What about males? Exploring sex differences in the relationship between emotion difficulties and eating disorders.

OBJECTIVE: While eating disorders (EDs) are more commonly diagnosed in females, there is growing awareness that men also experience EDs and may do so in a different way. Difficulties with emotion processing and emotion regulation are believed to be important in EDs, but as studies have involved predominantly female samples, it is unclear whether this is also true for males. METHODS: In a sample of 1604 participants (n = 631 males), we assessed emotion processing and emotion regulation in males with EDs (n = 109) and compared results to both females with EDs (n = 220) and males from the general population (n = 522). We also looked at whether emotion processing and emotion regulation difficulties predicted various aspects of eating psychopathology and whether this was moderated by sex. We assessed emotion processing with the Toronto Alexithymia Scale, emotion regulation with the Difficulties in Emotion Regulation Scale and the Emotion Regulation Questionnaire, and eating psychopathology with the Eating Disorder Examination Questionnaire. RESULTS: We found that males with ED, like their female counterparts, suffered from emotion processing and emotion regulation deficits. We did find some sex differences, in that males with EDs tended to report more difficulties with their emotions as well as a more externally oriented thinking style compared to females with EDs. Difficulties with emotion processing and emotion regulation were strongly predictive of various aspects of eating psychopathology in both sexes. Importantly, we found that sex moderated the relationship between cognitive reappraisal and eating restraint. As such, low use of reappraisal was found to be associated with higher levels of restraint in females but not in males. DISCUSSION: Difficulties with emotion processing and emotion regulation are associated with eating psychopathology in both males and females. Reappraisal was not found to be associated with reduced eating psychopathology in males, suggesting a cautious approach to interventions targeting this strategy. Research around explanatory mechanisms and interventions must adopt a broader viewpoint including those that are traditionally overlooked in EDs.

While eating disorders (EDs) are more common in females, males also suffer from these conditions and are generally neglected in research around EDs. Difficulty identifying and managing emotions is believed to be important in the development and maintenance of EDs, but as studies have been conducted mostly in females, it is unclear whether this is also true for males. We recruited 1604 participants (631 were males, and 329 were diagnosed with EDs comprising 109 males and 220 females) and compared how males and females processed and regulated their emotions. We found that males with EDs, like their female counterparts, suffered from difficulties identifying and regulating their emotions, though they showed a slightly different profile of difficulties. While difficulties with emotions were associated with ED behaviours in both sexes, difficulties using reappraisal, an emotion regulation strategy where one reinterprets an event from a different perspective, were associated with restraint in females but not in males. This suggests that while interventions to help with emotional functioning could be beneficial for both women and men with EDs, the different emotional profiles of men with EDs must be considered, as interventions targeting particular emotional processes (e.g. reappraisal) may be relevant for women but not men.

The key challenges of discussing end-of-life stroke care with patients and families: a mixed-methods electronic survey of hospital and community healthcare professionals.

BACKGROUND: Communication between professionals, patients and families about palliative and end-of-life care after stroke is complex and there is a need for educational resources in this area. METHODS: To explore the key learning needs of healthcare professionals, a multidisciplinary, expert group developed a short electronic survey with open and closed questions, and then distributed it to six UK multiprofessional networks and two groups of local clinicians. RESULTS: A total of 599 healthcare professionals responded. Educational topics that were either definitely or probably needed were: ensuring consistent messages to families and patients (88%); resolving conflicts among family members (83%); handling unrealistic expectations (88%); involving families in discussions without them feeling responsible for decisions (82%); discussion of prognostic uncertainties (79%); likely mode of death (72%); and oral feeding for 'comfort' in patients at risk of aspiration (71%). The free-text responses (n = 489) and 82 'memorable' cases identified similar themes. CONCLUSION: Key topics of unmet need for education in end-of-life care in stroke have been identified and these have influenced the content of an open access, web-based educational resource.

Practice Variation among an International Group of Genetic Counselors on when to Offer Predictive Genetic Testing to Children at Risk of an Inherited Arrhythmia or Cardiomyopathy.

