A randomised controlled trial of compression therapies for the treatment of venous leg ulcers (VenUS 6): study protocol for a pragmatic, multicentre, parallel-group, three-arm randomised controlled trial.

BACKGROUND: Venous leg ulcer(s) are common, recurring, open wounds on the lower leg, resulting from diseased or damaged leg veins impairing blood flow. Wound healing is the primary treatment aim for venous leg ulceration, alongside the management of pain, wound exudate and infection. Full (high) compression therapy delivering 40 mmHg of pressure at the ankle is the recommended first-line treatment for venous leg ulcers. There are several different forms of compression therapy available including wraps, two-layer hosiery, and two-layer or four-layer bandages. There is good evidence for the clinical and cost-effectiveness of four-layer bandage and two-layer hosiery but more limited evidence for other treatments (two-layer bandage and compression wraps). Robust evidence is required to compare clinical and cost-effectiveness of these and to investigate which is the best compression treatment for reducing time to healing of venous leg ulcers whilst offering value for money. VenUS 6 will therefore investigate the clinical and cost-effectiveness of evidence-based compression, two-layer bandage and compression wraps for time to healing of venous leg ulcers. METHODS: VenUS 6 is a pragmatic, multi-centre, three-arm, parallel-group, randomised controlled trial. Adult patients with a venous leg ulcer will be randomised to receive (1) compression wraps, (2) two-layer bandage or (3) evidence-based compression (two-layer hosiery or four-layer bandage). Participants will be followed up for between 4 and 12 months. The primary outcome will be time to healing (full epithelial cover in the absence of a scab) in days since randomisation. Secondary outcomes will include key clinical events (e.g. healing of the reference leg, ulcer recurrence, ulcer/skin deterioration, amputation, admission/discharge, surgery to close/remove incompetent superficial veins, infection or death), treatment changes, adherence and ease of use, ulcer related pain, health-related quality of life and resource use. DISCUSSION: VenUS 6 will provide robust evidence on the clinical and cost-effectiveness of the different forms of compression therapies for venous leg ulceration. VenUS 6 opened to recruitment in January 2021 and is currently recruiting across 30 participating centres. TRIAL REGISTRATION: ISRCTN67321719 . Prospectively registered on 14 September 2020.

APPLICATION OF THE MONTE CARLO METHOD FOR THE EVALUATION OF SCATTERED RADIATION DOSE DUE TO THE USE OF HANDHELD X-RAY IN DENTISTRY.

The object of this study was to evaluate the dose of scattered radiation in the organs of the operator and assistant located in different positions within a dental room when acquiring intraoral images with a portable handheld X-ray device, using Monte Carlo simulations for recommended and traditional techniques. A typical dental installation was modeled, where the operator and assistant were placed. The beam is represented by 60-kV spectrum. Ten scenarios were simulated, representing different positions and use of the lead apron. The results of the simulations were carried out with typical parameters of the annual workload, showing significant increases in dose in the organs of the operator due to the angulation. The minimum dose in the organs of the assistant occurred when he was located 2-m away and 45° from the direction of the beam. The dose received by the operator is significantly reduced with the use apron.

Magnetic resonance imaging assessment of juvenile idiopathic arthritis using OMERACT and EuroTMjoint classifications.

This retrospective case-control study compared inflammatory and structural damage in the temporomandibular joint of patients with juvenile idiopathic arthritis (JIA) and its subtypes and healthy patients using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) and EuroTMjoint classifications. Correlations between the scores of the two classifications and time of diagnosis were evaluated. Twenty-nine JIA patients and 48 age-matched healthy participants were examined. TMJ images on each side were considered individually. Oligoarticular and polyarticular subtypes were present in 44.8% and 55.2% of patients, respectively. The JIA group presented a higher frequency and more severe signs of inflammatory and structural changes (P < 0.05), except for effusion (P = 0.83). The polyarticular subtype showed a higher change intensity. The time of JIA diagnosis was not correlated with inflammatory and structural changes. Positive correlations between inflammation and bone deformity scores were observed for the EuroTMjoint classification (r = 0.462, P < 0.001; low correlation) and OMERACT classification (r = 0.737, P < 0.001; high correlation). Positive correlations between the OMERACT and EuroTMjoint classifications were found for inflammation score (r = 0.907, P < 0.001; very high correlation) and bone deformity score (r = 0.854, P < 0.001; high correlation). Both classifications showed a higher frequency and intensity of inflammation and bone deformity in JIA patients. The results of this study suggest that the appropriate management of inflammation may reduce the potential for structural damage to the TMJ.

