There is a high prevalence of smoking among people who experience severe mental ill health (SMI).... more There is a high prevalence of smoking among people who experience severe mental ill health (SMI). Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health, increase longevity and also reduce health inequalities. Around half of people with SMI who smoke express an interest in cutting down or quitting smoking. There is limited evidence that smoking cessation can be achieved for people with SMI. Those with SMI rarely access routine NHS smoking cessation services. This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI. The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment, randomisation and follow-up. We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness. The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual general practitioner (GP) care for people with SMI. A pilot pragmatic two-arm individually randomised controlled trial (RCT). Simple randomisation was used following a computer-generated random number sequence. Participants and practitioners were not blinded to allocation. Primary care and secondary care mental health services in England. Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking. A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual GP care. The primary outcome was carbon monoxide-verified smoking cessation at 12 months. Smoking-related secondary outcomes were reduction of number of cigarettes smoked, Fagerstrom test of nicotine dependence and motivation to quit (MTQ). Other secondary outcomes were Patient Health Questionnaire-9 items and Short Form Questionnaire-12 items to assess whether there were improvements or deterioration in mental health and quality of life. We also measured body mass index to assess whether or not smoking cessation was associated with weight gain. These were measured at 1, 6 and 12 months post randomisation. The trial recruited 97 people aged 19-73 years who smoked between 5 and 60 cigarettes per day (mean 25 cigarettes). Participants were recruited from four mental health trusts and 45 GP surgeries. Forty-six people were randomised to the BSC intervention and 51 people were randomised to usual GP care. The odds of quitting at 12 months was higher in the BSC intervention (36% vs. 23%) but did not reach statistical significance (odds ratio 2.9; 95% confidence interval 0.8% to 10.5%). At 3 and 6 months there was no evidence of difference in self-reported smoking cessation. There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence. MTQ and number of quit attempts all increased in the BSC group compared with usual care. There was no difference in terms of quality of life at any time point, but there was evidence of an increase in depression scores at 12 months for the BSC group. There were no serious adverse events thought likely to be related to the trial interventions. The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis. It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication. The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants. A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research (NIHR) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness. Current Controlled Trials ISRCTN79497236. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 19, No. 25. See the NIHR Journals Library website for further project information.
To assess how initial severity of depression affects the benefit derived from low intensity inter... more To assess how initial severity of depression affects the benefit derived from low intensity interventions for depression. Meta-analysis of individual patient data from 16 datasets comparing low intensity interventions with usual care. Primary care and community settings. 2470 patients with depression. Low intensity interventions for depression (such as guided self help by means of written materials and limited professional support, and internet delivered interventions). Depression outcomes (measured with the Beck Depression Inventory or Center for Epidemiologic Studies Depression Scale), and the effect of initial depression severity on the effects of low intensity interventions. Although patients were referred for low intensity interventions, many had moderate to severe depression at baseline. We found a significant interaction between baseline severity and treatment effect (coefficient -0.1 (95% CI -0.19 to -0.002)), suggesting that patients who are more severely depressed at basel...
Computerised therapies play an integral role in efforts to improve access to psychological treatm... more Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a co-morbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the 'non-specific' or 'common' factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of 'self' in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement.
Although trade-offs between reproductive effort and other fitness components are frequently docum... more Although trade-offs between reproductive effort and other fitness components are frequently documented in wild populations, the underlying physiological mechanisms remain poorly understood. Parasitism has been suggested to mediate reproductive trade-offs, yet only a limited number of parasite taxa have been studied, and reproductive effort-induced changes in parasitism are rarely linked to trade-offs observed in the same population. We conducted a brood size manipulation experiment in blue tits (Cyanistes caeruleus) infected with malaria (Plasmodium) parasites, and used quantitative PCR to measure changes in parasitaemia. In one of two years investigated, parasitaemia increased as a result of brood enlargement, and was also positively associated with two other indicators of reproductive effort: clutch size and single parenthood. These associations between both experimental and naturally varying reproductive effort and parasitaemia suggest that immune control of chronic malaria infections can be compromised when parents are working hard. Brood size manipulation significantly affected the number of independent offspring produced, which was maximised when brood size was unchanged. Moreover, when parents were infected with one of two common Plasmodium species, the shape of this trade-off curve was more pronounced, suggesting that parasitic infection may exacerbate the trade-off between quantity and quality of offspring. Although the involvement of parasites in survival costs of reproduction has received much attention, these results suggest their role in other commonly documented reproductive trade-offs, such as that between number and quality of offspring, warrants further study.
