Comparison of the welfare of beef cattle in housed and grazing systems: hormones, health, and behaviour.

Animal welfare encompasses all aspects of an animal's life and the interactions between animals. Consequently, welfare must be measured across a variety of factors that consider aspects such as health, behaviour, and mental state. Decisions regarding housing and grazing are central to farm management. In this study, two beef cattle systems and their herds were compared from weaning to slaughter across numerous indicators. One herd ("HH") were continuously housed, the other ("HG") were housed only during winter. Inspections of animals were conducted to assess body condition, cleanliness, diarrhoea, hairlessness, nasal discharge, and ocular discharge. Hair and nasal mucus samples were taken for quantification of cortisol and serotonin. Qualitative behaviour assessments (QBA) were also conducted and performance monitored. Physical health indicators were similar between herds with the exception of nasal discharge which was more prevalent in HH (P < 0.001). During winter, QBA yielded differences between herds over PC1 (arousal) (P = 0.032), but not PC2 (mood) (P = 0.139). Through summer, there was a strong difference across both PC1 (P < 0.001) and PC2 (P = 0.002), with HG exhibiting more positive behaviour. A difference was found in hair cortisol levels, with the greatest concentrations observed in HG (P = 0.011), however such a pattern was not seen for nasal mucus cortisol, or for serotonin. Overall, providing summer grazing (HG) appeared to afford welfare benefits to the cattle as shown with more positive QBA assessments, but also slightly better health indicators, notwithstanding the higher levels of cortisol in that group.

V-QBA vs. QBA-How Do Video and Live Analysis Compare for Qualitative Behaviour Assessment?

Animal welfare is an inextricable part of livestock production and sustainability. Assessing welfare, beyond physical indicators of health, is challenging and often relies on qualitative techniques. Behaviour is a key component of welfare to consider and Qualitative Behaviour Assessment (QBA) aims to achieve this by systematically scoring behaviour across specific terms. In recent years, numerous studies have conducted QBA by using video footage, however, the method was not originally developed using video and video QBA (V-QBA) requires validation. Forty live QBAs were conducted, by two assessors, on housed beef cattle to help fill this validation gap. Video was recorded over the assessment period and a second video assessment was conducted. Live and video scores for each term were compared for both correlation and significant difference. Principle component analysis (PCA) was then conducted and correlations and differences between QBA and V-QBA for the first two components were calculated. Of the 20 terms, three were removed due to an overwhelming majority of scores of zero. Of the remaining 17 terms, 12 correlated significantly, and a significant pairwise difference was found for one ("Bored"). QBA and V-QBA results correlated across both PC1 (defined as "arousal") and PC2 (defined as "mood"). Whilst there was no significant difference between the techniques for PC1, there was for PC2, with V-QBA generally yielding lower scores than QBA. Furthermore, based on PC1 and PC2, corresponding QBA and V-QBA scores were significantly closer than would be expected at random. Results found broad agreement between QBA and V-QBA at both univariate and multivariate levels. However, the lack of absolute agreement and muted V-QBA results for PC2 mean that caution should be taken when implementing V-QBA and that it should ideally be treated independently from live QBA until further evidence is published. Future research should focus on a greater variety of animals, environments, and assessors to address further validation of the method.

'Would it sell more pork?' Pig farmers' perceptions of Real Welfare, the welfare outcome component of their farm assurance scheme.

In the UK, the pig industry is leading the way in the adoption of welfare outcome measures as part of their farm assurance scheme. The welfare outcome assessment (WOA), known as Real Welfare, is conducted by the farmers' own veterinary surgeon. For the first time, this has allowed the pig industry to evaluate welfare by directly assessing the animal itself and to document the welfare of the UK pig industry as a whole. Farmer perspectives of the addition of a welfare outcome assessment to their farm assurance scheme have yet to be explored. Here, we investigate how the introduction of the Real Welfare protocol has been perceived by the farmers involved, what value it has (if any), whether any practical changes on farm have been a direct consequence of Real Welfare and ultimately whether they consider that the welfare of their pigs has been improved by the introduction of the Real Welfare protocol. Semi-structured interviews with 15 English pig farmers were conducted to explore their perceptions and experiences of the Real Welfare process. Our findings fall into three key areas: the lived experience of Real Welfare, on-farm changes resulting from Real Welfare and suggested improvements to the Real Welfare process as it currently stands. In all the three areas, the value farmers placed on the addition of WOA appeared to reflect their veterinary surgeon's attitude towards the Real Welfare protocol. If the vet was engaged in the process and actively included the farmer, for example through discussion of their findings, the farmers interviewed had a greater appreciation of the benefits of Real Welfare themselves. It is recommended that future similar schemes should work with veterinary surgeons to ensure their understanding and engagement with the process, as well as identifying and promoting how the scheme will practically benefit individual farmers rather than assuming that they will be motivated to engage for the good of the industry alone. Retailers should be encouraged to use Real Welfare as a marketing tool for pig products to enhance the perceived commercial value of this protocol to farmers.

Identifying behavioural differences in working donkeys in response to analgesic administration.

