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Background: Acute lower respiratory tract infections (ALRTIs) account for most antibiotics prescribed in primary care despite lack of efficacy, partly due to clinician uncertainty about aetiology and patient concerns about illness course. Nucleic acid amplification tests could assist antibiotic targeting. Methods: In this prospective cohort study, 645 patients presenting to primary care with acute cough and suspected ALRTI, provided throat swabs at baseline. These were tested for respiratory pathogens by real-time polymerase chain reaction and classified as having a respiratory virus, bacteria, both or neither. Three hundred fifty-four participants scored the symptoms severity daily for 1 week in a diary (0 = absent to 4 = severe problem). Results: Organisms were identified in 346/645 (53.6%) participants. There were differences in the prevalence of seven symptoms between the organism groups at baseline. Those with a virus alone, and those with both virus and bacteria, had higher average severity scores of all symptoms combined during the week of follow-up than those in whom no organisms were detected [adjusted mean differences 0.204 (95% confidence interval 0.010 to 0.398) and 0.348 (0.098 to 0.598), respectively]. There were no differences in the duration of symptoms rated as moderate or severe between organism groups. Conclusions: Differences in presenting symptoms and symptoms severity can be identified between patients with viruses and bacteria identified on throat swabs. The magnitude of these differences is unlikely to influence management. Most patients had mild symptoms at 7 days regardless of aetiology, which could inform patients about likely symptom duration.
\n \n\n \n \nBackground: Colorectal cancer (CRC) is a common and important disease. There are different tests for diagnosis, one of which is computed tomographic colonography (CTC). No test is perfect, and patients with normal CTC may subsequently develop CRC (either because it was overlooked originally, or because it has developed in the interim). This is termed post-investigation colorectal cancer (PICRC) or \"interval cancer\". How frequently this occurs after CTC is not known. The purpose of this systematic review and meta-analysis is to use the primary literature to estimate the PICRC rate after CTC, and explore associated factors. Methods: Primary studies reporting post-investigation colorectal cancer (PICRC) rates after CTC will be identified from PubMed, Embase and Cochrane Register of Controlled Trials databases. Peer-reviewed studies published after 1994 (the year CTC was introduced) will be included and the rate of PICRC within 36months of CTC recorded. Data will be extracted from selected studies for a random effects meta-analysis. Heterogeneity, risk of bias and publication bias will be assessed, and exploratory analysis will examine factors associated with higher PICRC rates in the literature. Conclusion: PICRC rates are the ultimate benchmark of diagnostic quality for colonic investigations. This systematic review and meta-analysis will identify and synthesise evidence to determine PICRC rates after CTC and explore factors that may contribute to higher rates. Systematic review registration: PROSPERO (registration number CRD42016042437 ).
\n \n\n \n \nAs evidence accumulates within a meta-analysis, it is desirable to determine when the results could be considered conclusive to guide systematic review updates and future trial designs. Adapting sequential testing methodology from clinical trials for application to pooled meta-analytic effect size estimates appears well suited for this objective. In this paper, we describe a Bayesian sequential meta-analysis method, in which an informative heterogeneity prior is employed and stopping rule criteria are applied directly to the posterior distribution for the treatment effect parameter. Using simulation studies, we examine how well this approach performs under different parameter combinations by monitoring the proportion of sequential meta-analyses that reach incorrect conclusions (to yield error rates), the number of studies required to reach conclusion, and the resulting parameter estimates. By adjusting the stopping rule thresholds, the overall error rates can be controlled within the target levels and are no higher than those of alternative frequentist and semi-Bayes methods for the majority of the simulation scenarios. To illustrate the potential application of this method, we consider two contrasting meta-analyses using data from the Cochrane Library and compare the results of employing different sequential methods while examining the effect of the heterogeneity prior in the proposed Bayesian approach. Copyright \u00a9 2016 John Wiley & Sons, Ltd.
