Implementation of Early Intervention Protocol in Australia for 'High Risk' Injured Workers is Associated with Fewer Lost Work Days Over 2 Years Than Usual (Stepped) Care.

Purpose To evaluate whether a protocol for early intervention addressing the psychosocial risk factors for delayed return to work in workers with soft tissue injuries would achieve better long-term outcomes than usual (stepped) care. Methods The study used a controlled, non-randomised prospective design to compare two case management approaches. For the intervention condition, workers screened within 1-3 weeks of injury as being at high risk of delayed returned to work by the Örebro Musculoskeletal Pain Screening Questionnaire-short version (ÖMPSQ-SF) were offered psychological assessment and a comprehensive protocol to address the identified obstacles for return to work. Similarly identified injured workers in the control condition were managed under usual (stepped) care arrangements. Results At 2-year follow-up, the mean lost work days for the Intervention group was less than half that of the usual care group, their claim costs were 30% lower, as was the growth trajectory of their costs after 11 months. Conclusions The findings supported the hypothesis that brief psychological risk factor screening, combined with a protocol for active collaboration between key stakeholders to address identified psychological and workplace factors for delayed return to work, can achieve better return on investment than usual (stepped) care.

Correction to: Implementation of Early Intervention Protocol in Australia for 'High Risk' Injured Workers is Associated with Fewer Lost Work Days Over 2 Years Than Usual (Stepped) Care.

The original version of this article unfortunately contained a spelling error in one of the co-authors's names. The family name of the co-author was incorrectly displayed as "James McCauley" instead of "James McAuley. The original article has been corrected.

The Development and Content of the Vocational Advice Intervention and Training Package for the Study of Work and Pain (SWAP) Trial (ISRCTN 52269669).

Purpose There are substantial costs associated with sickness absence and struggling at work however existing services in the UK are largely restricted to those absent from work for greater than 6 months. This paper details the development of an early Vocational Advice Intervention (VAI) for adult primary care consulters who were struggling at work or absent due to musculoskeletal pain, and the structure and content of the training and mentoring package developed to equip the Vocational Advisors (VAs) to deliver the VAI, as part of the Study of Work and Pain (SWAP) cluster randomised trial. Methods In order to develop the intervention, we conducted a best-evidence literature review, summarised evidence from developmental studies and consulted with stakeholders. Results A novel early access, brief VAI was developed consisting of case management and stepped care (three steps), using the Psychosocial Flags Framework to identify and overcome obstacles associated with the health-work interface. Four healthcare practitioners were recruited to deliver the VAI; three physiotherapists and one nurse (all vocational advice was actually delivered by the three physiotherapists). They received training in the VA role during a 4-day course, with a refresher day 3 months later, along with monthly group mentoring sessions. Conclusions The process of development was sufficient to develop the VAI and associated training package. The evidence underpinning the VAI was drawn from an international perspective and key components of the VAI have the potential to be applied to other settings or countries, although this has yet to be tested.

Predicting Return to Work in a Heterogeneous Sample of Recently Injured Workers Using the Brief ÖMPSQ-SF.

Purpose (1) to examine the ability of the Örebro Musculoskeletal Pain Screening Questionnaire-short version (ÖMPSQ-SF) to predict time to return to pre-injury work duties (PID) following a work-related soft tissue injury (regardless of body location); and (2) to examine the appropriateness of 50/100 as a suitable cut-off score for case identification. Methods Injured workers (IW) from six public hospitals in Sydney, Australia, who had taken medically-sanctioned time off work due to their injury, were recruited by insurance case managers within 5-15 days of their injury. Eligible participants (N = 213 in total) were administered the ÖMPSQ-SF over the telephone by the case manager. For objective (1) Cox proportional hazards regression analysis was used to predict days to return to PID using the ÖMPSQ-SF. For objective (2) receiver operator characteristic (ROC) analysis was used to determine the ÖMPSQ-SF total score that optimises sensitivity and specificity in detecting whether or not participants had returned to PID within 2-7 weeks. Results The total ÖMPSQ-SF score significantly predicted number of days to return to PID, such that for every 1-point increase in the total ÖMPSQ-SF score the predicted chance of returning to work reduced by 4% (i.e., hazard ratio = 0.96), p < 0.001. Sensitivity and specificity for the ROC analysis comparing ÖMPSQ-SF total score to return to PID within 2-7 weeks suggested 48 as the optimal cut off (sensitivity = 0.65, specificity = 0.79). Conclusion The results provide strong support for the use of the ÖMPSQ-SF in an applied setting for identifying those IW likely to have delayed RTW when administered within 15 days of the injury. While a score of 48/100 was the optimal cut point for sensitivity and specificity, pragmatically, 50/100 should be acceptable as a cut-off in future studies of this type.