Distribution of galling insects and their parasitoids on Caryocar brasiliense tree crowns / Distribuição de insetos galhadores e seus parasitoides em copas de pequizeiros (Caryocar brasiliense)

Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) is widely distributed in the Brazilian savanna and its fruits are used by humans for food, production of cosmetics, lubricants, and in the pharmaceutical industry. This plant is damaged by galling insects. Number of these galling insects and their parasitoids was recorded, in the field (galls) and in the laboratory (adults emerged from the galls), from three C. brasiliense crown heights, during three years. Numbers of adults of Eurytoma sp. (Hymenoptera: Eurytomidae), galling insect (younger attack) and Sycophila sp. (Hymenoptera: Eurytomidae) (a parasitoid of Eurytoma sp.), were greater on the apical parts of C. brasiliense tree crowns. Numbers and groups of Eurytoma sp. globoid galls (older attack) were higher in the median and basal crown parts. The numbers of Eurytoma sp. galls were higher on apical part of C. brasiliense tree crown and also of their parasitoids.

Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) é, amplamente, distribuída no cerrado brasileiro e seus frutos são utilizados para alimentação humana, produção de cosméticos, lubrificantes e na indústria farmacêutica, no entanto, é danificada por insetos galhadores. O número de insetos galhadores e seus parasitoides foram avaliados, em campo (galhas) e em laboratório (emergência de adultos das galhas), em três alturas do dossel de C. brasiliense, durante três anos. Os números de adultos Eurytoma sp. (Hymenoptera: Eurytomidae), inseto galhador (galhas novas) e de Sycophila sp. (Hymenoptera: Eurytomidae), parasitoide de Eurytoma sp., foram maiores na parte apical do dossel da copa de árvores de C. brasiliense. A quantidade de galhas globoides de Eurytoma sp., isoladas ou em grupo (galhas velhas), foi maior na parte mediana e basal da copa. Os números de adultos do galhador Eurytoma sp. e de seus parasitoides, que os seguem, foram maiores na parte apical da copa de árvores de C. brasiliense.

Distribution of galling insects and their parasitoids on Caryocar brasiliense tree crowns

Abstract Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) is widely distributed in the Brazilian savanna and its fruits are used by humans for food, production of cosmetics, lubricants, and in the pharmaceutical industry. This plant is damaged by galling insects. Number of these galling insects and their parasitoids was recorded, in the field (galls) and in the laboratory (adults emerged from the galls), from three C. brasiliense crown heights, during three years. Numbers of adults of Eurytoma sp. (Hymenoptera: Eurytomidae), galling insect (younger attack) and Sycophila sp. (Hymenoptera: Eurytomidae) (a parasitoid of Eurytoma sp.), were greater on the apical parts of C. brasiliense tree crowns. Numbers and groups of Eurytoma sp. globoid galls (older attack) were higher in the median and basal crown parts. The numbers of Eurytoma sp. galls were higher on apical part of C. brasiliense tree crown and also of their parasitoids.

Resumo Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) é, amplamente, distribuída no cerrado brasileiro e seus frutos são utilizados para alimentação humana, produção de cosméticos, lubrificantes e na indústria farmacêutica, no entanto, é danificada por insetos galhadores. O número de insetos galhadores e seus parasitoides foram avaliados, em campo (galhas) e em laboratório (emergência de adultos das galhas), em três alturas do dossel de C. brasiliense, durante três anos. Os números de adultos Eurytoma sp. (Hymenoptera: Eurytomidae), inseto galhador (galhas novas) e de Sycophila sp. (Hymenoptera: Eurytomidae), parasitoide de Eurytoma sp., foram maiores na parte apical do dossel da copa de árvores de C. brasiliense. A quantidade de galhas globoides de Eurytoma sp., isoladas ou em grupo (galhas velhas), foi maior na parte mediana e basal da copa. Os números de adultos do galhador Eurytoma sp. e de seus parasitoides, que os seguem, foram maiores na parte apical da copa de árvores de C. brasiliense.

