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1.
BMJ Open ; 14(3): e079105, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38490661

ABSTRACT

INTRODUCTION: For artificial intelligence (AI) to help improve mental healthcare, the design of data-driven technologies needs to be fair, safe, and inclusive. Participatory design can play a critical role in empowering marginalised communities to take an active role in constructing research agendas and outputs. Given the unmet needs of the LGBTQI+ (Lesbian, Gay, Bisexual, Transgender, Queer and Intersex) community in mental healthcare, there is a pressing need for participatory research to include a range of diverse queer perspectives on issues of data collection and use (in routine clinical care as well as for research) as well as AI design. Here we propose a protocol for a Delphi consensus process for the development of PARticipatory Queer AI Research for Mental Health (PARQAIR-MH) practices, aimed at informing digital health practices and policy. METHODS AND ANALYSIS: The development of PARQAIR-MH is comprised of four stages. In stage 1, a review of recent literature and fact-finding consultation with stakeholder organisations will be conducted to define a terms-of-reference for stage 2, the Delphi process. Our Delphi process consists of three rounds, where the first two rounds will iterate and identify items to be included in the final Delphi survey for consensus ratings. Stage 3 consists of consensus meetings to review and aggregate the Delphi survey responses, leading to stage 4 where we will produce a reusable toolkit to facilitate participatory development of future bespoke LGBTQI+-adapted data collection, harmonisation, and use for data-driven AI applications specifically in mental healthcare settings. ETHICS AND DISSEMINATION: PARQAIR-MH aims to deliver a toolkit that will help to ensure that the specific needs of LGBTQI+ communities are accounted for in mental health applications of data-driven technologies. The study is expected to run from June 2024 through January 2025, with the final outputs delivered in mid-2025. Participants in the Delphi process will be recruited by snowball and opportunistic sampling via professional networks and social media (but not by direct approach to healthcare service users, patients, specific clinical services, or via clinicians' caseloads). Participants will not be required to share personal narratives and experiences of healthcare or treatment for any condition. Before agreeing to participate, people will be given information about the issues considered to be in-scope for the Delphi (eg, developing best practices and methods for collecting and harmonising sensitive characteristics data; developing guidelines for data use/reuse) alongside specific risks of unintended harm from participating that can be reasonably anticipated. Outputs will be made available in open-access peer-reviewed publications, blogs, social media, and on a dedicated project website for future reuse.


Subject(s)
Mental Health , Sexual and Gender Minorities , Female , Humans , Delphi Technique , Artificial Intelligence , Data Collection , Review Literature as Topic
2.
BMC Med Educ ; 23(1): 335, 2023 May 16.
Article in English | MEDLINE | ID: mdl-37193974

ABSTRACT

BACKGROUND: Involving patients and carers in medical students' learning aims to centralise the perspective of healthcare users and supports our future medical workforce in the development of key skills. Medical schools are increasingly using digital technology for teaching and it is timely to understand how to maintain patient and carer involvement in this context. METHODS: Ovid MEDLINE, Ovid EMBASE and medRxiv were searched in October 2020 and reference lists of key articles were hand searched. Eligible studies reported authentic patient or carer involvement in undergraduate medical education where technology was also used. Study quality was assessed by the Mixed Methods Appraisal Tool (MMAT). Levels of patient or carer involvement were assessed using Towle et al.'s (2010) taxonomy, from Level 1 (lowest level) to Level 6 (highest level). RESULTS: Twenty studies were included in this systematic review. In 70% of studies, patients and carers featured in video or web-based case scenarios with no interaction between healthcare users and students. The remaining 30% of studies reported real-time interactions between students and patients via remote clinical encounters. Digital teaching sessions involving patients or carers were perceived to be valuable by students and educators, and increased student engagement, patient-centred attitudes, clinical knowledge, and communication skills. No studies reported the perspective of patients or carers. DISCUSSION: Digital technology has not yet driven higher levels of patient and carer involvement in medical training. "Live" interactions between students and patients are becoming more common but challenges need addressing to ensure positive experiences for all involved. Future teaching should enhance the role of patients and carers in medical education and support them to overcome any potential barriers to doing so remotely.