Implementing core NICE guidelines for osteoarthritis in primary care with a model consultation (MOSAICS): a cluster randomised controlled trial.

OBJECTIVE: To determine the effectiveness of a model osteoarthritis consultation, compared with usual care, on physical function and uptake of National Institute for Health and Care Excellence (NICE) osteoarthritis recommendations, in adults ≥45 years consulting with peripheral joint pain in UK general practice. METHOD: Two-arm cluster-randomised controlled trial with baseline health survey. Eight general practices in England. PARTICIPANTS: 525 adults ≥45 years consulting for peripheral joint pain, amongst 28,443 population survey recipients. Four intervention practices delivered the model osteoarthritis consultation to patients consulting with peripheral joint pain; four control practices continued usual care. The primary clinical outcome of the trial was the SF-12 physical component score (PCS) at 6 months; the main secondary outcome was uptake of NICE core recommendations by 6 months, measured by osteoarthritis quality indicators. A Linear Mixed Model was used to analyse clinical outcome data (SF-12 PCS). Differences in quality indicator outcomes were assessed using logistic regression. RESULTS: 525 eligible participants were enrolled (mean age 67.3 years, SD 10.5; 59.6% female): 288 from intervention and 237 from control practices. There were no statistically significant differences in SF-12 PCS: mean difference at the 6-month primary endpoint was -0.37 (95% CI -2.32, 1.57). Uptake of core NICE recommendations by 6 months was statistically significantly higher in the intervention arm compared with control: e.g., increased written exercise information, 20.5% (7.9, 28.3). CONCLUSION: Whilst uptake of core NICE recommendations was increased, there was no evidence of benefit of this intervention, as delivered in this pragmatic randomised trial, on the primary outcome of physical functioning at 6 months. TRIAL REGISTRATION: ISRCTN06984617.

Simulating pathways of subsurface oil in the Faroe-Shetland Channel using an ocean general circulation model.

Little is known about the fate of subsurface hydrocarbon plumes from deep-sea oil well blowouts and their effects on processes and communities. As deepwater drilling expands in the Faroe-Shetland Channel (FSC), oil well blowouts are a possibility, and the unusual ocean circulation of this region presents challenges to understanding possible subsurface oil pathways in the event of a spill. Here, an ocean general circulation model was used with a particle tracking algorithm to assess temporal variability of the oil-plume distribution from a deep-sea oil well blowout in the FSC. The drift of particles was first tracked for one year following release. Then, ambient model temperatures were used to simulate temperature-mediated biodegradation, truncating the trajectories of particles accordingly. Release depth of the modeled subsurface plumes affected both their direction of transport and distance travelled from their release location, and there was considerable interannual variability in transport.

Integrating physical and psychological approaches to treatment in low back pain: the development and content of the STarT Back trial's 'high-risk' intervention (StarT Back; ISRCTN 37113406).

A new randomised controlled trial of intervention in low back pain has been described recently. In this trial, a screening and targeted approach was found to be more effective and cost-effective than current best practice. Nested within the intervention arm were three different interventions targeting patients identified as 'low', 'medium' or 'high' risk dependent on the presence of (mainly) psychosocial risk factors. In this paper, the development and content of the STarT Back trial's 'high-risk' intervention is described. It offers a systematic approach, termed 'psychologically informed practice', to the integration of physical and psychological approaches to treatment for the management of people with low back pain by physiotherapists. The term 'disability' is used to refer to self-reported pain-associated functional limitations, and 'psychological' is used to refer to the beliefs/expectations, emotional responses and behavioural responses associated with low back pain.

Impacts on work performance; what matters 6 months on?