Distribution of galling insects and their parasitoids on Caryocar brasiliense tree crowns / Distribuição de insetos galhadores e seus parasitoides em copas de pequizeiros (Caryocar brasiliense)

Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) is widely distributed in the Brazilian savanna and its fruits are used by humans for food, production of cosmetics, lubricants, and in the pharmaceutical industry. This plant is damaged by galling insects. Number of these galling insects and their parasitoids was recorded, in the field (galls) and in the laboratory (adults emerged from the galls), from three C. brasiliense crown heights, during three years. Numbers of adults of Eurytoma sp. (Hymenoptera: Eurytomidae), galling insect (younger attack) and Sycophila sp. (Hymenoptera: Eurytomidae) (a parasitoid of Eurytoma sp.), were greater on the apical parts of C. brasiliense tree crowns. Numbers and groups of Eurytoma sp. globoid galls (older attack) were higher in the median and basal crown parts. The numbers of Eurytoma sp. galls were higher on apical part of C. brasiliense tree crown and also of their parasitoids.

Caryocar brasiliense Camb. (Malpighiales: Caryocaraceae) é, amplamente, distribuída no cerrado brasileiro e seus frutos são utilizados para alimentação humana, produção de cosméticos, lubrificantes e na indústria farmacêutica, no entanto, é danificada por insetos galhadores. O número de insetos galhadores e seus parasitoides foram avaliados, em campo (galhas) e em laboratório (emergência de adultos das galhas), em três alturas do dossel de C. brasiliense, durante três anos. Os números de adultos Eurytoma sp. (Hymenoptera: Eurytomidae), inseto galhador (galhas novas) e de Sycophila sp. (Hymenoptera: Eurytomidae), parasitoide de Eurytoma sp., foram maiores na parte apical do dossel da copa de árvores de C. brasiliense. A quantidade de galhas globoides de Eurytoma sp., isoladas ou em grupo (galhas velhas), foi maior na parte mediana e basal da copa. Os números de adultos do galhador Eurytoma sp. e de seus parasitoides, que os seguem, foram maiores na parte apical da copa de árvores de C. brasiliense.

A new diabetic foot risk assessment tool: DIAFORA.

AIMS: This study aimed to derive a new model to classify subjects with diabetes and active diabetic foot ulcer by their risk of lower extremity amputation. METHODS: A prospective cohort study was conducted that included all subjects with diabetic foot ulcer attending our Hospital Diabetic Foot Clinic from 2010 to 2013. Variables were collected at baseline. Subjects were followed up until healing, lower extremity amputation, death or for at least 3 months. Logistic regression was used to derive the new model, and the area under the receiver operating characteristic curve was assessed to propose the model with the greatest discrimination. RESULTS: A total of 293 participants were included and followed for a median of 91 days. In 23.2% amputation was required, 5.1% died and 3.1% were lost. Our final model included the variables most commonly used in clinical practice for diabetic foot risk assessment (presence of neuropathy, foot deformity, peripheral arterial disease and previous foot complications) in addition to multiple diabetic foot ulcer, infection, gangrene and bone involvement. This model had an area under the receiver operating characteristic curve of 0.91 [95% confidence interval (CI) 0.87-0.95] and as classification of 0.89 (95% CI 0.84-0.93) for lower extremity amputation prediction. The high-risk group presented a positive likelihood ratio of 5 (95% CI 3-8) and predictive value of 58 (46-71). Only one minor lower extremity amputation occurred in the low-risk group. CONCLUSIONS: We propose a new classification: diabetic foot risk assessment (DIAFORA). This classification was equally or more accurate for lower extremity amputation prediction in diabetic foot ulcer patients when compared with the existing ones.

Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review.