\n \n\n \n \nBackground: The increasing prevalence of type 2 diabetes poses both clinical and public health challenges. Cost-effective approaches to prevent progression of the disease in primary care are needed. Evidence suggests that intensive multifactorial interventions including medication and behaviour change can significantly reduce cardiovascular morbidity and mortality among patients with established type 2 diabetes, and that patient education in self-management can improve short-term outcomes. However, existing studies cannot isolate the effects of behavioural interventions promoting self-care from other aspects of intensive primary care management. The ADDITION-Plus trial was designed to address these issues among recently diagnosed patients in primary care over one year. Methods/Design. ADDITION-Plus is an explanatory randomised controlled trial of a facilitator-led, theory-based behaviour change intervention tailored to individuals with recently diagnosed type 2 diabetes. 34 practices in the East Anglia region participated. 478 patients with diabetes were individually randomised to receive (i) intensive treatment alone (n = 239), or (ii) intensive treatment plus the facilitator-led individual behaviour change intervention (n = 239). Facilitators taught patients key skills to facilitate change and maintenance of key behaviours (physical activity, dietary change, medication adherence and smoking), including goal setting, action planning, self-monitoring and building habits. The intervention was delivered over one year at the participant's surgery and included a one-hour introductory meeting followed by six 30-minute meetings and four brief telephone calls. Primary endpoints are physical activity energy expenditure (assessed by individually calibrated heart rate monitoring and movement sensing), change in objectively measured dietary intake (plasma vitamin C), medication adherence (plasma drug levels), and smoking status (plasma cotinine levels) at one year. We will undertake an intention-to-treat analysis of the effect of the intervention on these measures, an assessment of cost-effectiveness, and analyse predictors of behaviour change in the cohort. Discussion. The ADDITION-Plus trial will establish the medium-term effectiveness and cost-effectiveness of adding an externally facilitated intervention tailored to support change in multiple behaviours among intensively-treated individuals with recently diagnosed type 2 diabetes in primary care. Results will inform policy recommendations concerning the management of patients early in the course of diabetes. Findings will also improve understanding of the factors influencing change in multiple behaviours, and their association with health outcomes. Trial registration. ISRCTN: ISRCTN99175498. \u00a9 2011 Griffin et al; licensee BioMed Central Ltd.
\n \n\n \n \nThe DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.
\n \n\n \n \nThe DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.
\n \n\n \n \nPurpose: DNA replication licensing factors and Aurora kinases play critical roles in maintaining genomic integrity. We used multiparameter analyses of these cell cycle regulatory proteins to investigate their role in the progression of epithelial ovarian carcinoma (EOC). Experimental Design: In a cohort of 143 patients, we linked the protein expression profiles of the proliferation marker Ki67, the replication licensing factors Mcm2 and geminin, and the Aurora A and B kinases to tumor DNA ploidy status and clinical outcome. Results: Ki67, Mcm2, geminin, and Aurora A and B are significantly associated with tumor grade and ploidy status (P < 0.0001). Aurora A and its substrate H3S10ph are also significantly associated with Federation of International Obstetricians and Gynecologists tumor stage (P = 0.006 and P = 0.002, respectively). Aurora A and tumor ploidy status are predictive of disease-free survival in this cohort [hazard ratio (HR), 1.29; 95% confidence intervals (95% CI), 1.06-1.58, P = 0.01 and HR, 1.80 (1.05-3.08), P = 0.03, respectively], with Aurora A of particular prognostic importance in early stage disease [HR, 1.72 (1.19-2.48), P = 0.004 for disease-free survival and HR, 1.81 (1.14-2.87), P = 0.01 for overall survival]. Conclusions: Our data show that Ki67, Mcm2, geminin and Aurora A and B can be used as an adjunct to conventional prognostic indicators and as an aid to develop a tumor progression model for EOC. Dysregulation of Aurora A seems to be an early event in EOC with a key role in tumor progression. In view of present drug development programs for specific Aurora kinase inhibitors, our findings have important implications for the use of Aurora A as a biomarker and as a potential therapeutic target. \u00a92007 American Association for Cancer Research.
\n \n\n \n \nMany cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0\u00b7001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0\u00b7001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.