Cascade predictive genetic testing is available for many families as a means to identify individuals at risk of long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). The general issue of offering predictive genetic testing to minors has been an area of ethical debate among genetic counselors and other healthcare professionals for many years. An online questionnaire was circulated to four international genetic counseling associations to assess the views of cardiac genetic counselors regarding when to offer predictive genetic testing to children at risk of LQTS, CPVT, HCM, and ARVC. Analysis was both quantitative and qualitative. The study sample comprised 98 respondents. The majority reported that they offer predictive genetic testing before 5 years of age to children at risk of LQTS (83%) and CVPT (75%) and before 10 years of age to children at risk of HCM (66%) or ARVC (70%). Influencing factors included country of practice, clinical setting, and years of experience. The rationale provided for when to offer predictive genetic testing is encompassed by the ethical principles of beneficence, non-maleficence, autonomy, and informed consent. In conclusion, significant practice variation exists among cardiac genetic counselors regarding predictive genetic testing for children at risk of an inherited cardiomyopathy. These variations call for more research in the area to assist with the development of evidence-based guidelines.

A centralized approach to out-of-province genetic testing leads to cost savings: the Alberta experience.

The Genetic Resource Center (GRC) is a centralized process for requesting genetic testing that is not available within the province (Alberta, Canada). In order to assess potential cost savings associated with this process, all applications received by the GRC in 2010 were reviewed, and cost savings were recorded for statistical analysis. Seven areas of cost savings were identified: (i) negotiated pricing, (ii) laboratory selection, (iii) testing setup in-province, (iv) duplicate testing, (v) inappropriate testing, (vi) sequential testing and (vii) testing offered within the province.The total test cost of the 615 applications submitted in 2010 without the GRC process would have been $766,783 (Canadian dollars). A total cost savings of $112,201 was achieved through the GRC, which represents 15% of the total cost of requested testing ($112,201/$766,783). This is the first study to examine areas of cost savings for genetic testing sent out-of-province. The greatest cost savings resulted from the areas of laboratory selection and negotiated pricing. A centralized process to manage out-of-province genetic test requests results in consistency in testing and significant cost savings.

Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss (RPL), defined as two or more miscarriages, affects 3-5% of couples trying to establish a family. Despite extensive evaluation, no factor is identified in ∼40% of cases. In this study, we investigated the possibility that submicroscopic chromosomal changes, not detectable by conventional cytogenetic analysis, exist in miscarriages with normal karyotypes (46,XY or 46,XX) from couples with idiopathic RPL. METHODS: Array comparative genomic hybridization (array-CGH) was used to assess for DNA copy number variants (CNVs) in 26 miscarriages with normal karyotypes. Parental array-CGH analysis was performed to determine if miscarriage CNVs were de novo or inherited. RESULTS: There were 11 unique (previously not described) CNVs, all inherited, identified in 13 miscarriages from 8 couples. The maternal origin of two CNVs was of interest as they involved the imprinted genes TIMP2 and CTNNA3, which are only normally expressed from the maternal copy in the placenta. Two additional cohorts, consisting of 282 women with recurrent miscarriage (RM) and 61 fertile women, were screened for these two CNVs using a Quantitative Multiplex Fluorescent PCR of Short Fragments assay. One woman with RM, but none of the fertile women, carried the CTNNA3-associated CNV. CONCLUSIONS: This preliminary study shows that array-CGH is useful for detecting CNVs in cases of RPL. Further investigations of CNVs, particularly those involving genes that are imprinted in placenta, in women with RPL could be worthwhile.

