Proof-of-concept: neonatal intravenous injection of adeno-associated virus vectors results in successful transduction of myenteric and submucosal neurons in the mouse small and large intestine

BACKGROUND: Despite the success of viral vector technology in the transduction of the central nervous system in both preclinical research and gene therapy, its potential in neurogastroenterological research remains largely unexploited. This study asked whether and to what extent myenteric and submucosal neurons in the ileum and distal colon of the mouse were transduced after neonatal systemic delivery of recombinant adeno-associated viral vectors (AAVs). METHODS: Mice were intravenously injected at postnatal day one with AAV pseudotypes AAV8 or AAV9 carrying a cassette encoding enhanced green fluorescent protein (eGFP) as a reporter under the control of a cytomegalovirus promoter. At postnatal day 35, transduction of the myenteric and submucosal plexuses of the ileum and distal colon was evaluated in whole-mount preparations, using immunohistochemistry to neurochemically identify transduced enteric neurons. KEY RESULTS: The pseudotypes AAV8 and AAV9 showed equal potential in transducing the enteric nervous system (ENS), with 25-30% of the neurons expressing eGFP. However, the percentage of eGFP-expressing colonic submucosal neurons was significantly lower. Neurochemical analysis showed that all enteric neuron subtypes, but not glia, expressed the reporter protein. Intrinsic sensory neurons were most efficiently transduced as nearly 80% of calcitonin gene-related peptide-positive neurons expressed the transgene. CONCLUSIONS & INFERENCES: The pseudotypes AAV8 and AAV9 can be employed for gene delivery to both the myenteric and the submucosal plexus, although the transduction efficiency in the latter is region-dependent. These findings open perspectives for novel preclinical applications aimed at manipulating and imaging the ENS in the short term, and in gene therapy in the longer term

Waiting for elective general surgery: impact on health related quality of life and psychosocial consequences

<p>Abstract</p> <p>Background</p> <p>Long waiting times for elective surgical treatment threaten timely care provision in several countries. The purpose of this study was to assess the impact of waiting for elective general surgery on the quality of life and psychosocial health of patients.</p> <p>Methods</p> <p>A cross-sectional questionnaire study with postoperative follow-up was performed among patients on waiting lists for surgical treatment of varicose veins (n = 176), inguinal hernia (n = 201), and gallstones (n = 128) in 27 hospitals.</p> <p>Results</p> <p>In each group the waiting period involved worse general health perceptions (GHPQ), more problems in quality of life (EuroQoL), and raised levels of anxiety (STAI) as compared to after surgery (all differences: p < 0.05). Quality of life was not affected in 19–36% of patients.</p> <p>Emotional reactions to waiting were most negative among patients with gallstones. Prior information about the duration of the wait reduced the negativity of these reactions (p < 0.05).</p> <p>Social activities were affected in 39% to 48% of the patients and 18%-23% of employed patients reported problems with work during the wait.</p> <p>Having waited a longer time was associated with worse quality of life among patients with inguinal hernia. Longer waited times also engendered more negative reactions to waiting among patients with inguinal hernia and gallstones (multilevel regression analysis, p < 0.01).</p> <p>Conclusion</p> <p>Waiting for general surgery mainly involves a prolonged period of decreased health and an affected psychological and social life of the patient in waiting. Variation in the severity of these consequences across patients indicates that the prioritisation of patients could reduce the overall burden of waiting. Early information about the duration of the delay could further promote a patient's acceptance of waiting.</p

The Role of Screenings Methods and Risk Profile Assessments in Prevention and Health Promotion Programmes: An Ethnographic Analysis

In prevention and health promotion interventions, screening methods and risk profile assessments are often used as tools for establishing the interventions’ effectiveness, for the selection and determination of the health status of participants. The role these instruments fulfil in the creation of effectiveness and the effects these instruments have themselves remain unexplored. In this paper, we have analysed the role screening methods and risk profile assessments fulfil as part of prevention and health promotion programmes in the selection, enrolment and participation of participants. Our analysis showed, that screening methods and health risk assessments create effects as they objectify health risks and/or the health status of individuals, i.e., they select the individuals ‘at risk’ and indicate the lifestyle modifications these people are required to make in order to improve their health. Yet, these instruments also reduce the group of participants thereby decreasing the possible effect of interventions, as they provide the legitimisation for people to make choices to whether they enrol or not and what lifestyle changes they incorporate into their lives. In other words, they present a space of interaction, in which agency is distributed across the practice nurses, the participants and the instruments. Decisions were not just made upon the projection of the outcomes of these instruments; decisions that were made by both the patients and practice nurses were the resultant of their opinions on these outcomes that were formed in interaction with the instruments