BACKGROUND: Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden of foot ulceration on both patient and health resources. A comprehensive analysis of reported interventions is not currently available, but is needed to better inform caregivers about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration. METHODS: The available medical scientific literature in PubMed, EMBASE, CINAHL and the Cochrane database was searched for original research studies on preventative interventions. Both controlled and non-controlled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers. RESULTS: From the identified records, a total of 30 controlled studies (of which 19 RCTs) and another 44 non-controlled studies were assessed and described. Few controlled studies, of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions, as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient. To prevent recurrence, some evidence exists for integrated foot care when it includes a combination of professional foot treatment, therapeutic footwear and patient education; for just a single session of patient education, no evidence exists. Surgical interventions can be effective in selected patients, but the evidence base is small. CONCLUSION: The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but is small for the use of other, sometimes widely applied, interventions and is practically nonexistent for the prevention of a first foot ulcer and non-plantar foot ulcer.

Informing a decision framework for when NICE should recommend the use of health technologies only in the context of an appropriately designed programme of evidence development.

BACKGROUND: The general issue of balancing the value of evidence about the performance of a technology and the value of access to a technology can be seen as central to a number of policy questions. Establishing the key principles of what assessments are needed, as well as how they should be made, will enable them to be addressed in an explicit and transparent manner. OBJECTIVES: The aims of this research are to (1) establish the key principles of what assessments are needed to inform an 'only in research' (OIR) or 'approval with research' (AWR) recommendation, (2) evaluate previous National Institute for Health and Clinical Evidence (NICE) guidance in which OIR or AWR recommendations were made or considered and (3) evaluate a range of alternative options to establish criteria, additional information and/or analysis that could be made available to inform the assessments needed. DATA SOURCES: All NICE draft and final guidance up to January 2010 was considered in the review of NICE technology appraisal guidance. Four case studies were used to evaluate the range of options of what information and analysis could be made available to inform the assessment required. These were based on a reanalysis of existing health technology appraisals for NICE or the Health Technology Assessment programme. REVIEW METHODS: A critical review of policies, practice and literature was undertaken using traditional systematic searching based on initial search terms informed by key publications. An iterative approach was adopted using 'pearl growing' evaluated through capture-recapture methods. In addition, grey literature, policy documents and other sources, such as special interest groups and the expertise of the Advisory Group for the project, were used to contribute to this process. RESULTS: A series of recommendations, or options, for NICE to consider were developed with the involvement of key stakeholders. These establish the key principles and associated criteria that might guide OIR and AWR recommendations and identify what, if any, additional information or analysis might be included in the technology appraisal process, including how such recommendations might be more likely to be implemented through publically funded and sponsored research. To meet these aims the research is broadly structured as follows. A critical review of policy, practice and literature in this area informs the development of a coherent conceptual framework to establish the key principles and the sequence of assessment and judgements required. This sequence of assessment and judgement is represented as an algorithm, which can also be summarised as a simple set of explicit criteria or a 7-point checklist of assessments. A review of previous NICE guidance in which OIR or AWR recommendations were either made or considered was undertaken to examine the extent to which the key principles are evident. The application of the checklist of assessment to a series of four case studies informs considerations of whether or not such assessments can be made based on existing information and analysis in current NICE appraisal and in what circumstances could additional information and/or analysis be useful. Finally, some of the implications that this more explicit assessment of OIR and AWR might have for policy (e.g. NICE guidance and drug pricing), the process of appraisal (e.g. greater involvement of research commissioners) and methods of appraisal (e.g. should additional information, evidence and analysis be required) are drawn together. At each stage this research has been informed by a diverse and international Advisory Group and the feedback from participants at two workshops involving a wide range of key stakeholders, which included members of NICE and its Advisory Committees (including lay members and other NICE programmes), patient advocates, manufacturers, and research and NHS commissioners, as well as relevant academics. LIMITATIONS: Further research is required to establish how these considerations could be integrated within a practical value-based pricing scheme. In addition, irrecoverable opportunity costs are commonly associated with many health technologies that offer future benefits following treatment. The significance of these types of irrecoverable costs is not widely recognised and further research to demonstrate their potential impact more generally is needed. CONCLUSIONS: The categories of guidance available to NICE have a wider application than is reflected in the review of previous guidance. Importantly, determining which category of guidance will be appropriate depends only partly on an assessment of expected cost-effectiveness. As well as AWR for technologies expected to be cost-effective and OIR for those not expected to be cost-effective, there are other important circumstances when OIR should be considered. In particular, for technologies expected to be cost-effective, OIR rather than approve may be appropriate when research is not possible with approval and OIR or even reject, rather than AWR or approve, may be appropriate even if research is possible with approval when there are significant irrecoverable costs. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of technologies used to visualise the seizure focus in people with refractory epilepsy being considered for surgery: a systematic review and decision-analytical model.

