements and argues that when determining the required standard of performance it is more appropriate to consider: (1) what it is important to achieve, and not how difficult it is to achieve it; (2) what all candidates should achieve, and not what a subgroup of candidates would achieve. In summary, current practice should be refined by using an anchor statement which refers to estimating the 'minimum acceptable performance by every candidate' for each item being tested, and then requiring each judge to score the relevant aspects of importance which could then be combined to derive a cut-score., (Copyright: © 2017 Burr SA et al.)

Aims To evaluate the self-perceived preparedness of final year dental undergraduate students in the United Kingdom.Methods Dental undergraduate students in their final year were invited by email through the Dental Schools Council (DSC) to provide their responses to an online preparedness assessment scale. The data analysis was carried out using the RUMM2030 software which is specifically designed for Rasch analysis, a measurement model based on item response theory.Results Students felt adequately prepared to carry out simple clinical procedures and communication skills. However, low scores were reported on ability to assess orthodontic treatment needs, treatment planning, crowns, endodontics, research skills, referral for suspected oral cancer and raising concerns regarding inappropriate behaviour of colleagues.Conclusions The scale used in this study explored the self-perceived preparedness on a range of cognitive, clinical and behavioural attributes. The data show that the students felt prepared for the majority of the attributes expected from dentists. However, a number of areas were identified where students may benefit from further training and consolidation.

Aims To compare the academic performance of undergraduate dental students with known learning disabilities (LDs) to their peers.Methods This study analysed the results of students in applied dental knowledge (ADK) progress tests across four cohorts of dental students. A mixed model analysis of variance (ANOVA) was conducted to compare the performance of students with known disability to their peers. ADK test sitting was treated as a repeated measures variable, and the outcome variable of interest was percentage score on the ADK.Results Students' performance data on five ADK test sittings (ADK15, ADK16, ADK17, ADK18, and ADK19) by disability showed a significant main effect of test but no significant effect of disability or any interaction between disability and test.Conclusions This is the first study that explores the academic performance of dental students with a diagnosis of disability. The findings give reassurance to all stakeholders that, within the study population, students with LDs are not disadvantaged in knowledge-based assessments, demonstrating compliance with the legal obligations. Further research is required to explore how generalisable these findings are, as well as assess academic, clinical, and behavioural attributes of students with learning disabilities.

Objective: Validation of the Emotional Logic Development Profile (ELDP) as a measure of improvements in emotional literacy and well-being resulting from emotional logic (EL) training; a programme designed to improve emotional literacy and reduce depression and anxiety., Method: A general adult population sample was recruited to obtain normative ELDP data, from which clinically significant change, reliability and psychometric properties could be assessed against a patient sample. This consisted of 53 patients at a UK primary care medical practice who were offered EL while on a waiting list for other psychological therapies. Patients completed the PHQ-9, GAD-7 and ELDP at initial and two-month follow-up sessions. ELDP factor structure and sensitivity were assessed, and semistructured follow-up interviews provided additional qualitative data on acceptability., Results: PHQ-9, GAD-7 and ELDP all showed significant improvements between pre- and post-EL measurement. The ELDP appears unidimensional, provides additional information to the PHQ-9 and GAD-7 and is sensitive to change. Furthermore, 17% of patients showed reliable, clinically significant improvements in ELDP scores. General practice (GP) consultations and medication use both significantly reduced., Conclusions: The ELDP reliably measures ELs impact on reducing depression and anxiety. Further evaluation of EL viability for wider use in primary care, and in other age groups, may prove beneficial.