BACKGROUND: Presenteeism often precedes and follows a period of work absence. Cross-sectional analysis of a workforce survey highlighted health, psychosocial and work characteristics as being particularly important in understanding current work performance, but it is unclear whether these variables predict future work performance. AIMS: To establish whether self-reported health, perceptions of work and objective characteristics of work measured at baseline can predict performance at 6 months follow-up. METHODS: Self-completed questionnaires to assess health, objective characteristics of work and perceptions of work were completed at two public sector organizations. Follow-up questionnaires were completed at 6 months to assess workplace performance using a visual analogue scale for self-rated performance and the Stanford Presenteeism Scale 6 (SPS6). RESULTS: Five hundred and five employees completed questionnaires at baseline and 310 (61%) of these completed follow-up questionnaires. Psychological distress as measured with the General Health Questionnaire and perceptions of work predicted both self-rated performance and SPS6 score. Objective characteristics of work were relatively unimportant in the prediction of future performance. CONCLUSIONS: This study has provided an initial indication of the factors that may predict performance at follow-up in the population studied. These findings may be used to generate hypotheses for future studies and highlights the need to assess a range of factors in relation to an individual's performance at work including health and perceptions of work.

The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems.

BACKGROUND: Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations. OBJECTIVES: To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS. DATA SOURCES: A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion. REVIEW METHODS: CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated. RESULTS: Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (639 euros) in each of the intervention clinics compared with a 2% (208 euros) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from 41.8 euros per patient per annum to 47.2 euros after implementation of the system. LIMITATIONS: The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA. CONCLUSIONS: If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs. STUDY REGISTRATION: Study registration 61.

Sickness certification and the GP: what really happens in practice?

BACKGROUND: GPs typically sanction absence from work by issuing sickness certificates. There has been some debate recently about changing the way sickness certificates are issued and by whom. However, without understanding GPs' certification practices, their requirements in terms of training and education and how they feel the certification process should or should not be changed, measures aimed at improving the system are unlikely to succeed. OBJECTIVE: To investigate and describe British GPs' sickness certification practices. METHODS: A cross-sectional nationwide postal survey of 2154 UK GPs was conducted. GPs were asked about perceived certification practices, training in sickness certification, their opinions about the certification process and potential to improve the system. RESULTS: Adjusted response was 42% (n = 878). GPs do ask about a patient's work situation but lack training in sickness certification. GPs would like to maintain their role in sickness certification but felt there was scope for other health professionals to issue some sickness certificates. GPs report more frequent sickness certification for mental health and musculoskeletal conditions compared to any other condition. CONCLUSIONS: This study has highlighted the main issues that GPs face during a consultation where sickness certification is a possible outcome. Lack of training in certification was a recurrent theme. However, GPs felt there was scope to improve training and recommendations were made as to how this might be achieved. The survey has highlighted that GPs feel there are opportunities to improve the system and that other health professionals may play a role in the certification process.

Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

OBJECTIVES: To review the evidence on the clinical effects and associated treatment costs of surgical procedures and non-surgical devices for the management of non-apnoeic snoring. DATA SOURCES: Major electronic databases were searched for relevant studies published between 1980 and 2007. All treatment costs were estimated based on data from NHS reference costs, device manufacturers and clinical opinion. REVIEW METHODS: Studies were screened, data extracted and quality assessed according to standard methods. Results were broadly grouped according to the intervention and comparator when applicable, and further subgrouped according to the specific intervention type and study design. Results were combined using a narrative synthesis with relevant quantitative results tabulated. Differences between studies assessing the same intervention were explored narratively by examining differences in the intervention, study duration and study quality. RESULTS: The systematic review included 27 studies (three randomised controlled trials, two controlled clinical trials and 22 pre-post studies) reported in 30 publications assessing uvulopalatopharyngoplasty (UP3) versus laser-assisted uvulopalatoplasty (LAUP), UP3 alone, LAUP alone, palatal stiffening techniques (Pillar implants and injection snoreplasty), radiofrequency ablation (RFA) of the soft palate or tongue base, continuous positive airway pressure (CPAP) devices and mandibular advancement splints (MAS). Studies were generally of a low methodological quality with small sample sizes. A total of 1191 patients was included. Both UP3 and LAUP reduced the number of snores per hour and produced a modest reduction in snoring loudness. UP3 was effective in reducing a number of subjectively reported snoring indices, but results on objective measures were equivocal. Limited evidence indicates that subjectively assessed snoring is improved after LAUP; no objective measures were assessed. RFA was associated with a reduction in partner-assessed snoring intensity, though evidence for an objective reduction in snoring sound levels was mixed. Pillar implants were moderately effective at reducing partner-rated snoring intensity, but had no effect on objective snoring indices. Use of CPAP reduced the number of snores per hour; no subjective measures were evaluated. Use of MAS improved objective snoring outcomes, including the maximal snoring sound volume, the mean snoring sound volume and the percentage of time spent in loud snoring; no subjective measures were evaluated. The cost for UP3 ranges from approximately 1230 pounds to approximately 1550 pounds. For LAUP the cost varies from 790 pounds to 2070 pounds depending on the number of stages of the procedure. The treatment costs associated with the use of Pillar implants range from 1110 pounds to 1160 pounds. The approximate annual treatment costs associated with the use of a CPAP machine and MAS are 220 pounds and 130 pounds respectively. CONCLUSIONS: This study highlighted the paucity and poor quality of the evidence available on the effects of both surgical procedures and non-surgical devices for the management of primary snoring. Any conclusions to be drawn from the results are therefore somewhat tentative. There was no procedure that was clearly the least-cost option. Further research should focus on standardising methods of measuring outcomes and reporting, undertaking active controlled trials, and investigating the longer-term effects of treatments.

Should men with asymptomatic non-specific urethritis be identified and treated?

There is currently a debate as to whether microscopy is necessary in asymptomatic men presenting for a sexual health screen. Arguments favouring microscopy include finding chlamydia in a significant proportion of sexual partners of men with non-specific urethritis (NSU) in studies that included symptomatic men. We aimed to investigate the proportion of partners of men with asymptomatic NSU who were diagnosed with a sexually transmitted infection. A retrospective case-note review was carried out for all men diagnosed with asymptomatic pathogen-negative NSU, and their traced sexual contacts, during a nine-month period. As a result of contact-tracing, we identified 42 partners who attended the clinic. Only one partner (2.4%) tested positive for chlamydia. A further two partners were diagnosed with a viral sexually transmitted infection (STI). The low level of chlamydia and other STIs in partners of asymptomatic men with pathogen-negative NSU does not support the routine use of microscopy to identify these patients.

Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

OBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in adults and children aged over 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies was conducted. Cost comparison and cost-consequence analyses were performed where appropriate. RESULTS: The assessment of clinical effectiveness was based on the 67 randomised controlled trials selected from the 5175 reports identified through the systematic literature search. The most frequently reported relevant outcomes were lung function, symptoms, use of rescue medication and adverse events. The trials varied considerably. In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, there were few significant differences in clinical effectiveness, although a few of the trials had assessed non-inferiority between the comparators rather than superiority. At doses of 400, 800 and 'high-level' doses of 1500 or 1600 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. A significant treatment benefit for combination ICS/LABA therapy across a range of outcomes compared with ICS alone was identified [when the ICS was double the accepted clinically equivalent dose of the ICS in the combination inhaler, and dry powder inhalers (DPIS) were used to deliver the drugs]. When a formoterol fumarate (FF)/salmeterol (SAL) combination inhaler and a budesonide (BUD)/FF combination inhaler were each compared with their constituent drugs delivered in separate inhalers, there were very few statistically significant differences between the treatments across the various efficacy outcomes and the rate of adverse events. Combination inhalers were more often cheaper than doubling the dose of ICS alone. However, the costs were highly variable and dependent on both the dose required and the preparation used in the trials. The estimated mean annual cost of FP/SAL combination varied from being 94 pounds cheaper to 109 pounds more expensive than the alternative of BUD at a higher dose. The BUD/FF combination varied from being 163 pounds cheaper to 66 pounds more expensive than the higher dose of either BUD or FP. When the combination inhalers were compared to each other, the results were mixed, with the FP/SAL combination significantly superior on some outcomes and the BUD/FF combination superior on others; however, meta-analysis showed that there were no significant differences between the two treatments in the rate of adverse events. Taking an ICS with a LABA as either of the two currently available combination products, FP/SAL and BUD/FF, is usually cheaper than taking the relevant constituent drugs in separate inhalers. At very high doses of BUD (1600 microg/day), however, the BUD/FF combination inhaler can be up to 156 pounds more expensive than having the same drugs in separate inhalers. In terms of the relative costs associated with taking one of the combination inhalers, at low dose (400 microg BUD or 200 microg FP/day) the cheapest combination inhaler is FP/SAL as a pressurised metered dose inhaler (pMDI) (Seretide Evohaler). However, this is only slightly cheaper than using BUD/FF as a DPI (Symbicort Turbohaler). At higher dose levels (800 microg BUD or 500 microg FP/day) FP/SAL as either pMDI aerosol (Seretide Evohaler) or a DPI (Seretide Accuhaler) is the cheapest combination product available, but again only slightly cheaper than the DPI BUD/FF combination (Symbicort Turbohaler). It should be highlighted, however, that the three head-to-head trials that compared the effects of FP/SAL with BUD/FF used the FP/SAL DPI combination inhaler, Seretide Accuhaler. CONCLUSIONS: The evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available and tend to remain so as the daily ICS dose required increases. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed for all outcome measures. The cost differences between combination therapy compared with ICS monotherapy are highly variable and dependent on the dose required and the particular preparations used. For the combination therapies of ICS/LABA there are potential cost savings with the use of combination inhalers compared with separate inhalers, with few differences between the two treatment strategies in terms of effects. The only exception to this cost saving is with BUD/FF at doses higher than 1200 microg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. Neither of the two combination inhalers (FP/SAL or BUD/FF) is consistently superior in terms of treatment effect. A comparison of the costs associated with each combination therapy indicates that at low dose FP/SAL delivered via a pMDI is currently the cheapest combination inhaler but only marginally cheaper than BUD/FF delivered as a DPI. At higher doses, both the FP/SAL combination inhalers (PMDI and DPI) are marginally cheaper than BUD/FF (DPI). Future trials of treatment for chronic asthma should standardise the way in which outcome measures are defined and measured, with a greater focus on patient-centred outcomes. For informing future cost-utility and cost-effectiveness analyses from a UK NHS perspective, there is a need for longitudinal studies that comprehensively track the care pathways followed when people experience asthma exacerbations of different severity. Further research synthesis, quantifying the adverse effects of the different ICS, is required for treatment choices by patients and clinicians to be fully informed.

Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in children under the age of 12 years.

OBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in children aged under 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies and economic analyses were carried out. A flexible framework was used to allow different types of economic analyses as appropriate, with either a cost comparison or cost-consequence comparison conducted. RESULTS: Of 5175 records identified through systematic literature searching, 34 records describing 25 studies were included (16 were fully published randomised controlled trials, six were systematic reviews, and three were post-2004 conference abstracts). The most frequently reported relevant outcomes in the 16 RCTs were peak expiratory flow rate (13 trials), FEV1 (13 trials), symptoms (13 trials), adverse events or exacerbations (13 trials), use of rescue medication (12 trials), markers of adrenal function (e.g. blood or urine cortisol concentrations) (13 trials), height and/or growth rate (seven trials) and markers of bone metabolism (two trials). In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, no consistent significant differences or patterns in differential treatment effect among the outcomes were evident. Where differences were statistically significant at high doses, such as for lung function and growth, they favoured formoterol fumarate (FF), but this was generally in studies that did not compare the ICS at the accepted clinically equivalent doses. Differences between the drugs in impact on adrenal suppression were only significant in two studies. At doses of 200, 400 and 800 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. In the trials comparing ICS at a higher dose with ICS and LABA in combination, most outcomes favoured the combined inhaler. Only the combination inhaler, Seretide Evohaler, is slightly cheaper than the weighted mean cost of all types of ICS at increased dose except BDP 400 microg/day (including CFC-propelled products). Both the combination inhalers, Seretide Accuhaler and Symbicort Turbohaler, are more expensive than the weighted mean cost for all types of ICS at a two-fold increased dose. Compared with the lowest cost preparation for each ICS drug, all the combination inhalers are always more expensive than the ICS products at increased dose. CONCLUSIONS: The limited evidence available indicates that there are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. BDP CFC-propelled products are often the cheapest ICS currently available at both low and high dose, and may remain so even when CFC-propelled products are excluded. Exclusion of CFC-propelled products increases the mean annual cost of all budesonide (BUD) and BDP, while the overall cost differences between the comparators diminish. There is very limited evidence available for the efficacy and safety of ICS and LABAs in children. From this limited evidence, there appear to be no significant clinical differences in effects between the use of a combination inhaler versus the same drugs in separate inhalers. There is a lack of evidence comparing ICS at a higher dose with ICS and LABA in combination and comparing the combination products with each other. In the absence of any evidence concerning the effectiveness of ICS at higher dose with ICS and LABA, a cost-consequence analysis gives mixed results. There are potential cost savings with the use of combination inhalers compared to separate inhalers. At present prices, the BUD/FF combination is more expensive than those containing FP/SAL, but it is not known whether there are clinically significant differences between them. A scoping review is required to assess the requirements for additional primary research on the clinical effectiveness of treatment for asthma in children under 5 years old. Such a review could also usefully include all treatment options, pharmacological and non-pharmacological, for asthma. A direct head-to-head trial that compares the two combination therapies of FP/SAL and BUD/FF is warranted, and it is important to assess whether the addition of a LABA to a lower dose of ICS could potentially be as effective as an increased dose of ICS alone, but also be steroid sparing. There is also a need for the long-term adverse events associated with ICS use to be assessed systematically. Future trials of treatment for chronic asthma in children should aim to standardise further the way in which outcome measures are defined. There should be a greater focus on patient-centred outcomes to provide a more meaningful estimation of the impact of treatment on asthma control. Methods of reporting also require standardisation.