\n \n\n \n \nThe objective was to evaluate the effect of an assessment strategy using the computer decision support system (the GRAIDS software), on the management of familial cancer risk in British general practice in comparison with best current practice. The design included cluster randomised controlled trial, and involved forty-five general practice teams in East Anglia, UK. Randomised to GRAIDS (Genetic Risk Assessment on the Internet with Decision Support) support (intervention n=23) or comparison (n=22). Training in the new assessment strategy and access to the GRAIDS software (GRAIDS arm) was conducted, compared with an educational session and guidelines about managing familial breast and colorectal cancer risk (comparison) were mailed. Outcomes were measured at practice, practitioner and patient levels. The primary outcome measure, at practice level, was the proportion of referrals made to the Regional Genetics Clinic for familial breast or colorectal cancer that were consistent with referral guidelines. Other measures included practitioner confidence in managing familial cancer (GRAIDS arm only) and, in patients: cancer worry, risk perception and knowledge about familial cancer. There were more referrals to the Regional Genetics Clinic from GRAIDS than comparison practices (mean 6.2 and 3.2 referrals per 10 000 registered patients per year; mean difference 3.0 referrals; 95% confidence interval (CI) 1.2-4.8; P=0.001); referrals from GRAIDS practices were more likely to be consistent with referral guidelines (odds ratio (OR)=5.2; 95% CI 1.7-15.8, P=0.006). Patients referred from GRAIDS practices had lower cancer worry scores at the point of referral (mean difference -1.44 95% CI -2.64 to -0.23, P=0.02). There were no differences in patient knowledge about familial cancer. The intervention increased GPs' confidence in managing familial cancer. Compared with education and mailed guidelines, assessment including computer decision support increased the number and quality of referrals to the Regional Genetics Clinic for familial cancer risk, improved practitioner confidence and had no adverse psychological effects in patients. Trials are registered under N0181144343 in the UK National Research Register. \u00a9 2007 Cancer Research UK.
\n \n\n \n \nBackground: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests.
\n \n\n \n \nObjectives: To assess whether residential proximity to industrial incinerators in England is associated with increased risk of cancer incidence and mortality. Design: Retrospective study using matched case-control areas. Setting: Five circular regions of radius 10 km near industrial incinerators in England (case regions) and five matched control regions, 1998-2008. Participants: All cases of diseases of interest within the circular areas. Primary and secondary outcome measures: Counts of childhood cancer incidence (<15 years); childhood leukaemia incidence (<15 years); leukaemia incidence; liver cancer incidence; lung cancer incidence; non-Hodgkin's lymphoma incidence; allcause mortality; infant mortality (<1 year) and liver cancer mortality. Results: The estimated relative risks for case circles versus control circles for the nine outcomes considered range from 0.94 to 1.14, and show neither elevated risk in case circles compared to control areas nor elevated risk with proximity to incinerators within case circles. Conclusions: This study applies statistical methods for analysing spatially referenced health outcome data in regions with a hypothesised exposure relative to matched regions with no such exposure. There is no evidence of elevated risk of cancer incidence or mortality in the vicinity of large industrial incinerators in England.
\n \n\n \n \nBackground At the time of an infant's initial vaccination at age \u223c2 to 3 months, some infants already have maternal antibodies against vaccine antigens and these can suppress the immune response to vaccination. Modelling the effects of maternal antibody and the timing of infant doses on the antibody response to vaccination, requires estimates of the rate of maternal antibody decay. Decay rates are not well characterised in the medical literature. We investigated variation in the prevalence of maternal anti-capsular pneumococcal and meningococcal antibodies in infants in 14 countries, and estimated type-specific half-lives. Methods Individual participant serological data were obtained from clinical trials. Half-lives were estimated from antibody concentrations in infants who did not receive meningococcal or pneumococcal vaccines. Results The seroprevalence of maternal pneumococcal antibodies was highest for serotypes 14, and 19F (92% and 80% respectively) and lowest for serotypes 4 and 1 (30% and 34% respectively). Half-life estimates ranged from 38.7 days (95% CI 36.6\u201341.0) for serotype 6B, to 48.3 days (95% CI 46.7\u201350.2) for serotype 5. The overall half-life was 42.6 days (95% CI 41.5\u201343.7). Seroprevalence was highest in Mali, Nigeria, India, and the Philippines, (all >65%) and lowest in the Czech Republic and Finland (both <45%). In studies of meningococcal vaccines, seroprevalence was 13% for group C (half-life 39.8 days, 95% CI 33.4\u201349.4) and 43% for group A (half-life 43.1 days 95% CI 39.8\u201347.2). Conclusion Substantial proportions of infants in many countries have antibodies to vaccine serotypes of pneumococcus, however fewer infants have maternally acquired antibodies to groups A and C meningococcus. Passively-acquired antibodies to capsular polysaccharides decay with a half-life of approximately 6 weeks. These estimates are useful for modelling the impact of proposed vaccination programmes, and consideration of schedules with a delayed start.