Determining the age of sharks using vertebral banding is a vital component of management, but the causes of banding are not fully understood. Traditional shark ageing is based on fish otolith ageing methods where growth bands are assumed to result from varied seasonal calcification rates. Here we investigate these assumptions by mapping elemental distribution within the growth bands of vertebrae from six species of sharks representing four different taxonomic orders using scanning x-ray fluorescence microscopy. Traditional visual growth bands, determined with light microscopy, were more closely correlated to strontium than calcium in all species tested. Elemental distributions suggest that vertebral strontium bands may be related to environmental variations in salinity. These results highlight the requirement for a better understanding of shark movements, and their influence on vertebral development, if confidence in age estimates is to be improved. Analysis of shark vertebrae using similar strontium-focused elemental techniques, once validated for a given species, may allow more successful estimations of age on individuals with few or no visible vertebral bands.

Context: Developed by Jacobson and Truax, the reliable change index (RCI) provides a measure of whether the change in an individual's score over time is within or beyond that which might be accounted for by measurement variability. In combination with measures of whether an individual's final score is closer to those of one population or another, this provides useful individual-level information that can be used to supplement traditional analyses., Objectives: This article aims to highlight the potential of the RCI for use within medical education, particularly as a novel means of monitoring progress at the student level across successive test occasions or academic years., Methods: We provide an example of how the RCI can be applied informatively to assessment evaluation, and discuss its wider usage., Conclusions: The RCI approach can be used to identify and support failing students, as well as to determine best teaching and learning practices by identifying high-performing students. Furthermore, the individual-level nature of the RCI makes it well suited for educational research with small cohorts, as well as for tracking individual profiles within a larger cohort or addressing questions about individual performance that may be unanswerable at group level., (© 2016 John Wiley & Sons Ltd.)

In PET imaging, research groups have recently proposed different experimental set ups allowing multiple animals to be simultaneously imaged in a scanner in order to reduce the costs and increase the throughput. In those studies, the technical feasibility was demonstrated and the signal degradation caused by additional mice in the FOV characterized, however, the impact of the signal degradation on the outcome of a PET study has not yet been studied. Here we thoroughly investigated, using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies, different experimental designs for whole-body and brain acquisitions of two mice and assessed the actual impact on the detection of biological variations as compared to a single-mouse setting. First, we extended the validation of the PET-SORTEO Monte Carlo simulation platform for the simultaneous simulation of two animals. Then, we designed [18F]FDG and [11C]Raclopride input mouse models for the simulation of realistic whole-body and brain PET studies. Simulated studies allowed us to accurately estimate the differences in detection between single- and dual-mode acquisition settings that are purely the result of having two animals in the FOV. Validation results showed that PET-SORTEO accurately reproduced the spatial resolution and noise degradations that were observed with actual dual phantom experiments. The simulated [18F]FDG whole-body study showed that the resolution loss due to the off-center positioning of the mice was the biggest contributing factor in signal degradation at the pixel level and a minimal inter-animal distance as well as the use of reconstruction methods with resolution modeling should be preferred. Dual mode acquisition did not have a major impact on ROI-based analysis except in situations where uptake values in organs from the same subject were compared. The simulated [11C]Raclopride study however showed that dual-mice imaging strongly reduced the sensitivity to variations when mice were positioned side-by-side while no sensitivity reduction was observed when they were facing each other. This is the first study showing the impact of different experimental designs for whole-body and brain acquisitions of two mice on the quality of the results using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies.

It is incumbent on medical schools to show, both to regulatory bodies and to the public at large, that their graduating students are "fit for purpose" as tomorrow's doctors. Since students graduate by virtue of passing assessments, it is vital that schools quality assure their assessment procedures, standards, and outcomes. An important part of this quality assurance process is the appropriate use of psychometric analyses. This begins with development of an empowering, evidence-based culture in which assessment validity can be demonstrated. Preparation prior to an assessment requires the establishment of appropriate rules, test blueprinting and standard setting. When an assessment has been completed, the reporting of test results should consider reliability, assessor, demographic, and long-term analyses across multiple levels, in an integrated way to ensure the information conveyed to all stakeholders is meaningful.

