Translational and Regulatory Challenges for Exon Skipping Therapies

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.status: publishe

General practitioners’ perceptions on their role in light of the NHS five year forward view: a qualitative study

Background: The NHS is undergoing unprecedented change, central to which is policy aimed at integrating health and social care services, resulting in the implementation of new care models. GPs are at the forefront of this change. However, there is lack of academic literature on General Practitioners’ perceptions on their role in light of the new models of care proposed by the NHS Five Year Forward View which this small-scale study begins to address. Objectives: This study aims to produce a description of how GP’s construct their current and future general practice, professional status and identify within the context of the current NHS transformation agenda. Methods: Qualitative study using semi-structured interviews and one focus group to gather the perspective of GPs (n = 10) working across three clinical commissioning groups in South East England. Results: While the GPs embraced the principles underpinning the new care models, they were both willing and reluctant to adopt their new roles, struggled with inter-organisational and cultural barriers and their changing professional identity. Conclusion: Multi-professional education in primary and community care could be an effective model to offer support and resources to the development of the clinical and leadership skills GPs will require to respond effectively to the transformation agenda. The emergence of community education provider networks, innovative network organisations designed to support workforce transformation through education and training, can provide the vehicle through which clinical and leadership skills training are sourced and coordinated

Strategies and challenges to facilitate situated learning in virtual worlds post-Second Life

Virtual worlds can establish a stimulating environment to support a situated learning approach in which students simulate a task within a safe environment. While in previous years Second Life played a major role in providing such a virtual environment, there are now more and more alternative—often OpenSim-based—solutions deployed within the educational community. By drawing parallels to social networks, we discuss two aspects: how to link individually hosted virtual worlds together in order to implement context for immersion and how to identify and avoid “fake” avatars so people behind these avatars can be held accountable for their actions

Potential Reduction of Lung Dose via VMAT with Jaw Tracking in the Treatment of Single-Isocenter/Two-Lesion Lung SBRT

Purpose/objectives: Due to higher radiosensitivity, non‐target normal tissue dose is a major concern in stereotactic body radiation therapy (SBRT) treatment. The aim of this report was to estimate the dosimetric impact, specifically the reduction of normal lung dose in the treatment of single‐isocenter/two‐lesion lung SBRT via volumetric modulated arc therapy with jaw tracking (JT‐VMAT). Materials/methods: Twelve patients with two peripherally located early‐stage non‐small‐cell‐lung cancer (NSCLC) lung lesions underwent single‐isocenter highly conformal non‐coplanar JT‐VMAT SBRT treatment in our institution. The mean isocenter to tumors distance was 5.6 ± 1.9 (range 4.3–9.5) cm. The mean combined planning target volume (PTV) was 38.7 ± 22.7 (range 5.0–80.9) cc. A single isocenter was placed between the two lesions. Doses were 54 and 50 Gy in three and five fractions, respectively. Plans were optimized in Eclipse with AcurosXB algorithm utilizing jaw tracking options for the Truebeam with a 6 MV‐FFF beam and standard 120 leaf millennium multi‐leaf collimators. For comparison, the JT‐VMAT plans were retrospectively re‐computed utilizing identical beam geometry, objectives, and planning parameters, but without jaw tracking (no JT‐VMAT). Both plans were normalized to receive the same target coverage. The conformity and heterogeneity indices, intermediate‐dose spillage [D2cm, R50, Gradient Index (GI), Gradient Distance (GD)], organs at risks (OAR) doses including normal lung as well as modulation factor (MF) were compared for both plans. Results: For similar target coverage, GI, R50, GD, as well as the normal lung V5, V10, V20, mean lung dose (MLD), and maximum dose received by 1000 cc of lungs were statistically significant. Normal lung doses were reduced by 8%–11% with JT‐VMAT. Normal lung dose increased as a function of tumor distance from isocenter. For the other OAR, up to 1%–16% reduction of non‐target doses were observed with JT‐VMAT. The MF and beam‐on time were similar for both plans, however, MF increased as a function of tumors distance, consequently, delivering higher dose to normal lungs. Conclusion: Utilizing jaw tracking options during optimization for single‐isocenter/two‐lesion lung SBRT VMAT plans reduced doses to the normal lung and other OAR, reduced intermediate‐dose spillage and provided superior/similar target coverage. Application of jaw tracking did not affect delivery efficiency and provided excellent plan quality with similar MF and beam‐on time. Jaw tracking is recommended for future clinical SBRT plan optimization