The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

OBJECTIVES: To investigate the harmful health effects of taking ecstasy (3,4-methylenedioxymethamphetamine, MDMA) for recreational purposes. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and Web of Knowledge were searched. Additional information on deaths was collected from the General Mortality Register (GMR) and the Special Mortality Register collated by the National Programme on Substance Abuse Deaths (np-SAD). REVIEW METHODS: Studies were categorised according to design, with systematic research syntheses (Level I evidence) the most valid and least open to bias. Where Level I evidence was not available, controlled observational studies (Level II evidence) were systematically reviewed. If neither Level I nor Level II evidence was available, uncontrolled case series and case reports (Level III evidence) were systematically surveyed. Data were extracted by one reviewer and a sample checked by a second. The heterogeneity of Level II evidence was addressed by undertaking stratified analyses for current and former ecstasy users and comparing them either with control groups using other illegal drugs but not ecstasy (polydrug controls) or with controls naïve to illegal drugs (drug-naïve controls). Statistical heterogeneity was minimised by using a random-effects model throughout and investigated using study-level regression analysis (metaregression). RESULTS: Five Level I syntheses were identified; for each it was difficult to ascertain the exact methods adopted and evidence included. Small but significant deficits for ecstasy users compared to controls were reported in areas relating to attention, memory, psychomotor speed, executive systems functioning, and self-reported depressive symptoms. Data from Level II studies were directly pooled for seven individual outcomes, suggesting that ecstasy users performed worse than controls on common measures of immediate and delayed verbal recall (RAVLT, RBMT, digit span). No difference was seen in IQ (NART). The 915 outcome measures identified in Level II studies were analysed in broad domains: immediate and delayed verbal and visual memory, working memory, two measures of attention, three measures of executive function, perceptual organisation, self-rated depression, memory and anxiety, and impulsivity measured objectively and subjectively. Ecstasy users performed significantly worse than polydrug controls in 13/16 domains and significantly worse than drug-naïve controls in 7/12 domains for which sufficient data were available. The largest, most consistent exposure effects were seen in meta-analyses of memory (especially verbal and working memory, with less marked effects seen in visual memory). Former ecstasy users frequently showed deficits that matched or exceeded those seen amongst current users. At aggregate level, the effects do not appear to be dose-related, but are variably confounded by other drug use, particularly alcohol. Of Level III evidence, in the 10 years to 2006, the np-SAD and the GMR recorded an average of around 50 drug-related deaths per year involving ecstasy; it was the sole drug implicated in around 10 cases per year. Retrospective case series, based on hospital emergency department records, reported a death rate of 0-2% from emergency admissions related to ecstasy. Two major syndromes are most commonly reported as the immediate cause of death in fatal cases: hyperthermia and hyponatraemia. CONCLUSIONS: A broad range of relatively low-quality literature suggests that recreational use of ecstasy is associated with significant deficits in neurocognitive function (particularly immediate and delayed verbal memory) and increased psychopathological symptoms. The clinical significance of the exposure effect in individual cases will be variable but, on average, deficits are likely to be relatively small. Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.

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.

Surveillance of Barrett's oesophagus: is it worthwhile?

OBJECTIVE: To assess the cost-effectiveness of surveillance of Barrett's oesophagus. DESIGN: Cost-utility model. SETTING: UK NHS. PATIENTS: One thousand 55-year-old men with Barrett's oesophagus. INTERVENTION: Surveillance programme: endoscopy and biopsy at 3 yearly intervals for non-dysplastic Barrett's oesophagus; low-grade dysplasia yearly; high grade-dysplasia 3 monthly. OUTCOME MEASURES: Incremental cost-effectiveness ratio, expected value of perfect information. RESULTS: Non-surveillance dominated surveillance (i.e. cost less and conferred more benefit), but there was substantial uncertainty around many of the model inputs. Probabilistic analyses showed that non-surveillance cost less and conferred more benefit in 75% of model runs. Surveillance was cost-effective at usual levels of willingness to pay in 11% of runs. For people with Barrett's oesophagus in England and Wales, a value of pound6.5 million is placed on acquiring perfect information about surveillance of Barrett's oesophagus. CONCLUSIONS: The PenTAG cost-utility model suggests that surveillance programmes do more harm than good.