Aims: To investigate the cognitive processing of emotive pictorial warnings intended to curb alcohol misuse, using novel methodologies adapted from the reasoning literature to assess whether emotive pictorial warnings alter reasoning., Method: In Study 1, individuals completed a version of the Wason selection task-evaluating warnings in which content type (Alcohol and Non-Alcohol) and emotional valence (Positive and Negative) were manipulated through imagery. In Study 2, people evaluated the certainty of outcomes described by alcohol-related and non-alcohol-related warnings in the form of If-Then statements., Results: Study 1 found that in alcohol-related warnings, there was no difference in reasoning accuracy between positive and negative content. However, fewer correct responses followed exposure to negative general-health messages. Study 2 suggested that when a warning involves the potential consequences of drinking alcohol, accuracy is improved when the content is negative. However, when considering the consequences of abstinence, accuracy was greatest when the content was positive. This was supported by an inference by content interaction., Conclusion: In conclusion, negative imagery should be used with caution in health warnings, and goals carefully considered. In some cases imagery of negative outcomes may improve reasoning, however, its use in alcohol-related messages does not appear to be consistently beneficial., (© The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Objective: Individuals with autism spectrum disorder (ASD) are often characterized as having social engagement and language deficiencies, but a sparing of visuospatial processing and short-term memory (STM), with some evidence of supranormal levels of performance in these domains. The present study expanded on this evidence by investigating the observational learning of visuospatial concepts from patterns of covariation across multiple exemplars., Method: Child and adult participants with ASD, and age-matched control participants, viewed multishape arrays composed from a random combination of pairs of shapes that were each positioned in a fixed spatial arrangement., Results: After this passive exposure phase, a posttest revealed that all participant groups could discriminate pairs of shapes with high covariation from randomly paired shapes with low covariation. Moreover, learning these shape-pairs with high covariation was superior in adults with ASD than in age-matched controls, whereas performance in children with ASD was no different than controls., Conclusions: These results extend previous observations of visuospatial enhancement in ASD into the domain of learning, and suggest that enhanced visual statistical learning may have arisen from a sustained bias to attend to local details in complex arrays of visual features., (PsycINFO Database Record (c) 2015 APA, all rights reserved.)

Purpose: The in vivo binding parameters of the novel imidazopyridine TSPO ligand [(18)F]PBR102 were assessed and compared with those of [(18)F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC)., Methods: Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [(18)F]PBR102 or [(18)F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [(125)I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM., Results: The BPs of [(18)F]PBR102 [(18)F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [(11)C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP., Conclusion: [(18)F]PBR102 and [(18)F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [(11)C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.

The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer's disease to anxiety. Here we show that global C57BL/6-Tspo(tm1GuWu(GuwiyangWurra))-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from (GuwiyangWurra)TSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of (GuwiyangWurra)TSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.

Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To investigate the psychometric properties of the Work and Social Adjustment Scale (WSAS) as an outcome measure for the Improving Access to Psychological Therapy programme, assessing its value as an addition to the Patient Health (PHQ-9) and Generalised Anxiety Disorder questionnaires (GAD-7). Little research has investigated these properties to date., Methods: Reliability and responsiveness to change were assessed using data from 4,835 patients. Principal components analysis was used to determine whether the WSAS measures a factor distinct from the PHQ-9 and GAD-7., Results: The WSAS measures a distinct social functioning factor, has high internal reliability, and is sensitive to treatment effects., Conclusions: The WSAS, PHQ-9 and GAD-7 perform comparably on measures of reliability and sensitivity. The WSAS also measures a distinct social functioning component suggesting it has potential as an additional outcome measure.