BACKGROUND: For patients who continue to have seizures despite ongoing treatment, surgical resection of the epileptic focus may be considered, and can result in seizure-freedom. Currently, non-invasive tests provide information to inform the scope and positioning of invasive electroencephalography (EEG) electrodes. However, these technologies could replace intracranial EEG in at least some patients if their ability to accurately locate a seizure focus could be established. In order to inform clinical practice, studies need to investigate the clinical value of a test, and the impact of the results of that test on the decision-making process and subsequently on clinical outcomes. OBJECTIVES: The aims of this systematic review were to determine the diagnostic accuracy of non-invasive technologies, how these technologies impact on the decision-making process, associations with surgical outcome, and the gaps in the current evidence base. In addition, a decision-analytical model was designed to consider the potential use of existing data to determine the cost-effectiveness of options for presurgical work-up. DATA SOURCES: Eighteen electronic databases were searched without language restrictions [including MEDLINE, EMBASE, BIOSIS Previews, PASCAL, ClinicalTrials.gov, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Register of Diagnostic Studies] from 2003 to July 2010. A prior, wider-ranging HTA review in this area conducted by the Centre for Reviews and Dissemination was used as the source for studies prior to 2003. Reference lists of included studies and relevant reviews were also searched, and a citation search of key papers undertaken. REVIEW METHODS: Systematic reviews of the diagnostic accuracy, clinical utility and cost-effectiveness of non-invasive technologies used to define the seizure focus in patients with refractory epilepsy being considered for surgery were undertaken according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Thirteen diagnostic accuracy studies, seven outcome prediction studies and one study reporting the impact of test results on the decision-making process ('decision study') were included. The decision study was used to aid the development of a decision-analytical model to illustrate how data from appropriately designed clinical studies can be utilised. RESULTS: Data from the diagnostic accuracy studies could not determine the contribution of the tests to the decision-making process. The number of index tests that could not be classified as correctly, non- or wrongly localising as indicated by a surgical outcome was high, up to 53%. The decision study reported fluorodeoxyglucose positron emission tomography influencing the decision for or against surgery in 78 of the 110 patients. The constructed decision-analytical model provided provisional cost-effectiveness results from the included diagnostic strategies. It demonstrated the feasibility of extending such analysis to all diagnostic strategies if suitable data were to become available. LIMITATIONS: There were a number of limitations of the available evidence, and overall, the quality of the available evidence was poor; only one study met the inclusion criteria that evaluated the use an index test on the decision-making process. Most of the available data was from the diagnostic accuracy studies; those currently available did not provide information on either the diagnostic accuracy or clinical utility of the tests being evaluated. Further limitations were the generally small study sizes, patient selection bias and the substantial clinical heterogeneity across the studies. CONCLUSIONS: The current evidence base is abundant but not adequately informative; there is no acceptable reference standard, reporting of clinical outcomes tends to be only following surgery, and decision level and clinical effectiveness studies are lacking. The additional value of diagnostic technologies for the localisation of epileptic foci is related to the impact on treatment decisions and the value of the treatments themselves; this needs to be considered fully in informing cost-effectiveness. Appropriately designed studies are needed to determine the added value of diagnostic regimens. Ultimately, how research informs the actual decision problem(s) faced by clinicians and the NHS needs to be considered; decision modelling is central to this issue. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review and mixed treatment comparison: dressings to heal diabetic foot ulcers.