REASONS FOR PERFORMING STUDY: To identify pain-related behaviour in working donkeys in order to assist their owners and veterinarians to recognise and manage pain. OBJECTIVES: To identify general and specific behaviours associated with pain or its relief using a trial with the nonsteroidal anti-inflammatory drug meloxicam (Metacam). STUDY DESIGN: Observer-blinded, placebo-controlled trial. METHODS: Forty adult male working donkeys with common clinical abnormalities were randomly assigned to receive either a single loading dose of meloxicam (1.2 mg/kg bwt per os; n = 20) or a placebo (30 mg honey/250 ml water per os; n = 20). Observation of postural and event behaviours was undertaken at 2 pretreatment time points followed by 4 post treatment time points, using scan (instantaneous) and focal sampling. RESULTS: In comparison to pretreatment baselines, donkeys receiving meloxicam were more alert post treatment than the placebo group. They were observed lying down less frequently (P = 0.007), with their eyes closed less frequently (P = 0.04) and having a high head carriage more frequently (P = 0.02). Dozing behaviour decreased after meloxicam compared with the pretreatment baseline (P = 0.03). Donkeys given meloxicam also showed more interest in their environment, turning to look at environmental stimuli more frequently (P = 0.05) than those in the placebo group post treatment. Neither the meloxicam nor the placebo group showed a significant post treatment improvement in lameness scores. CONCLUSIONS: Working donkeys receiving meloxicam were more active and alert compared with their pretreatment behaviour, confirming the potential value of nonsteroidal anti-inflammatory drugs in identifying behaviours indicative of pain in working donkeys. Behavioural assessment of pain in working donkeys in field clinic conditions will enable veterinary staff and owners to identify welfare issues promptly and monitor response to analgesia. The Summary is available in Chinese--see Supporting information.

Clinical abnormalities in working donkeys and their associations with behaviour.

INTRODUCTIONS: Working donkeys are at risk of developing multiple, acute and chronic health problems. The ability to recognise and assess pain in donkeys associated with these health problems is important for people responsible for their care and treatment, including owners and veterinary or animal health workers. AIMS AND OBJECTIVES: The aims of this study were firstly to quantify the prevalence of a range of clinical abnormalities within a sample of working donkeys; and secondly to find out whether these abnormalities were associated with potential behavioural indicators of pain. MATERIALS AND METHODS: One hundred and thirty-three entire male adult working donkeys were observed for ten minutes before and after a one-hour rest period. Using an ethogram developed and refined in associated studies, posture and event behaviours were recorded by a single observer. The health of each donkey was then assessed by a veterinarian for specific clinical abnormalities. RESULTS: Working donkeys have a high prevalence of clinical abnormalities and a number of behaviours are associated with these. Significant associations were found between observed behaviours and systemic, ocular and limb-related clinical abnormalities. Cumulative clinical scores for limb-related problems were associated with a higher frequency of leg trembling, knuckling of the forelimb, leg-lifting and weight-shifting behaviours (all R≥0.4; P<0.001) and with a lower frequency of weight-bearing evenly on all four feet (R=-0.458; P<0.001). CONCLUSIONS: The specific behaviour changes associated with clinical abnormalities identified in this study, together with general changes in demeanour identified in related studies, may be useful in assessing the presence and severity of pain in working donkeys and their response to medical and palliative interventions.

A systematic review of risk assessment strategies for populations at high risk of engaging in violent behaviour: update 2002-8.

BACKGROUND: This review systematically examines the research literature published in the period 2002-8 on structured violence risk assessment instruments designed for use in mental health services or the criminal justice system. It adopted much broader inclusion criteria than previous reviews in the same area in order to capture and summarise data on the widest possible range of available instruments. OBJECTIVES: To address two questions: (1) what study characteristics are associated with a risk assessment instrument score being significantly associated with a violent outcome? and (2) which risk assessment instruments have the highest level of predictive validity for a violent outcome? DATA SOURCES: Nineteen bibliographic databases were searched from January 2002 to April 2008, including PsycINFO, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, British Nursing Index, International Bibliography of the Social Sciences, Education Resources Information Centre, The Cochrane Library and Web of Knowledge. REVIEW METHODS: Inclusion criteria for studies were (1) evaluation of a structured risk tool; (2) outcome measure of interpersonal violence; (3) participants aged 17 years or over; and (4) participants with a mental disorder and/or at least one offence and/or at least one indictable offence. A series of bivariate analyses using either a chi-squared test or Spearman's rank-order correlation were conducted to explore associations between study characteristics and outcomes. Data from a subset of studies reporting area under the curve (AUC) analysis were combined to provide estimates of mean validity. RESULTS: For the overall set of included studies (n = 959), over three-quarters (77%) were conducted in the USA, Canada or the UK. Two-thirds of all studies were conducted with offenders who had either no formal mental health diagnosis (43%) or forensic samples with a formal diagnosis (25%). The Psychopathy Checklist-Revised was tested in the largest number of studies (n = 192). Most studies (78%) reported a statistically significant (p < 0.05) relationship between the instrument score and a violent outcome. Prospective data collection (chi-squared = 4.4, p = 0.035), number of people recruited (U = 27.8, p = 0.012) and number of participants at end point (U = 26.9, p = 0.04) were significantly associated with predictive validity. For those instruments tested in five or more studies reporting AUC values, the General Statistical Information on Recidivism instrument had the highest mean AUC (0.73). LIMITATIONS: Agreement between pairs of reviewers in the initial pilot exercises was good but less than perfect, so discrepancies may be present given the complexity and subjectivity of some aspects of violence research. Only five of the seven calendar years (2003-7) are completely covered, with partial coverage of 2002 and 2008. There is no weighting for sample or effect sizes when results from studies are aggregated. CONCLUSIONS: A very large number of studies examining the relationship between a structured instrument and a violent outcome were published in this relatively short 7-year period. The general quality of the literature is weak in places (e.g. over-reliance on cross-sectional designs) and a vast range of distinct instruments have been tested to varying degrees. However, there is evidence of some convergence around a small number of high-performing instruments and identification of the components of a high-quality evaluation approach, including AUC analysis. The upper limits (AUC ≥ 0.85) of instrument-based prediction have probably been achieved and are unlikely to be exceeded using instruments alone. FUNDING: The National Institute for Health Research Health Technology Assessment and Research for Patient Benefit programmes.