\n \n\n \n \nBackground: We consider the problem of assessing inter-rater agreement when there are missing data and a large number of raters. Previous studies have shown only 'moderate' agreement between pathologists in grading breast cancer tumour specimens. We analyse a large but incomplete data-set consisting of 24177 grades, on a discrete 1-3 scale, provided by 732 pathologists for 52 samples. Methodology/principal findings: We review existing methods for analysing inter-rater agreement for multiple raters and demonstrate two further methods. Firstly, we examine a simple non-chance-corrected agreement score based on the observed proportion of agreements with the consensus for each sample, which makes no allowance for missing data. Secondly, treating grades as lying on a continuous scale representing tumour severity, we use a Bayesian latent trait method to model cumulative probabilities of assigning grade values as functions of the severity and clarity of the tumour and of rater-specific parameters representing boundaries between grades 1-2 and 2-3. We simulate from the fitted model to estimate, for each rater, the probability of agreement with the majority. Both methods suggest that there are differences between raters in terms of rating behaviour, most often caused by consistent over- or under-estimation of the grade boundaries, and also considerable variability in the distribution of grades assigned to many individual samples. The Bayesian model addresses the tendency of the agreement score to be biased upwards for raters who, by chance, see a relatively 'easy' set of samples. Conclusions/significance: Latent trait models can be adapted to provide novel information about the nature of inter-rater agreement when the number of raters is large and there are missing data. In this large study there is substantial variability between pathologists and uncertainty in the identity of the 'true' grade of many of the breast cancer tumours, a fact often ignored in clinical studies. \u00a9 2008 Fanshawe et al.
\n \n\n \n \nBackground: Osteoarthritis of the first metatarsophalangeal joint (hallux rigidus) leads to pain and poor function and mobility. Arthrodesis is the gold standard treatment for end-stage disease. Total joint arthroplasties have been attempted, but early loosening has been attributed to dorsally directed shear forces on the metatarsal component. Metallic proximal phalangeal hemiarthroplasty theoretically avoids this. Whilst early results are promising, no comparative trials exist comparing this to arthrodesis.Methods/Design: The primary objectives are to determine the range of outcome scores between the two treatment arms (to inform a power calculation). Outcome measures will include the MOXFQ, AOFAS-Hallux and EuroQol EQ-5D-5 L. Secondary objectives are to determine the accrual rate, dropout rate and trial acceptability to both patients and surgeons. These data will allow the development of a larger trial with longer follow-up.This is a prospective randomised controlled single-centre study comparing proximal phalanx hemiarthroplasty (AnaToemic, Arthrex Ltd., Sheffield, UK) with arthrodesis (15 patients in each arm). Randomisation will be performed using a 1:1 allocation ratio in blocks of six.Patients meeting the eligibility criteria will be recruited from three foot and ankle consultant surgeon's clinics (East Lancashire Hospitals NHS Trust). If agreeable, informed consent will be obtained before patients are randomised.The outcome measure scores will be completed pre-operatively and repeated at 6 weeks, 3 months and 12 months. A radiological review will be performed at 6 weeks and 12 months to determine rates of loosening (hemiarthroplasty) and union (arthrodesis). Data on length of stay, return to work, complications and re-operation rates will also be collected.The analysis will compare the change in outcome scores between treatment groups at all follow-up time points. Scores will be compared using a Student t-test, adjusting for scores at baseline.This study will be conducted in accordance with the current revision of the Declaration of Helsinki (1996) and the ICH-GCP Guideline (International Conference on Harmonisation, Good Clinical Practice, E6(R1), 1996). This study has been approved by the sponsor, the Trust Research & Development office. Ethical approval has been received from the National Research Ethics Service (North East: 12/NE/0385 for protocol version 5.3 dated 3 June 2013).Trial registration: Current Controlled Trials ISRCTN88273654. \u00a9 2014 Divecha et al.; licensee BioMed Central Ltd.
\n \n\n \n \nEnvironmental monitoring provides a typical setting that gives rise to spatio-temporal design problems. This chapter considers the model-based design, in which the optimal design problem requires two key features to be specified: (i) a statistical or mathematical model for the process under consideration; and, (ii) a criterion with respect to which the design is required to be optimized. After reviewing spatial and spatio-temporal adaptive designs it considers the performance of adaptive design-finding algorithms with respect to these for two different models for stochastic process S: the stationary Gaussian model; and a dynamic process convolution model. The chapter uses the second of these models to consider adaptive designs for the Upper Austria rainfall data. It concludes that adaptive designs should be constructed by a criterion that directly measures the extent to which the primary scientific goal of the analysis is being met, and should therefore be strongly context-dependent.