Background: The istone deacetylase (HDAC) inhibitor trichostatin A (TSA) is known to mediate the regulation of gene expression and anti proliferation activity in cancer cells. Kruppel-like factor 4 (klf4) is a zinc finger- containing transcription factor of the SP/KLF family, that is expressed in a variety of tissues and regulates cell proliferation, differentiation, tumorigenesis, and apoptosis. It may either either function as a tumor suppressor or an oncogene depending on genetic context of tumors., Aims: In this study, we tested the possibility that TSA may increase klf4 expression and cancer cell growth inhibition and apoptosis in SKOV-3 and A549 cells., Materials and Methods: The cytotoxicity of TSA was determined using the MTT assay test, while klf4 gene expression was assessed by real time PCR and to ability of TSA to induce apoptosis using a Vybrant Apoptosis Assay kit., Results: Our results showed that TSA exerted dose and time dependent cytotoxicity effect on SKOV-3 and A549 cells. Moreover TSA up-regulated klf4 expression. Flow cytometric analysis demonstrated that apoptosis was increased after TSA treatment., Conclusions: Taken together, this study showed that TSA increased klf4 expression in SKOV3 and A549 cell lines, consequently, klf4 may played a tumor-suppressor role by increasing both cell growth inhibition and apoptosis. This study sheds light on the details of molecular mechanisms of HDACI-induced cell cycle arrest and apoptosis.

Unlabelled: The Inveon small-animal SPECT system comes with several types of multipinhole collimator plates. We evaluate here the performance measurements of the Inveon SPECT system using 6 different collimators: 3 dedicated for mouse imaging and 3 for rat imaging., Methods: The measured performance parameters include the sensitivity, the spatial resolution using line sources, the ultra-micro Derenzo phantom, the recovery coefficient and the noise measurements using the National Electrical Manufacturers Association NU-4 image quality phantom, obtained with the 2 reconstruction algorithms available with the Inveon Acquisition Workplace, version 1.5-the 3-dimensional ordered-subset expectation maximization (3DOSEM) and the 3-dimensional maximum a posteriori (3DMAP). Further, the overall performance of the system is illustrated by an animal experiment., Results: The results show that the Inveon SPECT scanner offers a spatial resolution, measured at the center of the field of view, ranging from 0.6 to 1 mm with the collimator plates dedicated to mouse imaging and from 1.2 to less than 2 mm with rat collimator plates. The system sensitivity varies from 29 to 404 cps/MBq for mouse collimators and from 53 to 175 cps/MBq for rat collimators. The image quality study showed that 3DMAP allows better noise reduction while preserving the recovery coefficient, compared with other regularization strategies such as the premature termination of the 3DOSEM reconstruction or 3DOSEM followed by gaussian filtering., Conclusion: The acquisition parameters, such as the collimator set and the radius of rotation, offer a wide range of possibilities to apply to a large number of biologic studies. However, special care must be taken because this increase in sensitivity can be offset by image degradation, such as image artifacts caused by projection overlap and statistical noise due to a higher number of iterations required for convergence. 3DMAP allowed better noise reduction while maintaining relatively constant recovery coefficients, as compared with other reconstruction strategies.

Background: Cervical screening uptake has increased as a result of occurrences of cervical cancer in TV 'soap operas' and in real life celebrities such as Jade Goody. Media analysis at the time of Jade Goody's death suggested the NHS did not take sufficient advantage of this opportunity to improve cervical screening rates. Google AdWords has been used to recruit and raise awareness of health but we were not aware of its use to supplement media events., Methods: This was an opportunistic service evaluation to accompany a cervical cancer storyline in Eastenders (a TV 'soap opera'). We ran an AdWords campaign based on keywords such as 'Eastenders', and 'cervical cancer' in a one mile radius in East London, linked to one webpage giving details of 10 practices and other links on cervical cancer. We recorded costs of adverts and setting up the webpage. We used routine statistics from Tower Hamlets, City and Hackney, and Newham Primary Care Trusts (PCTs) of the number of smears, eligible populations, and coverage by practice by month from September 2010 to January 2012 to compare the ten intervention practices with controls., Results: Eight people per day in the target area viewed the project webpage. The cost of setting up the website and running Google AdWords was £1320 or £1.88 per person viewing the webpage. Unlike Jade Goody's death, there was no major impact from the Eastenders' storyline on Google searches for cervical cancer. There was considerable monthly variation in the number of smear tests in the 3 PCTs. The AdWords campaign may have had some effect on smear rates but this showed, at best, a marginal statistical difference. Assuming a 'real' effect, the intervention may have resulted in 110 'extra' women being screened but there was no change in coverage., Conclusions: Although the Eastenders storyline seemed to have no effect on interest in cervical cancer or screening, the AdWords campaign may have had some effect. Given the small scale exploratory nature of the study this was not statistically significant but the relatively modest cost of advertising suggests a larger study may be worthwhile. An outline of a possible study is described.