Subject(s)
Education, Medical, Undergraduate , Students, Medical , Humans , Caregivers , Health Personnel/education , Learning
3.
BMJ Open ; 12(12): e067034, 2022 12 29.
Article in English | MEDLINE | ID: mdl-36581431

ABSTRACT

INTRODUCTION: Increasing collaborative and integrated working between General practice (GP) and Community pharmacy (CP) is a key priority of the UK National Health Service and has been proposed as a solution to reducing health system fragmentation, improving synergies and coordination of care. However, there is limited understanding regarding how and under which circumstances collaborative and integrated working between GP and CP can be achieved in practice and how regulatory, organisational and systemic barriers can be overcome. METHODS AND ANALYSIS: The aim of our review is to understand how, when and why working arrangements between GP and CP can provide the conditions necessary for optimal communication, decision-making, and collaborative and integrated working. A realist review approach will be used to synthesise the evidence to make sense of the complexities inherent in the working relationships between GP and CP. Our review will follow Pawson's five iterative stages: (1) finding existing theories; (2) searching for evidence (our main searches were conducted in April 2022); (3) article selection; (4) data extraction and (5) synthesising evidence and drawing conclusions. We will synthesise evidence from grey literature, qualitative, quantitative and mixed-methods research. The research team will work closely with key stakeholders and include patient and public involvement and engagement throughout the review process to refine the focus of the review and the programme theory. Collectively, our refined programme theory will explain how collaborative and integrated working between GP and CP works (or not), for whom, how and under which circumstances. ETHICS AND DISSEMINATION: Formal ethical approval is not required for this review as it draws on secondary data from published articles and grey literature. Findings will be widely disseminated through: publication in peer-reviewed journals, seminars, international conference presentations, patients' association channels, social media, symposia and user-friendly summaries. PROSPERO REGISTRATION NUMBER: CRD42022314280.


Subject(s)
General Practice , Pharmacies , Humans , State Medicine , Family Practice , Review Literature as Topic
4.
Health Soc Care Community ; 30(6): 2037-2056, 2022 11.
Article in English | MEDLINE | ID: mdl-35703588

ABSTRACT

Policy guidance promotes supporting people to live in their own homes for as long as possible with support from homecare services. People living with dementia who need such support can experience a range of physical and cognitive difficulties, which can increase the risks associated with homecare for this group. We aimed to examine risk and safety issues for people with dementia and their homecare workers and risk mitigation practices adopted by homecare workers to address identified risks. We searched MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, ASSIA and Cochrane Central Register of Controlled Trials databases 5 March 2021. Included studies focussed on homecare for people with dementia and had a risk or safety feature reported. Risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal tools. Two authors assessed articles for potential eligibility and quality. A narrative synthesis combines the findings. The search identified 2259 records; 27 articles, relating to 21 studies, met the eligibility criteria. The review identified first-order risks that homecare workers in the studies sought to address. Two types of risk mitigation actions were reported: harmful interventions and beneficial interventions. Actions adopted to reduce risks produced intended benefits but also unintended consequences, creating second-order risks to both clients with dementia and homecare workers, placing them at greater risk. Risk mitigation interventions should be person-centred, the responsibility of all relevant professions, and planned to minimise the creation of unintended risks.