Balancing professional tension and deciding upon the status of death : making end-of-life decisions in intensive care units

This study investigated how intensivists make decisions regarding withholding and withdrawing treatment for patients at the end of their lives. This involved completing in-depth interviews from two sites of the South of England, United Kingdom by twelve intensivists. The data collected by these intensivists were analysed using thematic analysis. This resulted in the identification of three themes: intensivists’ role, treatment effectiveness, and patients’ best interest. Transcending these were two overarching themes relating to the balance between quantity and quality of life, and the intensivists’ sense of responsibility versus burden. The results are considered in terms of making sense of death and the role of beliefs in the decision-making process

Managing for change: October 11, 1989

Bi-weekly newsletter of University Hospital's Change Project, provided to managers at the hospital

Implementation of Integrated Learning Program in neurosciences during first year of traditional medical course: Perception of students and faculty

<p>Abstract</p> <p>Background</p> <p>Our college introduced an integrated learning program (ILP) for first year undergraduates with an aim to develop, implement and evaluate a module for CNS in basic sciences and to assess the feasibility of an ILP in phase I of medical education in a college following traditional medical curriculum.</p> <p>Methods</p> <p>The idea of implementing ILP for Central Nervous System (CNS) in phase one was conceived by curriculum development committee drawn from faculty of all phases. After a series of meetings of curriculum development committee, inputs from basic science and clinical departments, a time table was constructed. Various teaching learning methods, themes for integrated didactic lectures, case based learning and clinical exposure were decided. Basic science faculty were made to participate actively in both case based learning and hospital visits along with clinical experts. The completed program was evaluated based on structured questionnaire.</p> <p>Results</p> <p>Sixty percent students rated the program good to excellent with reference to appreciation, understanding and application of basic science knowledge in health and disease. Seventy eight percent felt that this program will help them perform better in later days of clinical training. However sixty percent students felt that ILP will not help them perform better at the first professional examination. Seventy two per cent of faculty agreed that this program improved understanding and application of basic science knowledge of students. Ninety percent of faculty felt that this program will help them perform better in later days of clinical training.</p> <p>Conclusion</p> <p>The adoption of present integrated module for CNS and the use of multiple teaching learning methods have been proven to be useful in acquisition of knowledge from the student satisfaction point of view. Students and faculty expressed an overall satisfaction towards ILP for CNS. The study showed that it is possible to adopt an integrated learning module in the first year of medical course under a conventional curriculum.</p

The need for education on health related-quality of life

<p>Abstract</p> <p>Background</p> <p>Health-related quality of life is increasingly recognised as an important outcome measure that complements existing measures of clinical effectiveness. The education available on this subject for different healthcare professionals is varied. This article describes the design, implementation and evaluation of a Special Study Module on Health-Related Quality of Life for undergraduate medical students at the University of Birmingham.</p> <p>Methods</p> <p>The course involves 10 hours of "guided discovery learning" covering core concepts of Health-Related Quality of Life assessment including methodological considerations, use in clinical trials, routine practice and in health policy followed by self-directed learning. The taught components aim to provide students with the skills and knowledge to enable them to explore and evaluate the use of quality of life assessments in a particular patient group, or setting, through self-directed learning supported by tutorials.</p> <p>Results</p> <p>The use of case studies, recent publications and research, and discussion with a research oncology nurse in task-based learning appeared to provide students with a stimulating environment in which to develop their ideas and was reflected in the diverse range of subjects chosen by students for self-directed study and the positive feedback on the module. Course evaluation and student assessment suggests that quality of life education appears to integrate well within the medical curriculum and allows students to develop and utilise skills of time-management and independent, self-directed learning that can be applied in any context.</p> <p>Conclusion</p> <p>We suggest that education and training initiatives in quality of life may improve the quality of studies, and help bridge the gap between research and clinical practice. Resources for curriculum development on health-related quality of life have been developed by the International Society for Quality of Life Research and may prove a useful tool to educators interested in this area.</p