1. Investigating the ecological context in which host-parasite interactions occur and the roles o... more 1. Investigating the ecological context in which host-parasite interactions occur and the roles of biotic and abiotic factors in forcing infection dynamics is essential to understanding disease transmission, spread and maintenance. 2. Despite their prominence as model host-pathogen systems, the relative influence of environmental heterogeneity and host characteristics in influencing the infection dynamics of avian blood parasites has rarely been assessed in the wild, particularly at a within-population scale. 3. We used a novel multievent modelling framework (an extension of multistate mark-recapture modelling) that allows for uncertainty in disease state, to estimate transmission parameters and assess variation in the infection dynamics of avian malaria in a large, longitudinally sampled data set of breeding blue tits infected with two divergent species of Plasmodium parasites. 4. We found striking temporal and spatial heterogeneity in the disease incidence rate and the likelihood of recovery within this single population and demonstrate marked differences in the relative influence of environmental and host factors in forcing the infection dynamics of the two Plasmodium species. 5. Proximity to a permanent water source greatly influenced the transmission rates of P. circumflexum, but not of P. relictum, suggesting that these parasites are transmitted by different vectors. 6. Host characteristics (age/sex) were found to influence infection rates but not recovery rates, and their influence on infection rates was also dependent on parasite species: P. relictum infection rates varied with host age, whilst P. circumflexum infection rates varied with host sex. 7. Our analyses reveal that transmission of endemic avian malaria is a result of complex interactions between biotic and abiotic components that can operate on small spatial scales and demonstrate that knowledge of the drivers of spatial and temporal heterogeneity in disease transmission will be crucial for developing accurate epidemiological models and a thorough understanding of the evolutionary implications of pathogens.
Understanding exactly when, where and how hosts become infected with parasites is critical to und... more Understanding exactly when, where and how hosts become infected with parasites is critical to understanding host-parasite co-evolution in natural populations. However, for host-parasite systems in which hosts or parasites are mobile, for example in vector-borne diseases, the spatial location of infection and the relative importance of parasite exposure at successive host life-history stages are often uncertain. Here, using a 6-year longitudinal data set from a spatially referenced population of blue tits, we test the extent to which infection by avian malaria parasites is determined by conditions experienced at natal or breeding sites, as well as by postnatal dispersal between the two. We show that the location and timing of infection differs markedly between two sympatric malaria parasite species. For one species (Plasmodium circumflexum), our analyses indicate that infection occurs after birds have settled on breeding territories, and because the distribution of this parasite is temporally stable across years, hosts born in malarious areas could in principle alter their exposure and potentially avoid infection through postnatal dispersal. Conversely, the spatial distribution of another parasite species (Plasmodium relictum) is unpredictable and infection probability is positively associated with postnatal dispersal distance, potentially indicating that infection occurs during this major dispersal event. These findings suggest that hosts in this population may be subject to divergent selection pressures from these two parasites, potentially acting at different life-history stages. Because this implies parasite species-specific predictions for many coevolutionary processes, they also illustrate the complexity of predicting such processes in multi-parasite systems.
We report a second-generation gene annotation of human chromosome 22. Using expressed sequence da... more We report a second-generation gene annotation of human chromosome 22. Using expressed sequence databases, comparative sequence analysis, and experimental verification, we have extended genes, fused previously fragmented structures, and identified new genes. The total length in exons of annotation was increased by 74% over our previously published annotation and includes 546 protein-coding genes and 234 pseudogenes. Thirty-two potential protein-coding annotations are partial copies of other genes, and may represent duplications on an evolutionary path to change or loss of function. We also identified 31 non-protein-coding transcripts, including 16 possible antisense RNAs. By extrapolation, we estimate the human genome contains 29,000-36,000 protein-coding genes, 21,300 pseudogenes, and 1500 antisense RNAs. We suggest that our revised annotation criteria provide a paradigm for future annotation of the human genome.