The use of equipment and training practices and the prevalence of owner-reported ridden behaviour problems in UK leisure horses.

REASONS FOR PERFORMING STUDY: UK leisure horses are owned primarily for riding. Ridden behaviour problems may compromise the use of the horse in this role and lead to harsh redress or relinquishment of the horse. Despite the consequences of these problems little is known about their prevalence or the working lives of UK leisure horses. OBJECTIVES: To generate data on the work undertaken by leisure horses, the equipment and training practices used with them and prevalence of ridden behaviour problems. METHODS: An internet survey was used to generate horse-level data from a convenience sample of leisure horse carers. Respondents were asked to report on their practices in the week prior to the survey's completion to minimise recall bias. The survey was online for one year to allow for seasonal variation in practices. Data were collected on the tack and equipment used on the horse, the regularity that professional services (e.g. farriers) were used, type of training employed and frequency the owner reported that horse displayed 15 ridden behaviour problems. RESULTS: The survey generated data on 1326 individual horses. Data describing practices relating to the horse's working life are presented. Ridden behaviour problems were reported in 91% of horses in the week preceding data collection. CONCLUSIONS AND POTENTIAL RELEVANCE: Descriptive data on the working lives of UK leisure horses provides valuable baseline statistics for this largest section of the UK horse population. High prevalence of owner-reported ridden behaviour problems represents a concern in such leisure horses and may indicate significant rider safety and horse welfare concerns.

A systematic review of the clinical effectiveness and cost-effectiveness of Pharmalgen® for the treatment of bee and wasp venom allergy.

BACKGROUND: Each year in the UK, there are between two and nine deaths from anaphylaxis caused by bee and wasp venom. Anaphylactic reactions can occur rapidly following a sting and can progress to a life-threatening condition within minutes. To avoid further reactions in people with a history of anaphylaxis to bee and wasp venom, the use of desensitisation, through a process known as venom immunotherapy (VIT), has been investigated and is in use in the UK. VIT consists of subcutaneous injections of increasing amounts of purified bee and/or wasp venom extract. Pharmalgen® products (ALK Abelló) have had UK marketing authorisation for VIT (as well as diagnosis) of allergy to bee venom (using Pharmalgen Bee Venom) and wasp venom (using Pharmalgen Wasp Venom) since March 1995. OBJECTIVE: This review assessed the clinical effectiveness and cost-effectiveness of Pharmalgen in providing immunotherapy to individuals with a history of type 1 [immunoglobulin E (IgE)-mediated] systemic allergic reaction to bee and wasp venom. DATA SOURCES: A comprehensive search strategy using a combination of index terms (e.g. Pharmalgen) and free-text words (e.g. allerg$) was developed and used to interrogate the following electronic databases: EMBASE, MEDLINE, The Cochrane Library. REVIEW METHODS: Papers were included if they studied venom immunotherapy using Pharmalgen (PhVIT) in patients who had previously experienced a systemic reaction to a bee and/or a wasp sting. Comparators were any alternative treatment options available in the NHS without VIT. Included outcomes were systemic reactions, local reactions, mortality, anxiety related to the possibility of future allergic reactions, health-related quality of life (QoL) and adverse reactions (ARs) to treatment. Cost-effectiveness outcomes included cost per quality-adjusted life-years (QALYs) gained. Because of the small number of published randomised controlled trials (RCTs), no meta-analyses were conducted. A de novo economic model was developed to assess the cost-effectiveness of PhVIT plus high-dose antihistamine (HDA) plus adrenaline auto-injector (AAI) plus avoidance advice in relation to two comparators. RESULTS: A total of 1065 citations were identified, of which 266 full-text papers were obtained. No studies were identified that compared PhVIT with any of the outlined comparators. When these criteria were widened to include different protocols and types of PhVIT administration, four RCTs and five quasi-experimental studies were identified for inclusion. The quality of included studies was poor, and none was conducted in the UK. Eight studies reported re-sting data (systemic reactions ranged from 0.0% to 36.4%) and ARs (systemic reactions ranged from 0.0% to 38.1% and none was fatal). No included studies reported quality of life. No published economic evidence relevant to the decision problem was identified. The manufacturer of PhVIT did not submit any clinical effectiveness or cost-effectiveness evidence to the National Institute for Health and Clinical Excellence in support of PhVIT. The results of the Assessment Group's (AG) base-case analysis show that the comparison of PhVIT + HDA + AAI versus AAI + HDA yields an incremental cost-effectiveness ratio (ICER) of £18,065,527 per QALY gained; PhVIT + HDA + AAI versus avoidance advice only yields an ICER of £7,627,835 per QALY gained. The results of the sensitivity analyses and scenario analyses showed that the results of the base-case economic evaluation were robust for every plausible change in parameter made. The results of the 'High Risk of Sting Patients' subgroup analysis show that PhVIT + HDA + AAI dominates both AAI + HDA and avoidance advice only (i.e. is less expensive and more effective). The 'VIT Anxiety QoL Improvement' subgroup analysis shows that PhVIT + HDA + AAI versus HDA + AAI has an ICER of £23,868 per QALY gained, and PhVIT + HDA + AAI versus avoidance advice only yields an ICER of £25,661 per QALY gained. LIMITATIONS: This review is limited to the use of Pharmalgen in the treatment of hymenoptera venom allergy and therefore does not assess the effectiveness of VIT in general. CONCLUSIONS: The current use of PhVIT in clinical practice in the NHS appears to be based on limited and poor-quality clinical effectiveness research. Available evidence indicates that sting reactions following the use of PhVIT are low and that the ARs related to treatment are minor and easily treatable. The results of the AG's de novo economic evaluation demonstrate that PhVIT + AAI + HDA compared with AAI + HDA and with avoidance advice only yields ICERs in the range of £8-20M per QALY gained. Two subgroups ('High Risk of Sting Patients' and 'VIT Anxiety QoL Improvement') were considered in the economic evaluation and the AG concludes that the use of PhVIT + AAI + HDA may be cost-effective in both groups. Future research should focus on clearly identifying groups of patients most likely to benefit from treatment and ensure that clinical practice is focussed on these groups. Furthermore, given the paucity of UK data in this area it would be informative if data could be collected routinely when VIT is administered in the NHS (e.g. rates of systemic adverse reactions to VIT, rates of systemic reactions to bee/wasp stings). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review of prevention and intervention strategies for populations at high risk of engaging in violent behaviour: update 2002-8.