A survey of UK medical schools' arrangements for early patient contact

Background: Many U.K. medical schools have patient contact in the first two years of the undergraduate course. Aim: To compare the purposes and organization of early patient contact in UK medical schools and to relate these arrangements to the schools' curricular objectives. Methods: A telephone survey of lead educators in UK medicals schools. Categories of contact were plotted against phases of the course to discern patterns of organisation. Results: The quantity of contact varies considerably (four to 65 days). There is a pattern, with learning objectives around the social context of health and illness preceding skills based work and integrated clinical knowledge for practice coming later. Schools fall into three categories: close adherence to the preclinical/clinical split, with limited early contact acting as an introduction to social aspects of health; provision of substantial patient contact to maximize the integration of knowledge and skills; and transitional, with limited clinical goals. General practice provides between one third and one half of early patient contact. Conclusions: Arrangements meet the objectives set by each school and reflect differing educational philosophies. Change is toward more early contact. There appears to be no national guidance which supports a minimum quantity of patient contact or specific educational purpose in the early years of U.K. basic medical training

An intervention modelling experiment to change GP's intentions to implement evidence-based practice : using theory-based interventions to promote GP management of upper respiratory tract infection without prescribing antibiotics #2

Background: Psychological theories of behaviour may provide a framework to guide the design of interventions to change professional behaviour. Behaviour change interventions, designed using psychological theory and targeting important motivational beliefs, were experimentally evaluated for effects on the behavioural intention and simulated behaviour of GPs in the management of uncomplicated upper respiratory tract infection (URTI). Methods: The design was a 2 × 2 factorial randomised controlled trial. A postal questionnaire was developed based on three theories of human behaviour: Theory of Planned Behaviour; Social Cognitive Theory and Operant Learning Theory. The beliefs and attitudes of GPs regarding the management of URTI without antibiotics and rates of prescribing on eight patient scenarios were measured at baseline and post-intervention. Two theory-based interventions, a "graded task" with "action planning" and a "persuasive communication", were incorporated into the post-intervention questionnaire. Trial groups were compared using co-variate analyses. Results: Post-intervention questionnaires were returned for 340/397 (86%) GPs who responded to the baseline survey. Each intervention had a significant effect on its targeted behavioural belief: compared to those not receiving the intervention GPs completing Intervention 1 reported stronger self-efficacy scores (Beta = 1.41, 95% CI: 0.64 to 2.25) and GPs completing Intervention 2 had more positive anticipated consequences scores (Beta = 0.98, 95% CI = 0.46 to 1.98). Intervention 2 had a significant effect on intention (Beta = 0.90, 95% CI = 0.41 to 1.38) and simulated behaviour (Beta = 0.47, 95% CI = 0.19 to 0.74). Conclusion: GPs' intended management of URTI was significantly influenced by their confidence in their ability to manage URTI without antibiotics and the consequences they anticipated as a result of doing so. Two targeted behaviour change interventions differentially affected these beliefs. One intervention also significantly enhanced GPs' intentions not to prescribe antibiotics for URTI and resulted in lower rates of prescribing on patient scenarios compared to a control group. The theoretical frameworks utilised provide a scientific rationale for understanding how and why the interventions had these effects, improving the reproducibility and generalisability of these findings and offering a sound basis for an intervention in a "real world" trial. Trial registration: Clinicaltrials.gov NCT00376142This study is funded by the European Commission Research Directorate as part of a multi-partner program: Research Based Education and Quality Improvement (ReBEQI): A Framework and tools to develop effective quality improvement programs in European healthcare. (Proposal No: QLRT-2001-00657)