There is a high prevalence of smoking among people who experience severe mental ill health (SMI).... more There is a high prevalence of smoking among people who experience severe mental ill health (SMI). Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health, increase longevity and also reduce health inequalities. Around half of people with SMI who smoke express an interest in cutting down or quitting smoking. There is limited evidence that smoking cessation can be achieved for people with SMI. Those with SMI rarely access routine NHS smoking cessation services. This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI. The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment, randomisation and follow-up. We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness. The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual general practitioner (GP) care for people with SMI. A pilot pragmatic two-arm individually randomised controlled trial (RCT). Simple randomisation was used following a computer-generated random number sequence. Participants and practitioners were not blinded to allocation. Primary care and secondary care mental health services in England. Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking. A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual GP care. The primary outcome was carbon monoxide-verified smoking cessation at 12 months. Smoking-related secondary outcomes were reduction of number of cigarettes smoked, Fagerstrom test of nicotine dependence and motivation to quit (MTQ). Other secondary outcomes were Patient Health Questionnaire-9 items and Short Form Questionnaire-12 items to assess whether there were improvements or deterioration in mental health and quality of life. We also measured body mass index to assess whether or not smoking cessation was associated with weight gain. These were measured at 1, 6 and 12 months post randomisation. The trial recruited 97 people aged 19-73 years who smoked between 5 and 60 cigarettes per day (mean 25 cigarettes). Participants were recruited from four mental health trusts and 45 GP surgeries. Forty-six people were randomised to the BSC intervention and 51 people were randomised to usual GP care. The odds of quitting at 12 months was higher in the BSC intervention (36% vs. 23%) but did not reach statistical significance (odds ratio 2.9; 95% confidence interval 0.8% to 10.5%). At 3 and 6 months there was no evidence of difference in self-reported smoking cessation. There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence. MTQ and number of quit attempts all increased in the BSC group compared with usual care. There was no difference in terms of quality of life at any time point, but there was evidence of an increase in depression scores at 12 months for the BSC group. There were no serious adverse events thought likely to be related to the trial interventions. The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis. It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication. The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants. A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research (NIHR) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness. Current Controlled Trials ISRCTN79497236. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 19, No. 25. See the NIHR Journals Library website for further project information.
To assess how initial severity of depression affects the benefit derived from low intensity inter... more To assess how initial severity of depression affects the benefit derived from low intensity interventions for depression. Meta-analysis of individual patient data from 16 datasets comparing low intensity interventions with usual care. Primary care and community settings. 2470 patients with depression. Low intensity interventions for depression (such as guided self help by means of written materials and limited professional support, and internet delivered interventions). Depression outcomes (measured with the Beck Depression Inventory or Center for Epidemiologic Studies Depression Scale), and the effect of initial depression severity on the effects of low intensity interventions. Although patients were referred for low intensity interventions, many had moderate to severe depression at baseline. We found a significant interaction between baseline severity and treatment effect (coefficient -0.1 (95% CI -0.19 to -0.002)), suggesting that patients who are more severely depressed at basel...
Computerised therapies play an integral role in efforts to improve access to psychological treatm... more Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a co-morbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the 'non-specific' or 'common' factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of 'self' in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement.
Although trade-offs between reproductive effort and other fitness components are frequently docum... more Although trade-offs between reproductive effort and other fitness components are frequently documented in wild populations, the underlying physiological mechanisms remain poorly understood. Parasitism has been suggested to mediate reproductive trade-offs, yet only a limited number of parasite taxa have been studied, and reproductive effort-induced changes in parasitism are rarely linked to trade-offs observed in the same population. We conducted a brood size manipulation experiment in blue tits (Cyanistes caeruleus) infected with malaria (Plasmodium) parasites, and used quantitative PCR to measure changes in parasitaemia. In one of two years investigated, parasitaemia increased as a result of brood enlargement, and was also positively associated with two other indicators of reproductive effort: clutch size and single parenthood. These associations between both experimental and naturally varying reproductive effort and parasitaemia suggest that immune control of chronic malaria infections can be compromised when parents are working hard. Brood size manipulation significantly affected the number of independent offspring produced, which was maximised when brood size was unchanged. Moreover, when parents were infected with one of two common Plasmodium species, the shape of this trade-off curve was more pronounced, suggesting that parasitic infection may exacerbate the trade-off between quantity and quality of offspring. Although the involvement of parasites in survival costs of reproduction has received much attention, these results suggest their role in other commonly documented reproductive trade-offs, such as that between number and quality of offspring, warrants further study.