BACKGROUND: It has been estimated that violence accounts for more than 1.6 million deaths worldwide each year and these fatal assaults represent only a fraction of all assaults that actually occur. The problem has widespread consequences for the individual and for the wider society in physical, psychological, social and economic terms. A wide range of pharmacological, psychosocial and organisational interventions have been developed with the aim of addressing the problem. This review was designed to examine the effectiveness of these interventions when they are developed in mental health and criminal justice populations. OBJECTIVE: To update a previous review that examined the evidence base up to 2002 for a wide range of pharmacological, psychosocial and organisational interventions aimed at reducing violence, and to identify the key variables associated with a significant reduction in violence. DATA SOURCES: Nineteen bibliographic databases were searched from January 2002 to April 2008, including PsycINFO (CSA) MEDLINE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), British Nursing Index/Royal College of Nursing, International Bibliography of the Social Sciences (IBSS), Education Resources Information Center (ERIC)/International ERIC, The Cochrane Library (Cochrane reviews, other reviews, clinical trials, methods studies, technology assessments, economic evaluations), Web of Science [Science Citation Index Expanded (SCIE), Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (A&HCI)]. REVIEW METHODS: The assessment was carried out according to accepted procedures for conducting and reporting systematic reviews, including identification of studies, application of inclusion criteria, data extraction and appropriate analysis. Studies were included in meta-analyses (MAs) if they followed a randomised control trial (RCT) design and reported data that could be converted into odds ratios (ORs). For each MA, both a fixed-effects model and a random-effects model were fitted, and both Q statistic and I2 estimates of heterogeneity were performed. RESULTS: A total of 198 studies were identified as meeting the inclusion criteria; of these, 51 (26%) were RCTs. Bivariate analyses exploring possible sources of variance in whether a study reported a statistically significant result or not, identified six variables with a significant association. An outcome was less likely to be positive if the primary intervention was something other than a psychological or pharmacological intervention, the study was conducted in an penal institution, the comparator was another active treatment or treatment as usual and if a between-groups design had been used. An outcome was more likely to be positive if it was conducted with people with a mental disorder. The variation attributable to these variables when added to a binary logistic regression was not large (Cox and Snell R(2) = 0.12), but not insignificant given the small number of variables included. The pooled results of all included RCTs suggested a statistically significant advantage for interventions over the various comparators [OR 0.59, 95% confidence interval (CI) 0.53 to 0.65, fixed effects; OR 0.35, 95% CI 0.26 to 0.49 random effects, 40 studies]. However, there was high heterogeneity {I(2) = 86, Q = 279 [degrees of freedom (df) = 39], p < 0.0001}, indicating the need for caution in interpreting the observed effect. Analysis by subgroups showed that most results followed a similar pattern, with statistically significant advantages of treatments over comparators being suggested in fixed- and/or random-effects models but in the context of large heterogeneity. Three exceptions were atypical antipsychotic drugs [OR 0.21, 95% CI 0.16 to 0.27, fixed effects; OR 0.24, 95% CI 0.14 to 0.43, random effects; 10 studies, I(2) = 72.2, Q = 32.4 (df = 9), p < 0.0001], psychological interventions [OR 0.63, 95% CI 0.48 to 0.83, fixed effects; OR 0.53, 95% CI 0.31 to 0.93, random effects; nine studies, I(2) = 62.1, Q = 21.1 (df = 8), p = 0.007] and cognitive behavioural therapy (CBT) as a primary intervention [OR 0.61, 95% CI 0.42 to 0.88, fixed effects; OR 0.61, 95% CI 0.37 to 0.99, random effects; seven studies, I(2) = 21.6, Q = 7.65 (df = 6), p = 0.26]. LIMITATIONS: The heterogenity of the included studies inhibits both robust MA and the clear application of findings to establishing improvements in clinical practice. CONCLUSIONS: Results from this review show small-to-moderate effects for CBT, for all psychological interventions combined, and larger effects for atypical antipsychotic drugs, with relatively low heterogeneity. There is also evidence that interventions targeted at mental health populations, and particularly male groups in community settings, are well supported, as they are more likely to achieve stronger effects than interventions with the other groups. Future work should focus on improving the quality of evidence available and should address the issue of heterogenity in the literature. FUNDING: The National Institute for Health Research Health Technology Assessment programme and the Research for Patient Benefit programme.

Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence consisted of the IRESSA Pan-ASian Study (IPASS); a phase III open-label randomised controlled trial conducted in 87 centres in East Asia which compared the use of gefitinib with paclitaxel/carboplatin in 1217 chemotherapy (CTX)-naive patients with stage IIIB/IV pulmonary adenocarcinoma. The manufacturer's submission focused on a subgroup of patients in IPASS who were epidermal growth factor receptor (EGFR) gene mutation-positive (M+) (n = 261; 21% of the total IPASS population). The primary clinical outcome was progression-free survival (PFS). Secondary outcomes included overall survival, clinically relevant improvement in quality of life and adverse events (AEs). Cost-effectiveness was measured in terms of incremental cost per quality-adjusted life-year (QALY). In the overall population, PFS was significantly longer in patients treated with gefitinib than in those treated with paclitaxel/carboplatin (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85; p < 0.0001). The manufacturer reported an incremental cost-effectiveness ratio (ICER) of 20,744 pounds per QALY gained for the target population. The probabilistic sensitivity analysis illustrated that for patients who are EGFR M+, gefitinib compared with doublet CTX was not likely to be cost-effective at what would usually be considered standard levels of willingness to pay for an additional QALY; the mean ICER for gefitinib EGFR M+ versus doublet CTX EGFR M+ was reported as 35,700 pounds per QALY. Additional analysis by the ERG included amendments to the base-case analysis, including an alternative approach to projecting survival, inclusion of two important additional comparators, sensitivity to EGFR M+ prevalence, and AE costs and disutilities. The manufacturer's submission provides clinical evidence to support the use of gefitinib in EGFR M+ patients with adenocarcinoma histology only. Before patients can be offered first-line treatment with gefitinib they must undergo EGFR mutation status testing which is currently not routinely available in the NHS. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that 'Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme'.

Systematic review and cost-effectiveness evaluation of 'pill-in-the-pocket' strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy.

BACKGROUND: Atrial fibrillation (AF) is a tachyarrhythmia characterised by uncoordinated atrial activation with consequent deterioration of impairment of atrial function and a rapid, irregular heartbeat. The annual incidence rate of paroxysmal AF (PAF) has been estimated at 1.0 per 1000 person-years (95% confidence interval 0.9 to 1.1), and reported prevalence rates show wide variations depending on age and country. Conventional treatment strategies for PAF focus on the suppression of paroxysms of AF and return to normal sinus rhythm. OBJECTIVES: To summarise the results of the rapid reviews of the clinical effectiveness and cost-effectiveness literature describing the pill-in-the-pocket (PiP) approach for the treatment of patients with PAF; and to develop an economic model to assess the cost-effectiveness of PiP compared with in-hospital treatment (IHT) or continuous antiarrhythmic drugs (AADs) for the treatment of patients with PAF. DATA SOURCES: Ovid MEDLINE and Ovid OLDMEDLINE 1950 to present with Daily Update were searched. The following electronic databases were searched for ongoing trials: Health Services Research Projects in Progress, ClinicalTrials.gov, metaRegister of Current Controlled Trials, BioMed Central, World Health Organization International Clinical Trials Registry Platform, ClinicalStudyResults.org and the National Library of Medicine Gateway. REVIEW METHODS: Inclusion criteria, which included patients suffering from PAF, were independently applied to all identified references by two reviewers (JH and CMS). Electronic searches were conducted to identify clinical effectiveness and cost-effectiveness evidence describing the use of a PiP strategy for the treatment of PAF, published since the release of the Royal College of Physicians' national guidelines on AF in June 2006. A Markov model was constructed to examine differences between three PAF strategies (PiP, AAD and IHT) in terms of cost per quality-adjusted life-year (QALY). A Markov model structure was chosen because it is assumed that PAF is a condition that causes patients to move between a limited number of relevant health states during their lives. RESULTS: The search strategies for clinical studies identified 201 randomised controlled trials (RCTs). Of the 201 RCTs identified, 12 were deemed to be relevant to the decision problem as they included drugs used to treat PAF; summary data were abstracted from these studies in order to inform the development of the economic model only. The model results indicate that the PiP strategy is slightly less effective than the other two strategies, but also less costly (incremental cost-effectiveness ratio of 45,916 pounds per QALY when compared to AAD, and 12,424 pounds per QALY when compared to IHT). The one-way sensitivity analyses performed do not show substantial changes in relative cost-effectiveness except in relation to the age of patients, where PiP dominates AAD in men over 65 years and in women over 70 years. At a threshold of 25,000 pounds per QALY, IHT has the maximum probability of being cost-effective at this threshold. For threshold values between 0 pounds and 9266 pounds per QALY, PiP is the option exhibiting the maximum probability of being cost-effective. The AAD strategy has a very poor probability of being cost-effective under any threshold. However, none of the strategies considered has more than a 40% probability of being cost-effective at a threshold of 25,000 pounds per QALY at any threshold level. This demonstrates the uncertainty around the parameters and its effect on the decision to choose any one strategy over the others. LIMITATIONS: Most of the data used to populate the model have been taken from studies with populations that do not match the patient population specified in the decision problem. Populating the model in this way was unavoidable as there was a paucity of published clinical effectiveness and cost-effectiveness data describing a PiP strategy for this highly specific group of patients. CONCLUSIONS: Overall, a PiP strategy seems to be slightly less effective (i.e. fewer QALYs gained) than AAD and IHT, but is associated with cost savings. A PiP strategy seems to be more efficacious and cost-effective than an AAD strategy in men over 65 years and women over 70 years, but this is principally due to a very slight difference in QALY gained by the PiP strategy. A change in clinical practice that includes the introduction of PiP may save costs, but also involves a reduction in clinical effectiveness compared to existing approaches used to treat patients with PAF. Uncertainty in the available clinical data means there was insufficient evidence to support a recommendation for the use of PiP strategy in patients with PAF. Further research should identify outcomes of interest such as adverse events and recurrent AF episodes in an RCT setting because the only clinical study addressing these issues, even partially, is not an RCT but a descriptive analysis. Patient preferences also need to be considered in any future research designs.