Alcohol consumption and psychological distress in patients with psoriasis.

BACKGROUND: Psoriasis has been associated with excessive alcohol consumption and psychological distress. OBJECTIVES: To investigate the level of alcohol use in a psoriasis population and to determine whether alcohol consumption is linked to psychological distress in patients with psoriasis. METHODS: Ninety-five patients with chronic plaque psoriasis completed validated questionnaires designed to assess psychological distress, current and past alcohol consumption and self-reported physical severity of psoriasis. RESULTS: Using different measures of alcohol consumption, between 17% and 30% of patients were classified as having difficulties with alcohol. Thirteen per cent and 18% of patients with psoriasis believed that they had a current or past drinking problem, respectively. There was a modest but significant association between levels of anxiety and depression and weekly alcohol consumption (r = 0.29, P < 0.01 and r = 0.24, P = 0.03, respectively). Those patients who believed that they had an alcohol problem had higher levels of anxiety (P = 0.03), depression (P < 0.01) and psoriasis-associated disability (P = 0.04). There was a modest but significant association between physical severity of psoriasis and weekly alcohol consumption (r = 0.27, P = 0.02). CONCLUSIONS: A significant minority of patients with psoriasis consumes excessive alcohol. Patients with psoriasis should be assessed for excessive alcohol use and appropriate interventions initiated. Further studies are required to investigate whether such interventions are effective in combating alcohol abuse and in improving the psychological and physical aspects of psoriasis.

Cryptococcosis in Gilbert's and long-nosed potoroo.

Two cases of fatal cryptococcosis are described, one of Cryptococcus neoformans infection in a Gilbert's potoroo (Potorous gilbertii) and one of Cryptococcus gattii infection in a long-nosed potoroo (Potorous tridactylus). The diagnoses were confirmed by culture and specific immunohistochemistry, respectively. The long-nosed potoroo tested positive using the latex cryptococcal antigen test (LCAT), whereas the Gilbert's potoroo had a negative LCAT result despite having advanced disease of some duration. In both cases, the clinical presentation was a progressive neurologic disease associated with a central nervous system infection. Pulmonary infection was also observed in the long-nosed potoroo. Specific treatment with antifungal agents was unsuccessful in the long-nosed potoroo.

Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH) monotherapy and paclitaxel used alone or in combination with a platinum-based compound for the second-line or subsequent treatment of advanced ovarian cancer. DATA SOURCES: Electronic databases covering publication years 2000-4. Company submissions. REVIEW METHODS: Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of PLDH, topotecan and paclitaxel and economic evaluations of the cost-effectiveness of PLDH, topotecan and paclitaxel. Selected studies were quality assessed and data extracted, as were the three company submissions. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results. RESULTS: Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five, three included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes of participants were PLDH versus topotecan, topotecan versus paclitaxel and PLDH versus paclitaxel. In the further two trials that included participants with the subtype of platinum-sensitive disease, the comparators that were assessed were single-agent paclitaxel versus a combination of cyclophosphamide, doxorubicin and cisplatin (CAP) and paclitaxel plus platinum-based chemotherapy versus conventional platinum-based therapy alone. A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were oxaliplatin versus paclitaxel, paclitaxel given weekly versus every 3 weeks, paclitaxel at two different dose levels and oral versus intravenous topotecan. Four studies met the inclusion criteria for the cost-effectiveness review. The review of the economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of PLDH, topotecan and paclitaxel. Analysis 1 assessed the cost-effectiveness of PLDH, topotecan and paclitaxel administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data and alternative assumptions regarding treatment and monitoring costs. In the base-case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, topotecan was dominated by PLDH. Hence the options considered in the estimation of the ICERs were paclitaxel and PLDH. The ICER for PLDH compared with paclitaxel was pound 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive, -refractory and -resistant patients). The ICER was more favourable in the platinum-sensitive group ( pound 5777 per QALY) and less favourable in the platinum-refractory/resistant group ( pound 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of the additional trial data resulted in less favourable estimates for the ICER for PLDH versus paclitaxel compared with the base-case results. The ICER of PLDH compared with paclitaxel was pound 20,620 per QALY in the overall patient population, pound 16,183 per QALY in the platinum-sensitive population and pound 26,867 per QALY in the platinum-resistant and -refractory population. The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model comprised PLDH, topotecan, paclitaxel-monotherapy, CAP, paclitaxel/platinum combination therapy and platinum monotherapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum monotherapy, CAP and paclitaxel-platinum combination therapy. Of these three alternatives, platinum monotherapy was the least costly and least effective. The ICER for CAP compared with platinum monotherapy was pound 16,421 per QALY. The ICER for paclitaxel-platinum combination therapy compared with CAP was pound 20,950 per QALY. CONCLUSIONS: For participants with platinum-resistant disease there was a low probability of response to treatment with PLDH, topotecan or paclitaxel. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three comparators differed significantly in terms of their toxicity profiles, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs. For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that PLDH is more effective than topotecan. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three comparators did, however, differ significantly in terms of their toxicity profiles across the trials. Although treatment with PLDH may therefore be more beneficial than that with topotecan, patient and physician choice as to the potential toxicities associated with each of the comparators and the patient's ability and willingness to tolerate these are of importance. Assuming the NHS is willing to pay up to pound 20,000-40,000 per additional QALY, PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of additional trial data gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. On the strength of the evidence reviewed here, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs. To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.

Response of the hypothalamic-pituitary-adrenal axis to psychological stress in patients with psoriasis.

BACKGROUND: Psoriasis may, in some patients, be triggered and/or exacerbated by stress. OBJECTIVES: As activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical to a successful stress response we investigated this in patients with psoriasis. METHODS: Forty patients with chronic plaque psoriasis and 40 age-matched normal controls experienced three randomly presented acute psychological stressors (cognitive, emotional and social). Serial serum cortisol, pulse rate and blood pressure assessments were undertaken at baseline and following each of the stressors. Salivary cortisol samples were collected at 09.00 h on the day of testing. RESULTS: In control subjects there was a significant (r = 0.38; P < 0.05) correlation between pulse rate and serum cortisol level following the social performance stressor; this was not evident in the psoriasis group (r = 0.07; not significant). Patients who believed that their psoriasis was highly stress responsive had significantly lower salivary cortisol levels at baseline (P < 0.01) and lower serum cortisol levels following the social performance stressor (P = 0.016) than patients with nonstress-responsive disease who believed that stress had no impact. In contrast, there was no difference between the groups for change in pulse rate poststressor. CONCLUSIONS: This study shows that patients with psoriasis, and in particular those whose disease appears to be stress responsive, exhibit an altered HPA response to acute social stress. The implication is that such patients may perhaps be primed to flares of their psoriasis. Whether this is genetically predetermined and/or a consequence of the distress of living with psoriasis remains to be determined.