Subject(s)
Dementia , Home Care Services , Home Health Aides , Humans
5.
Health Technol Assess ; 25(9): 1-378, 2021 02.
Article in English | MEDLINE | ID: mdl-33629950

ABSTRACT

BACKGROUND: Cognitive-behavioural therapy aims to increase quality of life by changing cognitive and behavioural factors that maintain problematic symptoms. A previous overview of cognitive-behavioural therapy systematic reviews suggested that cognitive-behavioural therapy was effective for many conditions. However, few of the included reviews synthesised randomised controlled trials. OBJECTIVES: This project was undertaken to map the quality and gaps in the cognitive-behavioural therapy systematic review of randomised controlled trial evidence base. Panoramic meta-analyses were also conducted to identify any across-condition general effects of cognitive-behavioural therapy. DATA SOURCES: The overview was designed with cognitive-behavioural therapy patients, clinicians and researchers. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Child Development & Adolescent Studies, Database of Abstracts of Reviews of Effects and OpenGrey databases were searched from 1992 to January 2019. REVIEW METHODS: Study inclusion criteria were as follows: (1) fulfil the Centre for Reviews and Dissemination criteria; (2) intervention reported as cognitive-behavioural therapy or including one cognitive and one behavioural element; (3) include a synthesis of cognitive-behavioural therapy trials; (4) include either health-related quality of life, depression, anxiety or pain outcome; and (5) available in English. Review quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2. Reviews were quality assessed and data were extracted in duplicate by two independent researchers, and then mapped according to condition, population, context and quality. The effects from high-quality reviews were pooled within condition groups, using a random-effect panoramic meta-analysis. If the across-condition heterogeneity was I2 < 75%, we pooled across conditions. Subgroup analyses were conducted for age, delivery format, comparator type and length of follow-up, and a sensitivity analysis was performed for quality. RESULTS: A total of 494 reviews were mapped, representing 68% (27/40) of the categories of the International Classification of Diseases, Eleventh Revision, Mortality and Morbidity Statistics. Most reviews (71%, 351/494) were of lower quality. Research on older adults, using cognitive-behavioural therapy preventatively, ethnic minorities and people living outside Europe, North America or Australasia was limited. Out of 494 reviews, 71 were included in the primary panoramic meta-analyses. A modest effect was found in favour of cognitive-behavioural therapy for health-related quality of life (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.05 to 0.50, I2 = 32%), anxiety (standardised mean difference 0.30, 95% confidence interval 0.18 to 0.43, prediction interval -0.28 to 0.88, I2 = 62%) and pain (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.28 to 0.74, I2 = 64%) outcomes. All condition, subgroup and sensitivity effect estimates remained consistent with the general effect. A statistically significant interaction effect was evident between the active and non-active comparator groups for the health-related quality-of-life outcome. A general effect for depression outcomes was not produced as a result of considerable heterogeneity across reviews and conditions. LIMITATIONS: Data extraction and analysis were conducted at the review level, rather than returning to the individual trial data. This meant that the risk of bias of the individual trials could not be accounted for, but only the quality of the systematic reviews that synthesised them. CONCLUSION: Owing to the consistency and homogeneity of the highest-quality evidence, it is proposed that cognitive-behavioural therapy can produce a modest general, across-condition benefit in health-related quality-of-life, anxiety and pain outcomes. FUTURE WORK: Future research should focus on how the modest effect sizes seen with cognitive-behavioural therapy can be increased, for example identifying alternative delivery formats to increase adherence and reduce dropout, and pursuing novel methods to assess intervention fidelity and quality. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017078690. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 9. See the NIHR Journals Library website for further project information.


This report is a summary of research examining if a psychological therapy called cognitive­behavioural therapy can improve the quality of life of people living with physical and/or mental conditions. Cognitive­behavioural therapy uses a set of techniques that help individuals to identify and change problematic thoughts or behaviour patterns that might contribute to and maintain their physical or mental symptoms. It can be delivered face to face or through mediums such as the internet. We aimed to understand if cognitive­behavioural therapy helps patients with specific conditions only, or if it can help patients with any condition. We searched relevant databases to find articles that combine the results from multiple trials testing cognitive­behavioural therapy. These are known as systematic reviews. We graded these reviews as providing good- or poor-quality evidence. We identified the conditions for which we had good-quality evidence on whether or not cognitive­behavioural therapy was helpful. From each review, we took numerical data that told us if cognitive­behavioural therapy improved quality of life for that specific condition. Next, we combined all the numerical data together, across all the conditions, to see if there was a consistent benefit of cognitive­behavioural therapy. The statistical analyses found that cognitive­behavioural therapy consistently improved quality of life across all the conditions where it has been tested. We have evidence that it can help children, adolescents and adults, of either sex, who are living in Europe, North America and Australasia. We are unsure if it will help older adults or people living in Africa, Asia or South America, nor do we know if cognitive­behavioural therapy is equally effective across different ethnic groups. It is recommended that future research should prioritise understanding how cognitive­behavioural therapy works, why some people do not want to use cognitive­behavioural therapy and why some patients do not benefit from it.