Rituximab for the treatment of rheumatoid arthritis.

This paper presents a summary of the evidence review group's critical review of the evidence for the clinical effectiveness and cost-effectiveness of rituximab for the treatment of severe rheumatoid arthritis (RA) following failure of previous therapy, including one or more tumour necrosis factor-alpha inhibitors (TNFi), compared with current standards of care, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's clinical evidence came from one randomised, placebo-controlled, double-blind trial (REFLEX--Random Evaluation of Long-term Efficacy of Rituximab in Rheumatoid Arthritis) comparing rituximab plus methotrexate (MTX) with placebo plus MTX in 517 patients with long-standing refractory RA. Rituximab plus MTX was more effective than placebo plus MTX across a range of primary and secondary outcome measures, e.g. American College of Rheumatology (ACR) responses, Health Assessment Questionnaire (HAQ). However, this evidence cannot be used directly to address the manufacturer's analysis of the decision problem because, in the REFLEX trial, rituximab was not compared with a relevant comparator (e.g. leflunomide or second or third TNFi). Long-term efficacy data for retreatment with rituximab are favourable, with an estimated mean time to retreatment of 307 days (n = 164). Evidence from a further five trials is presented as the basis for indirect comparisons with other disease-modifying antirheumatic drugs (DMARDs); however, it is not clear that all relevant clinical studies have been included in the indirect comparison exercise, the rationale for the choice of indirect comparison method adopted is unclear and the indirect comparison method used to adjust the ACR responses only uses a single value for the reference placebo. The submitted microsimulation Markov model was based upon the REFLEX trial. For the 'NICE-recommended' scenario and the 'sequential TNFi' scenario, the original submission reports incremental cost-effectiveness ratios (ICERs) of 14,690 pounds and 11,601 pounds per quality-adjusted life-year (QALY) gained respectively. After model assumptions were adjusted to more realistic estimates by the ERG, the ICERs for the NICE-recommended scenario and the sequential use of TNFi range from 37,002 pounds to 80,198 pounds per QALY gained and from 28,553 pounds to 65,558 pounds per QALY gained respectively. The guidance issued by NICE in August 2007 states that rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other DMARDs including treatment with at least one TNFi therapy.

Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma.

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group - Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHS's current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturer's economic model after altering several of the assumptions and parameter values in order to recalculate the cost-utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental cost-effectiveness ratio of 7721 pounds per QALY gained. The greatest clinical effectiveness is achieved by R-CHOP followed by rituximab maintenance (R-CHOP>R) and this treatment strategy had the greatest probability of being cost-effective for a QALY of approximately 18,000 pounds or greater. The guidance issued by NICE as a result of the STA states that in people with relapsed stage III or IV follicular NHL, rituximab is now an option in combination with chemotherapy to induce remission or alone as maintenance therapy during remission. Rituximab monotherapy is also an option for people with relapsed or refractory disease when all alternative treatment options have been exhausted.