The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of adjuvant carmustine wafers (BCNU-W) and also of adjuvant and concomitant temozolomide (TMZ), compared with surgery with radiotherapy. DATA SOURCES: Electronic databases were searched up to August 2005. REVIEW METHODS: Included trials were critically appraised for key elements of internal and external validity. Relevant data were extracted and a narrative synthesis of the evidence produced. Where possible, data on absolute survival at a fixed time point were meta-analysed using a random effects model. A Markov (state transition) model was developed to assess the cost-utility of the two interventions. The model compared BCNU-W or TMZ separately with current standard treatment with surgery and radiotherapy. The simulated cohort had a mean age of 55 years and was modelled over 5 years. RESULTS: Two randomised controlled trials (RCTs) (n = 32, n = 240) and two observational studies of BCNU-W compared with placebo wafers as adjuvant therapy to surgery and radiotherapy for newly diagnosed high-grade glioma were identified. All the studies were in adults and provided data on 193 patients who had received BCNU-W. The RCT findings excluded under 65-year-olds and those with a Karnofsky Performance Status of less than 60. The largest multi-centre RCT suggested a possible survival advantage with BCNU-W among a cohort of patients with grade III and IV tumours, adding a median of 2.3 months [95% confidence interval (CI) -0.5 to 5.1]. However, analysis using per-protocol, unstratified methods shows this difference to be not statistically significant (HR 0.77, 95% CI 0.57 to 1.03, p = 0.08). Long-term follow-up suggests a significant survival advantage using unstratified analysis. No difference in progression-free survival (PFS) was demonstrated. Subgroup analysis of those with grade IV tumours also showed no significant survival advantage with BCNU-W [hazard ratio (HR) 0.82, 95% CI 0.55 to 1.11, p = 0.20, unstratified analysis]. It is estimated that the cost of surgery and radiotherapy, with follow-up, treatment of adverse effects and end of life care is around 17,000 pounds per patient. Treatment with BCNU-W adds an additional 6600 pounds. Across the modelled cohort of 1000 patients, use of BCNU-W costs an additional 6.6 million pounds and confers an additional 122 quality-adjusted life-years (QALYs). On average, that is 6600 pounds per patient for 0.122 QALYs (6.3 quality-adjusted life-weeks). The base-case incremental cost-effectiveness ratio (ICER) is 54,500 pounds/QALY. In probabilistic sensitivity analyses, BCNU-W was not cost-effective in 89% of the simulations assuming a willingness to pay threshold of 30,000 pounds/QALY. In 15% of simulations, BCNU-W was dominated (i.e. did more harm than good, conferring fewer QALYs at greater cost). The cost-effectiveness acceptability curve (CEAC) suggests that it is very unlikely to be the most cost-effective option at normal levels of willingness to pay (11% probability at 30,000 pounds/QALY), only becoming likely to be the most cost-effective option at much higher levels of willingness to pay (50% probability at 55,000 pounds/QALY). Two RCTs (n = 130, n = 573) and two observational studies were included, giving evidence for 429 adult patients receiving TMZ. Currently, TMZ is licensed for use in those with newly diagnosed grade IV gliomas only. The RCTs excluded those with lower performance status and, in the larger RCT, those older than 70 years. TMZ provides a small but statistically significant median survival benefit of 2.5 months (95% CI 2.0 to 3.8), giving an HR of 0.63 (95% CI 0.52 to 0.75, p < 0.001). At 2 years, 26.5% of patients treated with TMZ were alive compared with 10.4% of those in the control arm. Median PFS is also enhanced with TMZ, giving a median 1.9 months' advantage (95% CI 1.4 to 2.7, p < 0.001). No analysis of the subgroup of patients with confirmed grade IV tumours was undertaken. Subgroup analysis of patients by O6-methylguanine-DNA methyltransferase (MGMT) activity showed a significant treatment advantage for those with reduced MGMT activity but not for those with normal activity, although this analysis was based on a selected sample of patients and the test used has proved difficult to replicate. A median gain of 6.4 (95% CI 4.4 to 9.5) more life-months is seen with TMZ among those with reduced MGMT, giving an HR of 0.51 (p < 0.007). PFS is increased by a median of 4.4 months (95% CI 1.2 to 6.3), giving an HR of 0.48 (p = 0.001). The model shows a cost per patient for being treated with surgery, radiotherapy and including adverse effects of treatment and end of life care of around 17,000 pounds per patient. TMZ in the adjuvant and concomitant phase adds an additional cost of around 7800 pounds. Across the modelled cohort of 1000 patients, use of TMZ costs an additional 7.8 million pounds and confers an additional 217 QALYs. For the average patient this is 7800 pounds for an additional 0.217 QALYs (11 quality-adjusted life-weeks). The base-case ICER is 36,000 pounds/QALY. Probabilistic sensitivity analyses shows that TMZ was not cost-effective in 77% of the simulations. The CEAC suggests that there is a 23% chance that TMZ is the most cost-effective option at a willingness to pay level of 30,000 pounds/QALY, rising to be more cost-effective than no TMZ at slightly higher levels (50% probability at 35,000 pounds/QALY). CONCLUSIONS: BCNU-W has not been proven to confer a significant advantage in survival for patients with grade III tumours when treated with the drug, compared with placebo. There does not appear to be a survival advantage for patients with grade IV tumours. No increase in PFS has been shown. Limited evidence suggests a small but significant advantage in both overall survival and PFS with TMZ among a mixed population with grade IV and grade III (7-8%) tumours. However, it remains unclear whether this is true in grade IV tumours alone. On the basis of best available evidence, the authors consider that neither BCNU-W nor TMZ is likely to be considered cost-effective by NHS decision-makers. However, data for the model were drawn from limited evidence of variable quality. Tumour type is clearly important in assessing patient prognosis with different treatments. Grade IV tumours are commonest and appear to have least chance of response. There were too few grade III tumours included to carry out a formal assessment, but they appear to respond better and drive results for both drugs. Future use of genetic and biomarkers may help identify subtypes which will respond, but current licensing indications do not specify these. Further research is suggested into the effectiveness of these drugs, and also into areas such as genetic markers, chemotherapy regimens, patient and carer quality of life, and patient views on survival advantages vs treatment disadvantages.