Subject(s)
Cognitive Behavioral Therapy , Quality of Life , Adolescent , Aged , Anxiety Disorders , Child , Humans , Systematic Reviews as Topic , Technology Assessment, Biomedical
6.
Prog Transplant ; 31(1): 32-39, 2021 03.
Article in English | MEDLINE | ID: mdl-33297879

ABSTRACT

INTRODUCTION: Although informed consent content elements are prescribed in detailed regulatory guidance, many live kidney donors describe feeling underprepared and under informed. The goal of this pilot study was to explore the educational components needed to support an informed decision-making process for living kidney donors. METHODS/APPROACH: A qualitative description design was conducted with thematic analysis of 5 focus groups with 2 cohorts: living kidney donor candidates (n = 11) and living kidney donors (n = 8). FINDINGS: The educational components needed to engage in an informed decision-making process were: 1) contingent upon, and motivated by, personal circumstances; 2) supported through explanation of risks and benefits; 3) enhanced by understanding the overall donation experience; and 4) personalized by talking to another donor. DISCUSSION: Tailoring education to meet the needs for fully informed decision-making is essential. Current education requirements, as defined by regulatory bodies, remain challenging to transplant teams attempting to ensure fully informed consent of living kidney donor candidates. Information on the emotional, financial, and overall life impact is needed, along with acknowledgement of relational ties driving donor motivations and the hoped-for recipient outcomes. Discussion of care practices, and access to peer mentoring may further strengthen the informed decision-making process.


Subject(s)
Kidney Transplantation , Decision Making , Humans , Informed Consent , Kidney , Living Donors , Pilot Projects
8.
Clin Transplant ; 34(11): e14064, 2020 11.
Article in English | MEDLINE | ID: mdl-32808320

ABSTRACT

The evaluation and care of non-US citizen, non-US residents who wish to come to the United States to serve as international living kidney donors (ILKDs) can pose unique challenges. We surveyed US transplant programs to better understand practices related to ILKD care. We distributed the survey by email and professional society list-servs (Fall 2018, assessing 2017 experience). Eighty-five programs responded (36.8% program response rate), of which 80 considered ILKD candidates. Only 18 programs had written protocols for ILKD evaluation. Programs had a median of 3 (range: 0,75) ILKD candidates who initiated contact during the year, from origin countries spanning 6 continents. Fewer (median: 1, range: 0,25) were approved for donation. Program-reported reasons for not completing ILKD evaluations included visa barriers (58.6%), inability to complete evaluation (34.3%), concerns regarding follow-up (31.4%) or other healthcare access (28.6%), and financial impacts (21.4%). Programs that did not evaluate ILKDs reported similar concerns. Staff time required to evaluate ILKDs was estimated as 1.5-to-3-times (47.9%) or >3-times (32.9%) that needed for domestic candidates. Among programs accepting ILKDs, on average 55% reported successful completion of 1-year follow-up. ILKD evaluation is a resource-intensive process with variable outcomes. Planning and commitment are necessary to care for this unique candidate group.