Erlotinib for the treatment of relapsed non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of erlotinib for the treatment of relapsed non-small cell lung cancer (NSCLC), according to its licensed indication, based upon the evidence submission from Roche Products to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence includes one randomised controlled trial (RCT) (BR21) investigating the effect of erlotinib versus placebo, which demonstrates that erlotinib significantly increases median overall survival, progression-free survival and response rate compared with placebo. The majority of patients in the trial experienced non-haematological drug-related adverse effects. Currently there are no trials that directly compare erlotinib with any other second-line chemotherapy agent. For the purposes of indirect comparison, the manufacturer's submission provides a narrative discussion of data from 11 RCTs investigating the use of docetaxel. From these data the manufacturer concludes that erlotinib has similar clinical efficacy levels to docetaxel but results in fewer serious haematological adverse events; however, it is difficult to compare the results of BR21 with those of the docetaxel trials or with current UK clinical practice because, for example, the BR21 patient population is younger than that expected to present in UK clinical practice and almost half of the BR21 participants received erlotinib as third-line chemotherapy, with third-line chemotherapy being rare in the UK. The manufacturer's submission included a three-state model comparing erlotinib with docetaxel, reporting an incremental cost-effectiveness ratio (ICER) of 1764 pounds per quality-adjusted life-year (QALY) gained for erlotinib compared with docetaxel. Rerunning the manufacturer's economic model with varied parameters and assumptions increases the ICER to in excess of 52,000 pounds per QALY gained. There is still a large amount of unquantifiable uncertainty in the model and it is unlikely that erlotinib could be considered to be cost-effective compared with docetaxel at a willingness to pay of 30,000 pounds and there may even be the potential for docetaxel to dominate erlotinib. Because of the limitations of the indirect analysis undertaken by the manufacturer and the subsequent economic modelling exercise there is a need for a head-to-head trial comparing erlotinib with docetaxel. The guidance issued by NICE in February 2007 as a result of the STA states that erlotinib is not recommended for the treatment of locally advanced or metastatic NSCLC.

The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of central venous catheters (CVCs) treated with anti-infective agents in preventing catheter-related bloodstream infection (CRBSI). DATA SOURCES: Major electronic databases were searched from 1985 to August 2005. REVIEW METHODS: The systematic clinical and economic reviews were conducted according to accepted procedures. Only full economic evaluations (synthesis of costs and benefits) comparing the use of anti-infective central venous catheters (AI-CVCs) with untreated CVCs or other treated catheters were selected for inclusion in the economic review. RESULTS: A total of 32 trials met the clinical inclusion criteria. Seven different types of AI-CVC were identified, with the most frequently tested being chlorhexidine and silver sulfadiazine (CHSS) (externally treated), CHSS (externally and internally treated) and minocycline rifampicin (internally and externally treated). In general, the trials were of a poor quality in terms of reported methodology, microbiological relevance and control of confounding variables. The pooled result suggests a statistically significant advantage for AI-CVCs in comparison to standard catheters in reducing CRBSI [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.34 to 0.60, 24 studies, I-squared = 0%, fixed effects]. Analysis by subgroups of catheters demonstrates that antibiotic-treated catheters and catheters treated internally and externally decrease CRBSI rates significantly (OR 0.26, 95% CI 0.15 to 0.46, six studies, I-squared = 0%, fixed effects, and OR 0.43, 95% CI 0.26 to 0.70, nine studies, I-squared = 0%, fixed effects, respectively). Catheters treated only externally demonstrate a wider CI and non-significant effect (OR 0.67, 95% CI 0.43 to 1.06, nine studies, I-squared = 0%, fixed effects). A treatment effect was also found for trials with an average duration of between 5 and 12 days, and for the one study with a mean duration of over 20 days. There was a statistically significant treatment effect for both femoral and jugular insertion sites and for those studies reporting a mix of insertion sites. The treatment effect was not observed in trials using exclusively subclavian insertion sites. Of the four trials that compared treated catheters, one reported a benefit of antibiotic-treated catheters over catheters treated externally with CHSS. All three sensitivity analyses testing for study design differences reported a statistically significant treatment effect. The review was limited owing to the quality of the trials included, marked differences in the definitions and methods of diagnosis of CRBSI, and inconsistent reporting of risk factors and patient population factors. Furthermore, two-thirds of trials were commercially funded. The economic performance (cost-effectiveness and potential cost-savings) of using AI-CVCs to reduce the number of CRBSIs in patients requiring a CVC was also reviewed. Results show that the use of AI-CVCs instead of standard CVCs can lead to a reduction in CRBSIs and decreased medical costs. To complement the reviews, a basic decision-analytic model was constructed to explore a range of possible scenarios for the NHS in England and Wales. Results show that for every patient who receives an AI-CVC there is an estimated cost-saving of 138.20 pounds. The multivariate sensitivity analyses estimate potentially large cost-savings, depending on the size of the population, under a wide range of cost and clinical assumptions. However, those considering the purchase of AI-CVCs should ensure that their patient populations and the important characteristics of local clinical practice are indeed similar to those described in this economic evaluation. CONCLUSIONS: Overall, AI-CVCs are clinically effective and relatively inexpensive and therefore their integration into clinical practice can be justified. However, the use of these anti-infective catheters without the appropriate use of other practical care initiatives will have only a limited success on the prevention of CRBSIs. Comparative trials are required to determine which, if any, of the treated catheters is the most effective. Pragmatic research related to the effectiveness of bundles of care that may reduce rates of CRBSI is also warranted.

First Report of Downy Mildew of Quinoa Caused by Peronospora farinosa f. sp. chenopodii in Denmark.

