Identification of ABC Transporter Interaction of a Novel Cyanoquinoline Radiotracer and Implications for Tumour Imaging by Positron Emission Tomography.

Background The epidermal growth factor receptor (EGFR) is overexpressed in many cancers including lung, ovarian, breast, head and neck and brain. Mutation of this receptor has been shown to play a crucial role in the response of non-small cell lung carcinoma (NSCLC) to EGFR-targeted therapies. It is envisaged that imaging of EGFR using positron emission tomography (PET) could aid in selection of patients for treatment with novel inhibitors. We recognised multi-drug resistant phenotype as a threat to development of successful imaging agents. In this report, we describe discovery of a novel cyanoquinoline radiotracer that lacks ABC transporter activity.Methods Cellular retention of the prototype cyanoquinoline [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-({[1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-but-2-enamide ([18F]FED6) and [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-[({1-[(2R,5S)-3-fluoro-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)amino]but-2-enamide ([18F]FED20) were evaluated to establish potential for imaging specificity. The substrate specificity of a number of cyanoquinolines towards ABC transporters was investigated in cell lines proficient or deficient in ABCB1 or ABCG2.Results FED6 demonstrated substrate specificity for both ABCG2 and ABCB1, a property that was not observed for all cyanoquinolines tested, suggesting scope for designing novel probes. ABC transporter activity was confirmed by attenuating the activity of transporters with drug inhibitors or siRNA. We synthesized a more hydrophilic compound [18F]FED20 to overcome ABC transporter activity. FED20 lacked substrate specificity for both ABCB1 and ABCG2, and maintained a strong affinity for EGFR. Furthermore, FED20 showed higher inhibitory affinity for active mutant EGFR versus wild-type or resistant mutant EGFR; this property resulted in higher [18F]FED20 cellular retention in active mutant EGFR expressing NSCLC.Conclusion [18F]FED20 binds EGFR but is devoid of ABC transporter activity, thus, has potential for EGFR imaging

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

In-reach specialist nursing teams for residential care homes : uptake of services, impact on care provision and cost-effectiveness

Background: A joint NHS-Local Authority initiative in England designed to provide a dedicated nursing and physiotherapy in-reach team (IRT) to four residential care homes has been evaluated.The IRT supported 131 residents and maintained 15 'virtual' beds for specialist nursing in these care homes. Methods: Data captured prospectively (July 2005 to June 2007) included: numbers of referrals; reason for referral; outcome (e.g. admission to IRT bed, short-term IRT support); length of stay in IRT; prevented hospital admissions; early hospital discharges; avoided nursing home transfers; and detection of unrecognised illnesses. An economic analysis was undertaken. Results: 733 referrals were made during the 2 years (range 0.5 to 13.0 per resident per annum)resulting in a total of 6,528 visits. Two thirds of referrals aimed at maintaining the resident's independence in the care home. According to expert panel assessment, 197 hospital admissions were averted over the period; 20 early discharges facilitated; and 28 resident transfers to a nursing home prevented. Detection of previously unrecognised illnesses accounted for a high number of visits. Investment in IRT equalled £44.38 per resident per week. Savings through reduced hospital admissions, early discharges, delayed transfers to nursing homes, and identification of previously unrecognised illnesses are conservatively estimated to produce a final reduction in care cost of £6.33 per resident per week. A sensitivity analysis indicates this figure might range from a weekly overall saving of £36.90 per resident to a 'worst case' estimate of £2.70 extra expenditure per resident per week. Evaluation early in implementation may underestimate some cost-saving activities and greater savings may emerge over a longer time period. Similarly, IRT costs may reduce over time due to the potential for refinement of team without major loss in effectiveness. Conclusion: Introduction of a specialist nursing in-reach team for residential homes is at least cost neutral and, in all probability, cost saving. Further benefits include development of new skills in the care home workforce and enhanced quality of care. Residents are enabled to stay in familiar surroundings rather than unnecessarily spending time in hospital or being transferred to a higher dependency nursing home setting

Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention

Background: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders.<p></p> Aims: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students.<p></p> Method: Students were recruited online (n = 1047, age: M = 21.8, SD = 4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n = 519) or a control intervention (n = 528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes.<p></p> Results: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p<.001, 95%CI [5.19, 1.98]) and anxiety scores by 2.87 (p = .018, 95%CI [1.31, 4.43]) in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating.<p></p> Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention

Communication style and exercise compliance in physiotherapy (CONNECT). A cluster randomized controlled trial to test a theory-based intervention to increase chronic low back pain patients’ adherence to physiotherapists’ recommendations: study rationale, design, and methods

Physical activity and exercise therapy are among the accepted clinical rehabilitation guidelines and are recommended self-management strategies for chronic low back pain. However, many back pain sufferers do not adhere to their physiotherapist’s recommendations. Poor patient adherence may decrease the effectiveness of advice and home-based rehabilitation exercises. According to self-determination theory, support from health care practitioners can promote patients’ autonomous motivation and greater long-term behavioral persistence (e.g., adherence to physiotherapists’ recommendations). The aim of this trial is to assess the effect of an intervention designed to increase physiotherapists’ autonomy-supportive communication on low back pain patients’ adherence to physical activity and exercise therapy recommendations. \ud \ud This study will be a single-blinded cluster randomized controlled trial. Outpatient physiotherapy centers (N =12) in Dublin, Ireland (population = 1.25 million) will be randomly assigned using a computer-generated algorithm to either the experimental or control arm. Physiotherapists in the experimental arm (two hospitals and four primary care clinics) will attend eight hours of communication skills training. Training will include handouts, workbooks, video examples, role-play, and discussion designed to teach physiotherapists how to communicate in a manner that promotes autonomous patient motivation. Physiotherapists in the waitlist control arm (two hospitals and four primary care clinics) will not receive this training. Participants (N = 292) with chronic low back pain will complete assessments at baseline, as well as 1 week, 4 weeks, 12 weeks, and 24 weeks after their first physiotherapy appointment. Primary outcomes will include adherence to physiotherapy recommendations, as well as low back pain, function, and well-being. Participants will be blinded to treatment allocation, as they will not be told if their physiotherapist has received the communication skills training. Outcome assessors will also be blinded. \ud \ud We will use linear mixed modeling to test between arm differences both in the mean levels and the rates of change of the outcome variables. We will employ structural equation modeling to examine the process of change, including hypothesized mediation effects. \ud \ud This trial will be the first to test the effect of a self-determination theory-based communication skills training program for physiotherapists on their low back pain patients’ adherence to rehabilitation recommendations. Current Controlled Trials ISRCTN63723433\u