1. Investigating the ecological context in which host-parasite interactions occur and the roles o... more 1. Investigating the ecological context in which host-parasite interactions occur and the roles of biotic and abiotic factors in forcing infection dynamics is essential to understanding disease transmission, spread and maintenance. 2. Despite their prominence as model host-pathogen systems, the relative influence of environmental heterogeneity and host characteristics in influencing the infection dynamics of avian blood parasites has rarely been assessed in the wild, particularly at a within-population scale. 3. We used a novel multievent modelling framework (an extension of multistate mark-recapture modelling) that allows for uncertainty in disease state, to estimate transmission parameters and assess variation in the infection dynamics of avian malaria in a large, longitudinally sampled data set of breeding blue tits infected with two divergent species of Plasmodium parasites. 4. We found striking temporal and spatial heterogeneity in the disease incidence rate and the likelihood of recovery within this single population and demonstrate marked differences in the relative influence of environmental and host factors in forcing the infection dynamics of the two Plasmodium species. 5. Proximity to a permanent water source greatly influenced the transmission rates of P. circumflexum, but not of P. relictum, suggesting that these parasites are transmitted by different vectors. 6. Host characteristics (age/sex) were found to influence infection rates but not recovery rates, and their influence on infection rates was also dependent on parasite species: P. relictum infection rates varied with host age, whilst P. circumflexum infection rates varied with host sex. 7. Our analyses reveal that transmission of endemic avian malaria is a result of complex interactions between biotic and abiotic components that can operate on small spatial scales and demonstrate that knowledge of the drivers of spatial and temporal heterogeneity in disease transmission will be crucial for developing accurate epidemiological models and a thorough understanding of the evolutionary implications of pathogens.
Understanding exactly when, where and how hosts become infected with parasites is critical to und... more Understanding exactly when, where and how hosts become infected with parasites is critical to understanding host-parasite co-evolution in natural populations. However, for host-parasite systems in which hosts or parasites are mobile, for example in vector-borne diseases, the spatial location of infection and the relative importance of parasite exposure at successive host life-history stages are often uncertain. Here, using a 6-year longitudinal data set from a spatially referenced population of blue tits, we test the extent to which infection by avian malaria parasites is determined by conditions experienced at natal or breeding sites, as well as by postnatal dispersal between the two. We show that the location and timing of infection differs markedly between two sympatric malaria parasite species. For one species (Plasmodium circumflexum), our analyses indicate that infection occurs after birds have settled on breeding territories, and because the distribution of this parasite is temporally stable across years, hosts born in malarious areas could in principle alter their exposure and potentially avoid infection through postnatal dispersal. Conversely, the spatial distribution of another parasite species (Plasmodium relictum) is unpredictable and infection probability is positively associated with postnatal dispersal distance, potentially indicating that infection occurs during this major dispersal event. These findings suggest that hosts in this population may be subject to divergent selection pressures from these two parasites, potentially acting at different life-history stages. Because this implies parasite species-specific predictions for many coevolutionary processes, they also illustrate the complexity of predicting such processes in multi-parasite systems.
We report a second-generation gene annotation of human chromosome 22. Using expressed sequence da... more We report a second-generation gene annotation of human chromosome 22. Using expressed sequence databases, comparative sequence analysis, and experimental verification, we have extended genes, fused previously fragmented structures, and identified new genes. The total length in exons of annotation was increased by 74% over our previously published annotation and includes 546 protein-coding genes and 234 pseudogenes. Thirty-two potential protein-coding annotations are partial copies of other genes, and may represent duplications on an evolutionary path to change or loss of function. We also identified 31 non-protein-coding transcripts, including 16 possible antisense RNAs. By extrapolation, we estimate the human genome contains 29,000-36,000 protein-coding genes, 21,300 pseudogenes, and 1500 antisense RNAs. We suggest that our revised annotation criteria provide a paradigm for future annotation of the human genome.
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