Downy mildew, caused by Peronospora farinosa (Fr.) Fr. f. sp. chenopodii Byford, is the most important disease of quinoa (Chenopodium quinoa Willd.) in the high mountainous areas of the Andes in South America (1), where the crop originated. While quinoa is not well known outside its traditional growing area, interest in this crop is increasing rapidly due to its high nutrient quality, many uses for human consumption, and agronomic characteristics of the plant; it is one of the most drought, salt, and frost tolerant crops known (2). From 1990 to 2001, several field trials were conducted in Denmark to study the performance of quinoa germ plasm of different origin under Danish conditions. Natural infection by downy mildew was observed each year on a range of cultivars, as well as on the common weed species, C. album L., which was observed growing near the quinoa. In 2001, 25 isolates of P. farinosa were collected from a field trial at the experimental station of the Royal Veterinary and Agricultural University in Taastrup, Denmark, from two Dutch quinoa cultivars (Carmen and Atlas) and one Danish breeding line (G205). Plants showed typical downy mildew symptoms: chlorotic lesions on the upper leaf surface and grayish spore masses on the lower leaf surface. Microscopic examination of the material showed the presence of dichotomously branched sporangiophores (200 to 400 µm long), which tapered to a blunt point and produced ellipsoidal, light brown sporangia with mean dimensions of 22 × 18 µm. The isolates were propagated and maintained by inoculation of detached quinoa leaves of two highly susceptible Peruvian cultivars (Toledo and Pandela) with a sporangium suspension (105 sporangia per ml), followed by incubation on water agar plates (10 to 15 leaves per plate) at 15°C and 12 h light/dark for 9 to 11 days. All isolates grew readily on these cultivars, and microscopic examination of the pathogen showed the same morphology as the original isolate. When the isolates were tested for their virulence on a range of quinoa cultivars with different geographic origin, specific interactions between host genotype and pathogen isolate were observed, measured as the degree of sporulation in the detached leaf assay, suggesting the presence of several pathotypes. To our knowledge, this is the first report of P. farinosa on quinoa in Denmark. Downy mildew should be considered as a potential problem for future large-scale quinoa production in Europe. References: (1) S. Danielsen. (Abstr.) Phytopathology 90(suppl):S17, 2000. (2) N. W. Galwey. Biologist 36:267, 1989.

Treatment with the Mycoparasite Pythium oligandrum Triggers Induction of Defense-Related Reactions in Tomato Roots When Challenged with Fusarium oxysporum f. sp. radicis-lycopersici.

ABSTRACT The influence exerted by the mycoparasite Pythium oligandrum in triggering plant defense reactions was investigated using an experimental system in which tomato plants were infected with the crown and root rot pathogen Fusarium oxysporum f. sp. radicis-lycopersici. To assess the antagonistic potential of P. oligandrum against F. oxysporum f. sp. radicis-lycopersici, the interaction between the two fungi was studied by scanning and transmission electron microscopy (SEM and TEM, respectively). SEM investigations of the interaction region between the fungi demonstrated that collapse and loss of turgor of F. oxysporum f. sp. radicis-lycopersici hyphae began soon after close contact was established with P. oligandrum. Ultrastructural observations confirmed that intimate contact between hyphae of P. oligandrum and cells of the pathogen resulted in a series of disturbances, including generalized disorganization of the host cytoplasm, retraction of the plasmalemma, and, finally, complete loss of the protoplasm. Cytochemical labeling of chitin with wheat germ agglutinin (WGA)/ovomucoid-gold complex showed that, except in the area of hyphal penetration, the chitin component of the host cell walls was structurally preserved at a time when the host cytoplasm had undergone complete disorganization. Interestingly, the same antagonistic process was observed in planta. The specific labeling patterns obtained with the exoglucanase-gold and WGA-ovomucoid-gold complexes confirmed that P. oligandrum successfully penetrated invading cells of the pathogen without causing substantial cell wall alterations, shown by the intense labeling of chitin. Cytological investigations of samples from P. oligandrum-inoculated tomato roots revealed that the fungus was able to colonize root tissues without inducing extensive cell damage. However, there was a novel finding concerning the structural alteration of the invading hyphae, evidenced by the frequent occurrence of empty fungal shells in root tissues. Pythium ingress in root tissues was associated with host metabolic changes, culminating in the elaboration of structural barriers at sites of potential fungal penetration. Striking differences in the extent of F. oxysporum f. sp. radicis-lycopersici colonization were observed between P. oligandrum-inoculated and control tomato plants. In control roots, the pathogen multiplied abundantly through much of the tissues, whereas in P. oligandrum-colonized roots pathogen growth was restricted to the outermost root tissues. This restricted pattern of pathogen colonization was accompanied by deposition of newly formed barriers beyond the infection sites. These host reactions appeared to be amplified compared to those seen in nonchallenged P. oligandrum-infected plants. Most hyphae of the pathogen that penetrated the epidermis exhibited considerable changes. Wall appositions contained large amounts of callose, in addition to be infiltrated with phenolic compounds. The labeling pattern obtained with gold-complexed laccase showed that phenolics were widely distributed in Fusarium-challenged P. oligandrum-inoculated tomato roots. Such compounds accumulated in the host cell walls and intercellular spaces. The wall-bound chitin component in Fusarium hyphae colonizing P. oligandrum-inoculated roots was preserved at a time when hyphae had undergone substantial degradation. These observations provide the first convincing evidence that P. oligandrum has the potential to induce plant defense reactions in addition to acting as a mycoparasite.