Rituximab therapy in patients with resistant rheumatoid arthritis: real-life experience.

OBJECTIVES: Rituximab has recently been shown to be effective in suppressing disease activity in patients with rheumatoid arthritis (RA) who fail anti-TNF therapy. We present our experience of treating patients with long-standing, multi-DMARD and anti-TNF resistant RA with rituximab in 'real-life' setting. METHODS: Patients with RA resistant to more than two anti-TNF drugs and with persistent disease activity (DAS28 > 5.1) were considered for treatment with rituximab (two infusions 1000 mg each, a fortnight apart). DAS28 and HAQ scores were performed at baseline, 3 and 6 months post-treatment. Response to rituximab was defined as per the EULAR response criteria. Re-treatment with a second cycle of rituximab was offered if they had responded to the earlier one but flared. RESULTS: Twenty patients received rituximab. Median disease duration was 16 yrs (range 5-39) and 90% were rheumatoid factor positive. Median number of biologics received pre-treatment was two (range 2-4). Rituximab treatment led to a significant reduction in DAS28 score (P < 0.0001) at 3 months and various other disease parameters. The benefit was sustained at 6 months. Moderate-to-good EULAR response was seen in 85% of patients at 3 months and 60% at 6 months. No significant side effects were observed. 50% of the patients flared and received re-treatment. Interval to re-treatment varied from 6 to 18 months. The majority of the RA patients responded to re-treatment with rituximab and no major side effects were observed. CONCLUSION: Rituximab was effective in controlling disease activity in anti-TNF therapy resistant RA patients in 'real-life' setting. Rituximab was safe with no major side effects. Re-treatment with rituximab was safe and efficacy was maintained.

Low-dose infliximab treatment for ankylosing spondylitis--clinically- and cost-effective.

OBJECTIVES: Infliximab has been shown to be effective in the treatment of ankylosing spondylitis (AS) when treated in a dose of 5 mg/kg at 6 weekly intervals. This dose of infliximab has not been determined by any structured randomized trials and has significant cost implications. We describe our experience of treating AS with low-dose infliximab (3mg/kg at 8 weekly intervals). The efficacy and cost implications are discussed. METHODS: Patients who had active AS [Bath AS Disease Activity Index (BASDAI) > or = 4] were treated with infliximab 3 mg/kg at 0, 2, 6 weeks and thereafter at 8 weekly intervals. Response to treatment was defined as 50% improvement in BASDAI. Other response criteria such as ASAS 20, 40 and five of the six criteria were also assessed. Direct drug costs for infliximab were determined. RESULTS: Twenty-two consecutive AS patients received infliximab. All 22 completed treatment for 3 months, 15 patients for 6 months and 14 for 12 months. Mean age was 45 years (range 21-62) and mean disease duration 14.5 years (range 2-43). Of the patients, 54% achieved a 50% BASDAI response at 3 months and the benefit was sustained at 12 months in 63%. Similar response rate was seen with the other assessment criteria. Direct drug costs were significantly lower when low-dose infliximab regimen was used. CONCLUSIONS: Low-dose infliximab (3 mg/kg at 8 weekly infusions) is effective in the treatment of AS. Higher doses are required in a small proportion of patients when treatment is only partially effective. Titrating the dose and frequency of infusions may be required in individual patients to achieve optimal response. Using low-dose infliximab has significant economic implications.