Subject(s)
Kidney Transplantation , Humans , Kidney , Living Donors , Surveys and Questionnaires , United States
9.
Clin Transplant ; 34(3): e13792, 2020 03.
Article in English | MEDLINE | ID: mdl-31991481

ABSTRACT

End-stage kidney disease patients in the United States may have family members or friends who are not US citizens or residents but are willing to serve as their living kidney donor in the United States ("international donors"). In July 2017, the American Society for Transplantation (AST) Live Donor Community of Practice (LDCOP) convened a multidisciplinary workgroup of experts in living donation care, including coordinators, social workers, donor advocates, administrators, and physicians, to evaluate educational gaps related to the evaluation and care of international donors. The evaluation of international living donor candidates is a resource-intensive process that raises key considerations for assessing risk of exploitation/inducement and addressing communication barriers, logistics barriers, and access to care in their home country. Through consensus-building discussions, we developed recommendations related to: (a) establishing program guidelines for international donor candidate evaluation and selection; (b) initial screening; (c) logistics planning; (d) comprehensive evaluation; and (e) postdonation care and follow-up. These recommendations are not intended to direct formal policy, but rather as guidance to help programs more efficiently and effectively structure and execute evaluations and care coordination. We also offer recommendations for research and advocacy to optimize the care of this unique group of living donors.


Subject(s)
Kidney Transplantation , Living Donors , Consensus , Humans , United States
11.
Am J Transplant ; 19(4): 1119-1128, 2019 04.
Article in English | MEDLINE | ID: mdl-30414243

ABSTRACT

The live donor assessment tool (LDAT) is the first psychosocial assessment tool developed to standardize live donor psychosocial evaluations. A multicenter study was conducted to explore reliability and validity of the LDAT and determine its ability to enhance the psychosocial evaluation beyond its center of origin. Four transplant programs participated, each with their own team of evaluators and unique demographics. Liver and kidney living donors (LDs) undergoing both standard psychosocial evaluation and LDAT from June 2015 to September 2016 were studied. LDAT interrater reliability, associations between LDAT scores and psychosocial evaluation outcome, and psychosocial outcomes postdonation were tested. 386 LD evaluations were compared and had a mean LDAT score of 67.34 ± 7.57. In 140 LDs with two LDATs by different observers, the interrater scores correlated (r = 0.63). LDAT scores at each center and overall stratified to the conventional grouping of psychosocial risk level. LDAT scores of 131 subjects who proceeded with donation were expectedly lower in LDs requiring postdonation counseling (t = -2.78, P = .01). The LDAT had good reliability between raters and predicted outcome of the psychosocial evaluation across centers. It can be used to standardize language among clinicians to communicate psychosocial risk of LD candidates and assist teams when anticipating postdonation psychosocial needs.


Subject(s)
Living Donors/psychology , Adult , Female , Humans , Kidney Transplantation/psychology , Liver Transplantation/psychology , Male , Middle Aged , Observer Variation , Reproducibility of Results
12.
BMJ Open ; 8(12): e025761, 2018 12 14.
Article in English | MEDLINE | ID: mdl-30552285

ABSTRACT

INTRODUCTION: Cognitive-behavioural therapy (CBT) is a psychological therapy that has been used to improve patient well-being across multiple mental and physical health problems. Its effectiveness has been examined in thousands of randomised control trials that have been synthesised into hundreds of systematic reviews. The aim of this overview is to map, synthesise and assess the reliability of evidence generated from these systematic reviews of the effectiveness of CBT across all health conditions, patient groups and settings. METHODS AND ANALYSIS: We will run our search strategy, to identify systematic reviews of CBT, within the Database of Abstracts of Reviews of Effects, the Cochrane Library of Systematic Reviews, MEDLINE, Embase, PsycInfo, CINAHL, Child Development and Adolescent Studies, and OpenGrey between January 1992 and 25 April 2018. Independent reviewers will sift, perform data extraction in duplicate and assess the quality of the reviews using the Assessing the Methodological Quality of Systematic Reviews (V.2) tool. The outcomes of interest include: health-related quality of life, depression, anxiety, psychosis and physical/physiological outcomes prioritised in the individual reviews. The evidence will be mapped and synthesised where appropriate by health problem, patient subgroups, intervention type, context and outcome. ETHICS AND DISSEMINATION: Ethical approval is not required as this is an overview of published systematic reviews. We plan to publish results in peer-reviewed journals and present at international and national academic, clinical and patient conferences. TRIAL REGISTRATION NUMBER: CRD42017078690.