AIMS/HYPOTHESIS: Foot ulcers in people with diabetes are a common and serious global health issue. Dressings form a key part of ulcer treatment. Existing systematic reviews are limited by the lack of head-to-head comparisons of alternative dressings in a field where there are several different dressing options. We aimed to determine the relative effects of alternative wound dressings on the healing of diabetic foot ulcers. METHODS: This study was a systematic review involving Bayesian mixed treatment comparison. We included randomised controlled trials evaluating the effects on diabetic foot ulcer healing of one or more wound dressings. There were no restrictions based on language or publication status. RESULTS: Fifteen eligible studies, evaluating nine dressing types, were included. Ten direct treatment comparisons were made. Whilst there was increased healing associated with hydrogel and foam dressings compared with basic wound contact materials, these findings were based on data from small studies at unclear or high risk of bias. The mixed treatment comparison suggested that hydrocolloid-matrix dressings were associated with higher odds of ulcer healing than all other dressing types; there was a high degree of uncertainty around these estimates, which were deemed to be of very low quality. CONCLUSIONS/INTERPRETATION: These findings summarise all available trial evidence regarding the use of dressings to heal diabetic foot ulcers. More expensive dressings may offer no advantages in terms of healing than cheaper basic dressings. In addition, evidence pointing to a difference in favour of 'advanced' dressing types over basic wound contact materials is of low or very low quality.

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis.

BACKGROUND: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES: To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES: Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS: Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS: Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS: As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS: Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Is the QALY blind, deaf and dumb to equity? NICE's considerations over equity.

INTRODUCTION/BACKGROUND: The quality-adjusted life year (QALY) is the preferred measure of health outcome used to inform decisions over the use of health care interventions in the UK NHS. This measure considers the overall impact of alternative interventions on both the quantity and quality of life. SOURCES OF DATA: Review of the relevant literature. Areas of agreement The QALY assumes that health improvement is equally valued between individuals. Areas of controversy Some can perceive as equitable, that is fair, the assumption that health improvement is equally valued between individuals in the QALY. However, others may believe that this assumption leaves no space for alternative views over equity to be explicitly considered in societal decision making. GROWING POINTS: The role of equity in decision making in the UK has been subject of intense debate, and controversy, and to-date there is no consensus on whether, or how, should NICE should change their general process. AREAS TIMELY FOR DEVELOPING RESEARCH: Further examination of the issues needs to be debated and researched.

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

A novel flow cytometric protocol for assessment of yeast cell adhesion.

Microbial adhesion is a field of recognized relevance and, as such, an impressive array of tools has been developed to understand its molecular mechanisms and ultimately for its quantification. Some of the major limitations found within these methodologies concern the incubation time, the small number of cells analyzed, and the operator's subjectivity. To overcome these aspects, we have developed a quantitative method to measure yeast cells' adhesion through flow cytometry. In this methodology, a suspension of yeast cells is mixed with green fluorescent polystyrene microspheres (uncoated or coated with host proteins). Within 2 h, an adhesion profile is obtained based on two parameters: percentage and cells-microsphere population's distribution pattern. This flow cytometry protocol represents a useful tool to quantify yeast adhesion to different substrata in a large scale, providing manifold data in a speedy and informative manner.

Hospital resource utilization and treatment cost of skeletal-related events in patients with metastatic breast or prostate cancer: estimation for the Portuguese National Health System.

BACKGROUND: Skeletal-related events (SREs) occur frequently in patients with bone metastases as a result of breast (BC) and prostate (PC) cancers. They increase both morbidity and mortality and lead to extensive health-care resource utilization. METHODS: Health care resource utilization by BC/PC patients with at least one SRE during the preceding 12 months was assessed through retrospective chart review. SRE-treatment costs were estimated using the Portuguese Ministry of Health cost database and analyzed using generalized linear models. RESULTS: This study included 152 patients from nine hospitals. The mean (SD) annual SRE-treatment cost per patient was €5963 (€3646) and €5711 (€4347), for BC (n=121) and PC (n=31) patients, respectively. Mean cost per single episode ranged between €1485 (radiotherapy) and €13,203 (spinal cord compression). Early onset of bone metastasis (P = 0.03) and diagnosis of bone metastases at or after the occurrence of the first SRE (P < 0.001) were associated with higher SRE-treatment costs. CONCLUSION: These results reveal the high hospital SRE-treatment costs, highlighting the need for early diagnosis and treatment, and identify key factors determining the economic value of therapies for patients with skeletal metastases.

Bevacizumab in combination with a taxane for the first-line treatment of HER2-negative metastatic breast cancer.