Surveillance of Barrett's oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

OBJECTIVES: To assess what is known about the effectiveness, safety, affordability, cost-effectiveness and organisational impact of endoscopic surveillance in preventing morbidity and mortality from adenocarcinoma in patients with Barrett's oesophagus. In addition, to identify important areas of uncertainty in current knowledge for these programmes and to identify areas for further research. DATA SOURCES: Electronic databases up to March 2004. Experts in Barrett's oesophagus from the UK. REVIEW METHODS: A systematic review of the effectiveness of endoscopic surveillance of Barrett's oesophagus was carried out following methodological guidelines. Experts in Barrett's oesophagus from the UK were invited to contribute to a workshop held in London in May 2004 on surveillance of Barrett's oesophagus. Small group discussion, using a modified nominal group technique, identified key areas of uncertainty and ranked them for importance. A Markov model was developed to assess the cost-effectiveness of a surveillance programme for patients with Barrett's oesophagus compared with no surveillance and to quantify important areas of uncertainty. The model estimates incremental cost--utility and expected value of perfect information for an endoscopic surveillance programme compared with no surveillance. A cohort of 1000 55-year-old men with a diagnosis of Barrett's oesophagus was modelled for 20 years. The base case used costs in 2004 and took the perspective of the UK NHS. Estimates of expected value of information were included. RESULTS: No randomised controlled trials (RCTs) or well-designed non-randomised controlled studies were identified, although two comparative studies and numerous case series were found. Reaching clear conclusions from these studies was impossible owing to lack of RCT evidence. In addition, there was incomplete reporting of data particularly about cause of death, and changes in surveillance practice over time were mentioned but not explained in several studies. Three cost--utility analyses of surveillance of Barrett's oesophagus were identified, of which one was a further development of a previous study by the same group. Both sets of authors used Markov modelling and confined their analysis to 50- or 55-year-old white men with gastro-oesophageal reflux disease (GORD) symptoms. The models were run either for 30 years or to age 75 years. As these models are American, there are almost certainly differences in practice from the UK and possible underlying differences in the epidemiology and natural history of the disease. The costs of the procedures involved are also likely to be very different. The expert workshop identified the following key areas of uncertainty that needed to be addressed: the contribution of risk factors for the progression of Barrett's oesophagus to the development of high-grade dysplasia (HGD) and adenocarcinoma of the oesophagus; possible techniques for use in the general population to identify patients with high risk of adenocarcinoma; effectiveness of treatments for Barrett's oesophagus in altering cancer incidence; how best to identify those at risk in order to target treatment; whether surveillance programmes should take place at all; and whether there are clinical subgroups at higher risk of adenocarcinoma. Our Markov model suggests that the base case scenario of endoscopic surveillance of Barrett's oesophagus at 3-yearly intervals, with low-grade dysplasia surveyed yearly and HGD 3-monthly, does more harm than good when compared with no surveillance. Surveillance produces fewer quality-adjusted life-years (QALYs) for higher cost than no surveillance, therefore it is dominated by no surveillance. The cost per cancer identified approaches pound 45,000 in the surveillance arm and there is no apparent survival advantage owing to high recurrence rates and increased mortality due to more oesophagectomies in this arm. Non-surveillance continues to cost less and result in better quality of life whatever the surveillance intervals for Barrett's oesophagus and dysplastic states and whatever the costs (including none) attached to endoscopy and biopsy as the surveillance test. The probabilistic analyses assess the overall uncertainty in the model. According to this, it is very unlikely that surveillance will be cost-effective even at relatively high levels of willingness to pay. The simulation showed that, in the majority of model runs, non-surveillance continued to cost less and result in better quality of life than surveillance. At the population level (i.e. people with Barrett's oesophagus in England and Wales), a value of pound 6.5 million is placed on acquiring perfect information about surveillance for Barrett's oesophagus using expected value of perfect information (EVPI) analyses, if the surveillance is assumed to be relevant over 10 years. As with the one-way sensitivity analyses, the partial EVPI highlighted recurrence of adenocarcinoma of the oesophagus (ACO) after surgery and time taken for ACO to become symptomatic as particularly important parameters in the model. CONCLUSIONS: The systematic review concludes that there is insufficient evidence available to assess the clinical effectiveness of surveillance programmes of Barrett's oesophagus. There are numerous gaps in the evidence, of which the lack of RCT data is the major one. The expert workshop reflected these gaps in the range of topics raised as important in answering the question of the effectiveness of surveillance. Previous models of cost-effectiveness have most recently shown that surveillance programmes either do more harm than good compared with no surveillance or are unlikely to be cost-effective at usual levels of willingness to pay. Our cost--utility model has shown that, across a range of values for the various parameters that have been chosen to reflect uncertainty in the inputs, it is likely that surveillance programmes do more harm than good -- costing more and conferring lower quality of life than no surveillance. Probabilistic analysis shows that, in most cases, surveillance does more harm and costs more than no surveillance. It is unlikely, but still possible, that surveillance may prove to be cost-effective. The cost-effectiveness acceptability curve, however, shows that surveillance is unlikely to be cost-effective at either the 'usual' level of willingness to pay ( pound 20,000-30,000 per QALY) or at much higher levels. The expected value of perfect information at the population level is pound 6.5 million. Future research should target both the overall effectiveness of surveillance and the individual elements that contribute to a surveillance programme, particularly the performance of the test and the effectiveness of treatment for both Barrett's oesophagus and ACO. In addition, of particular importance is the clarification of the natural history of Barrett's oesophagus.

Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH.

Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.