Subject(s)
Cognitive Behavioral Therapy , Meta-Analysis as Topic , Systematic Reviews as Topic , Humans , Mental Disorders/therapy , Quality of Life , Treatment Outcome
13.
Psychosomatics ; 58(5): 519-526, 2017.
Article in English | MEDLINE | ID: mdl-28526401

ABSTRACT

BACKGROUND: The psychosocial evaluation is an important part of the live organ donor evaluation process, yet this is not standardized across institutions. OBJECTIVE: This study was designed to prospectively test the reliability and validity of a semistructured psychosocial evaluation tool that was recently developed and reported in the literature (the Live Donor Assessment Tool [LDAT]). METHODS: A total of 248 live donor candidates who presented for evaluation were invited to participate in a study that involved the LDAT being scored as part of the standard psychosocial evaluation process; 222 provided informed consent. Evaluations were conducted by staff experienced with psychosocial evaluation of living donors and trained in the use of the LDAT. Furthermore, 123 donor candidates were evaluated twice, as per routine standard of care, and had 2 LDATs administered. Reliability of the LDAT was assessed by calculating the internal consistency of the LDAT items and inter-rater reliability. Validity was assessed by comparing LDAT scores across the risk-group categories (the traditional outcome designation of the psychosocial evaluation) and in 86 eventual donors, associations between LDAT scores, and indicators of psychosocial outcomes post-donation. RESULTS: The LDAT was found to have good internal consistency, strong inter-rater reliability, and showed signs of validity: LDAT scores differentiated the traditional risk-group categories, and a significant association between LDAT score and treatment adherence post-donation was revealed. CONCLUSIONS: The LDAT demonstrated good reliability and validity, but future research on the LDAT and the ability to implement the LDAT across institutions is warranted.


Subject(s)
Living Donors/psychology , Surveys and Questionnaires/standards , Adult , Female , Humans , Male , Prospective Studies , Reproducibility of Results
14.
J Anim Ecol ; 78(4): 866-79, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19302319

ABSTRACT

1. The co-existence of competitors in heterogeneous landscapes depends on the processes of colonization, extinction and spatial scale. In this study, we explore the metapopulation dynamics of competitive interactions. 2. Rather than simply evaluating the outcome of interspecific competition in the traditional manner, we focus on both the local population dynamic effects and the regional metapopulation processes affecting species co-existence. 3. We develop a theoretical model of regional co-existence to generate a set of predictions on the patterns of colonization necessary for co-existence and the regional processes that can lead to competitive exclusion. We empirically test these predictions using metacommunity microcosms of the interaction between two bruchid beetles (Callosobruchus chinensis, Callosobruchus maculatus). 4. Using well-replicated time series of the interaction between the bruchids and statistical methods of model fitting, we show how the qualitative and quantitative pattern of interspecific competition between the bruchid beetles is shaped by the structure of the metacommunity. 5. In unlimited dispersal metacommunities, the global exclusion of the inferior competitor is shown to be influenced more by the processes associated with extinction rather than low colonization ability. In restricted dispersal metacommunities, we show how the co-existence of competitors in a spatially heterogeneous habitat (patches connected through limited dispersal) is affected by Allee effects and life-history [colonization (dispersal) - competition] trade-offs.