Visual arguments in film

Nuestro objetivo es señalar algunas diferencias entre los argumentos verbales y visuales, y promover la perspectiva retórica de la argumentación, yendo más allá de la relevancia de la lógica y de la pragmática. En nuestra opinión, si ha de ser racional y aceptable como argumentación (visual), un film debe dirigirse a espectadores que tienen creencias informadas sobre el tema visto en la pantalla y sobre las limitaciones y las convenciones del medio. En nuestras reflexiones, aplicamos el análisis retórico al cine como un acto simbólico, humano y comunicativo que a veces puede entenderse como un argumento trazado visualmente. Como mezcla de estímulos visuales, auditivos y verbales, el film exige una interpretación y una (re)construcción activas y complejas. Nuestra sugerencia es concentrarse en cinco elementos diferentes, pero relacionados entre sí. La reconstrucción y la evaluación del argumento visual se basarán en esos elementos, y todo el proceso constituirá una argumentación visual.Our aim is to point out some differences between verbal and visual arguments, promoting the rhetorical perspective of argumentation beyond the relevance of logic and pragmatics. In our view, if it is to be rational and successful, film as (visual) argumentation must be addressed to spectators who hold informed beliefs about the theme watched on the screen and the medium’s constraints and conventions. In our reflections to follow, we apply rhetorical analysis to film as a symbolic, human, and communicative act that may sometimes be understood as a visually laid out argument. As a mixture of visual, auditory, and verbal stimuli, film demands active and complex interpretation and (re)construction. Our suggestion is to focus on five different but interrelated elements. The reconstruction and evaluation of the visual argument will be based on those elements, and the whole process will be one of visual argumentation

Impact of specialist rehabilitation services on hospital length of stay and associated costs

Background: Provision of specialist rehabilitation services in North Yorkshire and Humberside may be suboptimal. Local commissioning bodies need to prioritise investments in health care, but previous studies provide limited evidence to inform the decision to expand existing services on the basis of cost-effectiveness. We examine the impact of specialist rehabilitation services in the subregion on hospital length of stay (LoS) and associated costs compared to routine care. Methods: Comparison of hospital LoS and associated costs in centres with greater access (Hull) and limited access (i.e. routine care, York and Northern Lincolnshire), to specialist rehabilitation services for patients with complex disabilities following illness or injury, using Hospital Episodes Statistics data. Results: Average LoS and duration costs by Healthcare Resource Group (HRG) were lower for the majority of patients with greater access to specialist rehabilitation compared to routine care. Difference in LoS between groups widened with level of complexity within each HRG. For the more frequent HRG codes, the LoS difference was as high as 34 days longer for York compared to Hull and £7900 more costly. Conclusion: Rehabilitation patients within York and Northern Lincolnshire areas appear to have longer LoS and higher associated costs compared to those admitted to the Hull Trust. This analysis suggests that specialist rehabilitation may be cost saving compared to routine care and supports the case for expansion of the existing services to improve coverage in the area

The development of a body comparison measure: the CoSS

Purpose This study reports on the development and validation of a brief and widely applicable measure of body comparison (the Comparison of Self-Scale—CoSS), which is a maintaining feature of eating disorders. Methods A sample of 412 adults completed the CoSS, an existing measure of aspects of body comparison, and eating pathology and associated states. Test–retest reliability was examined over 2 weeks. Results Exploratory factor analysis showed that 22 CoSS items loaded onto two factors, resulting in two scales—Appearance Comparison and Social Comparison—with strong internal consistency and test–retest reliability. Conclusions In clinical terms, the CoSS was superior to the existing measure of body comparison in accounting for depression and anxiety. Given that it is a relatively brief measure, the CoSS could be useful in the routine assessment of body comparison, and in formulating and treating individuals with body image concerns. However, the measure awaits full clinical validation

A Framework to Support Interdisciplinary Engagement with Learning Analytics

Learning analytics can provide an excellent opportunity for instructors to get an in-depth understanding of students’ learning experiences in a course. However, certain technological challenges, namely limited availability of learning analytics data because of learning management system restrictions, can make accessing this data seem impossible at some institutions. Furthermore, even in cases where instructors have access to a range of student data, there may not be organized efforts to support students across various courses and university experiences. In the current chapter, the authors discuss the issue of learning analytics access and ways to leverage learning analytics data between instructors, and in some cases administrators, to create interdisciplinary opportunities for comprehensive student support. The authors consider the implications of these interactions for students, instructors, and administrators. Additionally, the authors focus on some of the technological infrastructure issues involved with accessing learning analytics and discuss the opportunities available for faculty and staff to take a multi-pronged approach to addressing overall student success.https://scholarworks.wm.edu/educationbookchapters/1045/thumbnail.jp