Unlabelled: Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111., Methods: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction., Results: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE., Conclusion: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies.

Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15 min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100 μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15 min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40 min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24 h later., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Despite the important role of cannabinoid CB(1) receptors (CB(1)R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB(1)R in adolescent and adult rats in vivo using positron emission tomography with [(18)F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [(18)F]MK-9470 values between the two groups revealed a main effect of age (F(1,109)=5.0, P = 0.02) on [(18)F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [(3)H]CP55,940 (F(10,99)=140.1, P < 0.0001). This ontogenetic pattern, suggesting increase of CB(1)R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period.

3D shape context is a method to define matching points between similar shapes. It can be used as a pre-processing step in a non-rigid registration. The main limitation of the method is point mismatching, which includes long geodesic distance mismatch causing wrong topological structure, and neighbors crossing mismatch between two adjacent points. In this paper, we propose a topological structure verification method to correct the long geodesic distance mismatch and a correspondence field smoothing method to correct the neighbors crossing mismatch. A robust 3D shape context model is generated and further combined with thin-plate spline model for non-rigid registration. The method was tested on phantoms and applied to rat hind limb and mouse hind limb skeletons registration from micro-CT images. Errors between the registered surfaces were reduced by using the proposed method. The robustness of the method is demonstrated., (Crown Copyright 2009. Published by Elsevier Ltd. All rights reserved.)

The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and beta-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta-arrestin pathway. Association of C5L2 with beta-arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta-arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.

Complement component C5a binds C5a receptor (C5aR) and facilitates leukocyte chemotaxis and release of inflammatory mediators. We used neutrophils from human C5aR knock-in mice, in which the mouse C5aR coding region was replaced with that of human C5aR, to immunize wild-type mice and to generate high-affinity antagonist monoclonal antibodies (mAbs) to human C5aR. These mAbs blocked neutrophil migration to C5a in vitro and, at low doses, both prevented and reversed inflammatory arthritis in the murine K/BxN model. Of approximately 40 mAbs generated to C5aR, all potent inhibitors recognized a small region of the second extracellular loop that seems to be critical for regulation of receptor activity. Human C5aR knock-in mice not only facilitated production of high-affinity mAbs against an important human therapeutic target but were also useful in preclinical validation of the potency of these antagonists. This strategy should be applicable to other important mAb therapeutics.

Non-tumorigenic SV40-immortalized human cells may be transformed to tumorigenicity by activated oncogenes, but the molecular genetics of this process are still poorly understood. We describe here 4SV40-transformed bronchial epithelial (BE) cell lines that became immortalized after a period of crisis, and then transfection of 6 BE lines or sub-lines with an activated c-Ha-ras (EJ-ras) oncogene. pSV2neo-transfected cells did not form any tumors in athymic nude mice. Even though each of the EJ-ras-transfected lines was shown to be expressing the mutant ras gene, only one cell line, BEAS-2B, and 2 of its sub-lines were tumorigenic after transfection. We conclude that immortalization is not sufficient for BE cells to be transformed by the EJ-ras oncogene. Thus there are at least 2 unknown genetic events in this in vitro model of carcinogenesis: escape from crisis (immortalization), and development of ability to cooperate with activated ras in tumorigenic transformation. We found no evidence that either immortalization or ability to complement ras is related to abnormalities of the SV40 T antigens, of p110RB or of p53.

Three RNs working on master's degrees in counseling helped hospitalized patients and their families, nurses, and physicians deal with psychological aspects of illness.