Design of the BRISC study: a multicentre controlled clinical trial to optimize the communication of breast cancer risks in genetic counselling

Background: Understanding risks is considered to be crucial for informed decision-making. Inaccurate risk perception is a common finding in women with a family history of breast cancer attending genetic counseling. As yet, it is unclear how risks should best be communicated in clinical practice. This study protocol describes the design and methods of the BRISC (Breast cancer RISk Communication) study evaluating the effect of different formats of risk communication on the counsellee's risk perception, psychological well-being and decision-making regarding preventive options for breast cancer. Methods and design: The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measurements using questionnaires. The intervention-an additional risk consultation-consists of one of 5 conditions that differ in the way counsellee's breast cancer risk is communicated: 1) lifetime risk in numerical format (natural frequencies, i.e. X out of 100), 2) lifetime risk in both numerical format and graphical format (population figures), 3) lifetime risk and age-related risk in numerical format, 4) lifetime risk and age-related risk in both numerical format and graphical format, and 5) lifetime risk in percentages. Condition 6 is the control condition in which no intervention is given (usual care). Participants are unaffected women with a family history of breast cancer attending one of three participating clinical genetic centres in the Netherlands. Discussion: The BRISC study allows for an evaluation of the effects of different formats of communicating breast cancer risks to counsellees. The results can be used to optimize risk communication in order to improve informed decision-making among women with a family history of breast cancer. They may also be useful for risk communication in other health-related services. Trial registration: Current Controlled Trials ISRCTNI4566836

Tailoring intervention procedures to routine primary health care practice; an ethnographic process evaluation

Background. Tailor-made approaches enable the uptake of interventions as they are seen as a way to overcome the incompatibility of general interventions with local knowledge about the organisation of routine medical practice and the relationship between the patients and the professionals in practice. Our case is the Quattro project which is a prevention programme for cardiovascular diseases in high-risk patients in primary health care centres in deprived neighbourhoods. This programme was implemented as a pragmatic trial and foresaw the importance of local knowledge in primary health care and internal, or locally made, guidelines. The aim of this paper is to show how this prevention programme, which could be tailored to routine care, was implemented in primary care. Methods. An ethnographic design was used for this study. We observed and interviewed the researchers and the practice nurses. All the research documents, observations and transcribed interviews were analysed thematically. Results. Our ethnographic process evaluation showed that the opportunity of tailoring intervention procedures to routine care in a pragmatic trial setting did not result in a well-organised and well-implemented prevention programme. In fact, the lack of standard protocols hindered the implementation of the intervention. Although it was not the purpose of this trial, a guideline was developed. Despite the fact that the developed guideline functioned as a tool, it did not result in the intervention being organised accordingly. However, the guideline did make tailoring the intervention possible. It provided the professionals with the key or the instructions needed to achieve organisational change and transform the existing interprofessional relations. Conclusion. As tailor-made approaches are developed to enable the uptake of interventions in routine practice, they are facilitated by the brokering of tools such as guidelines. In our study, guidelines facilitated organisational change and enabled the transformation of existing interprofessional relations, and thus made tailoring possible. The attractive flexibility of pragmatic trial design in taking account of local practice variations may often be overestimated

Measurement and Interpretation of Fermion-Pair Production at LEP energies above the Z Resonance

This paper presents DELPHI measurements and interpretations of cross-sections, forward-backward asymmetries, and angular distributions, for the e+e- -> ffbar process for centre-of-mass energies above the Z resonance, from sqrt(s) ~ 130 - 207 GeV at the LEP collider. The measurements are consistent with the predictions of the Standard Model and are used to study a variety of models including the S-Matrix ansatz for e+e- -> ffbar scattering and several models which include physics beyond the Standard Model: the exchange of Z' bosons, contact interactions between fermions, the exchange of gravitons in large extra dimensions and the exchange of sneutrino in R-parity violating supersymmetry.Comment: 79 pages, 16 figures, Accepted by Eur. Phys. J.