Subject(s)
Coleoptera/physiology , Ecosystem , Animals , Population Dynamics , Time Factors
15.
Neuropsychopharmacology ; 33(5): 1206-15, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17581529

ABSTRACT

Habituation, where a response is reduced when exposed to a continuous stimulus is one of the simplest forms of non-associative learning and has been shown in a number of organisms from sea slugs to rodents. However, very little has been reported in the zebrafish, a model that is gaining popularity for high-throughput compound screens. Furthermore, since most of the studies involving learning and memory in zebrafish have been conducted in adults, we sought to determine if zebrafish larvae could display non-associative learning and whether it could be modulated by compounds identified in previous rodent studies. We demonstrated that zebrafish larvae (7 days post fertilization) exhibit iterative reduction in a startle response to a series of acoustic stimuli. Furthermore, this reduction satisfied criteria for habituation: spontaneous recovery, more rapid reductions in startle to shorter intertrial intervals and dishabituation. We then investigated the pathways mediating this behavior using established compounds in learning and memory. Administration of rolipram (PDE4 inhibitor), donepezil (acetylcholinesterase inhibitor), and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) all increased the acoustic startle response and decreased habituation in the larvae, similar to previous rodent studies. Further studies demonstrated that NMDA blocked the memantine response and the effect of donepezil was blocked by mecamylamine but not atropine suggesting that the donepezil response was mediated by nicotinic rather than muscarinic receptors. Zebrafish larvae possess numerous advantages for medium to high-throughput screening; the model described herein therefore offers the potential to screen for additional compounds for further study on cognition function.


Subject(s)
Habituation, Psychophysiologic , Larva/physiology , Reflex, Startle/physiology , Acoustic Stimulation/methods , Age Factors , Analysis of Variance , Animals , Area Under Curve , Behavior, Animal/physiology , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Enzyme Inhibitors/administration & dosage , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Inhibition, Psychological , Memantine/pharmacology , N-Methylaspartate/pharmacology , Reflex, Startle/drug effects , Zebrafish
16.
Pharmacology ; 79(4): 250-8, 2007.
Article in English | MEDLINE | ID: mdl-17476122

ABSTRACT

BACKGROUND/AIMS: GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility. METHODS: We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man. RESULTS: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential. CONCLUSION: Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.


Subject(s)
Anticonvulsants/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Epilepsy/drug therapy , Ether-A-Go-Go Potassium Channels/metabolism , Myocardium/metabolism , Piperazines/pharmacology , Animals , Anticonvulsants/adverse effects , Arrhythmias, Cardiac/chemically induced , Dogs , Dopamine Uptake Inhibitors/adverse effects , Electrocardiography , Male , Mice , Piperazines/adverse effects , Rats , Rats, Sprague-Dawley , Zebrafish
17.
Epilepsy Res ; 75(1): 18-28, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17485198

ABSTRACT

The search for novel anticonvulsants requires appropriate model systems in which to test hypotheses through focused compound screening or genetic manipulation, or conduct black box screening of large numbers of compounds or potential genetic modifiers. Many models are currently in existence that subserve particular roles in achieving these aims, but all have their limitations. Zebrafish have been suggested as an additional model of epilepsy, but their optimum role is unclear. They are more amenable to high throughput analysis, but are more genetically removed from humans than rodents. We therefore sought to develop assay methodology applicable to medium/high throughput screening using an automated tracking system to measure the amount of movement induced by exposure to the proconvulsant, pentylene tetrazole (PTZ). We then used this system to explore how many known anti-epileptic drugs (AEDs) would be detected when running such a screen. We were able to detect suppression of PTZ-induced excessive movements with 13 out of 14 standard AEDs. A parallel sedation and toxicity screen suggested these effects were due to direct anti-epileptic effect, although non-specific effects cannot be fully excluded. These results suggest zebrafish may be a useful high throughput primary screen to pick up potential novel AEDs.


Subject(s)
Anticonvulsants/therapeutic use , Disease Models, Animal , Epilepsy/drug therapy , Animals , Behavior, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Interactions , Embryo, Nonmammalian , Epilepsy/chemically induced , Movement/drug effects , Pentylenetetrazole , Time Factors , Zebrafish
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