\n \n\n \n \nThe DNA replication (or origin) licensing machinery ensures precise duplication of the genome and contributes to the regulation of proliferative capacity in metazoa. Using an in vitro fibroblast model system coupled to a cell-free DNA replication assay, we have studied regulation of the origin licensing pathway during exit from and re-entry into the mitotic cell cycle. We show that in the quiescent state (G0) loss of proliferative capacity is achieved in part through down-regulation of the replication licensing factors Cdc6 and Mcm2-7. The origin licensing repressor geminin is absent in quiescent fibroblasts, suggesting that this powerful inhibitor of the licensing machinery is not required to suppress proliferative capacity in G0. Geminin expression is induced at a late stage in the G0-S transition post pre-RC assembly. Ectopic geminin can block re-acquisition of DNA replication competence during re-entry into the cell cycle, indicating that geminin levels must be tightly down-regulated for escape from G0. Analysis of geminin levels in thyroid shows that geminin expression is suppressed in anatomical compartments/tissues harbouring quiescent cells, confirming our in vitro data. Spatio-temporal control of geminin expression may therefore be of particular relevance for multi-potential stem cells which cycle infrequently. In support of this hypothesis, we have identified a unique population of cells in the putative stem cell niche of intestinal epithelium that are unlicensed and lack geminin expression, a prerequisite for successful re-entry into cycle. Our data argue that the prolonged cell cycle times observed for intestinal stem cells could be due to exit of progenitor cells from cycle into an unlicensed \"out-of-cycle\" state, a powerful mechanism by which rapidly proliferating tissues may resist genotoxic insult. \u00a9 2005 Elsevier Inc. All rights reserved.
\n \n\n \n \nObjectives: To compare patients' enablement and satisfaction after teaching and non-teaching consultations. To explore patients' views about the possible impact that increased community based teaching of student doctors in their practice may have on the delivery of service and their attitudes towards direct involvement with students. Design: Observational study using validated survey instruments (patient enablement index-PEI, and consultation satisfaction questionnaire-CSQ) administered after teaching consultations and non-teaching consultations. Ten focus groups (two from each practice), comprising five with patients participating in prearranged teaching sessions and five with patients not participating in these. Setting: Five general practices in west Suffolk and southern Norfolk, England, that teach student doctors on the Cambridge graduate medical course. Participants: 240 patients attending teaching consultations (response rate 82%, 196 patients) and 409 patients attending non-teaching consultations (response rate 72%, 294 patients) received survey instruments. Ten focus groups with a total of 34 patients participating in prearranged teaching sessions and 20 patients not participating in these. Main outcome measures: Scores on the patient enablement index and consultation satisfaction questionnaire, analysed at the level of all patients, allowing for age, sex, general practitioner, and practice, and at the level of the individual general practitioner teacher. Qualitative analysis of focus group data. Results: Patients' enablement or satisfaction was not reduced after teaching consultations compared with non-teaching consultations (mean difference in scores on the patient enablement index and consultation satisfaction questionnaire with adjustment for confounders 2.24% and 1.70%, respectively). This held true for analysis by all patients and by general practitioner teacher. Qualitative data showed that patients generally supported the teaching of student doctors in their practice. However, this support was conditional on receiving sufficient information about reasons for doctors' absence, the characteristics of students, and the nature of teaching planned. Many patients viewed their general practice as different from hospital and expected greater control over students' presence during their consultations. Conclusions: Patients' enablement and satisfaction are not impaired by students' participation in consultations. Patients generally support the teaching of student doctors in their general practice but expect to be provided with sufficient information and to have a choice about participation, so they can give informed consent Recognising this when organising general practice based teaching is important.
\n \n\n \n \nBackground: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Objectives: To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. Search methods: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers. Selection criteria: We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. Data collection and analysis: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. Main results: Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low-quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80). One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development. We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease-specific subgroups of patients. The included studies covered 25,290 participants,\u00a011,801 of whom used varenicline. The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high-quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high-quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate-quality evidence). Four trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high-quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow-up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern. Authors' conclusions: Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research. Future trials of cytisine may test extended regimens and more intensive behavioural support.
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