This paper presents a summary of the evidence review group (ERG) report into the use of bevacizumab (Avastin®, Roche) in combination with a taxane for the treatment of untreated metastatic breast cancer (mBC). The main clinical effectiveness data were derived from a single, open-label randomised controlled trial (RCT) (E2100) that evaluated the addition of bevacizumab to weekly (q.w.) paclitaxel in patients with human epidermal growth factor receptor 2-negative mBC who had not previously received chemotherapy for advanced disease. This trial reported statistically significant increases in median progression-free survival (PFS) for the addition of bevacizumab (5.8-11.3 months). Median overall survival was not significantly different between the two groups; whether this is a true null finding or due to crossover between treatment arms cannot be established, as relevant data were not collected. The manufacturer reported that the addition of bevacizumab to paclitaxel q.w. therapy was associated with a significant improvement in quality of life, as measured by FACT-B (functional assessment of cancer therapy for breast cancer) scores. However, the ERG noted that these results were based on extreme imputed values, the removal of which led to non-significant differences in quality of life. The manufacturer conducted an indirect comparison. However, owing to methodological limitations and concerns about the validity and exchangeability of the included trials, the ERG did not consider the findings to be reliable. One additional relevant RCT [AVADO (Avastin and Docetaxel); BO17708] evaluating the addition of bevacizumab to docetaxel was excluded from the manufacturer's submission. This was summarised by the ERG. In terms of response rate and PFS, AVADO reported a markedly smaller benefit of adding bevacizumab to docetaxel than that reported for adding bevacizumab to q.w. paclitaxel in E2100. AVADO also reported no statistically significant effect of combination therapy versus docetaxel in terms of overall survival. The manufacturer developed a de novo economic model that considered patients with the same baseline characteristics as women in the E2100 trial. The model assessed BEV + PAC - bevacizumab 10 mg/kg every 2 weeks in combination with paclitaxel 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; PAC q.w. - paclitaxel (monotherapy) 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; DOC - docetaxel (monotherapy) 75 mg/m2 on day 1 every 21 days (considered current UK NHS clinical practice in the submission); and GEM + PAC - gemcitabine 1250 mg/m2 on days 1 and 8 plus paclitaxel 175 mg/m2 on day 1 every 21 days. Pairwise comparisons were made between BEV + PAC and PAC (using the E2100 trial), BEV + PAC and DOC, and BEV + PAC and GEM + PAC. Based on NHS list prices, the manufacturer's model estimated incremental cost-effectiveness ratios (ICERs) for BEV + PAC of £ 117,803, £ 115,059 and £ 105,777 per QALY gained, relative to PAC, DOC and GEM + PAC regimens, respectively. If the NHS Purchasing and Supply Agency prices for PAC with a 10-g cap on the cost per patient of BEV were used instead, the ICERs for BEV + PAC were estimated at £ 77,314, £ 57,753 and £ 60,101 per QALY, respectively. The submission suggested that the regimen of BEV + DOC is not cost-effective because it is considered less effective and more costly than BEV + PAC. Analysis by the ERG suggested that alternative assumptions can increase the ICERs further and, based on current prices, no plausible changes to the model assumptions will bring the ICERs for BEV + PAC lower.

Economic evaluation of a randomized controlled trial of ultrasound therapy for hard-to-heal venous leg ulcers.

BACKGROUND: A pragmatic, multicentre randomized controlled trial (VenUS III) was conducted to determine whether low-dose ultrasound therapy increased the healing rate of hard-to-heal leg ulcers. This study was a cost-effectiveness analysis of the trial data. METHODS: Cost-effectiveness and cost-utility analyses were conducted alongside the VenUS III trial, in which patients were randomly allocated to either ultrasound treatment administered weekly for 12 weeks along with standard care, or standard care alone. The time horizon was 12 months and based on the UK National Health Service (NHS) perspective. RESULTS: The base-case analysis showed that ultrasound therapy added to standard care was likely to be more costly and provide no extra benefit over standard care alone. Individuals who received ultrasound treatment plus standard care took a mean of 14.7 (95 per cent confidence interval - 32.7 to 56.8) days longer to heal, had 0.009 (-0.042 to 0.024) fewer quality-adjusted life years and had higher treatment costs by £ 197.88 (-35.19 to 420.32). Based on these point estimates, ultrasound therapy plus standard care for leg ulcers was dominated by standard care alone. The analysis of uncertainty showed that this treatment strategy is unlikely to be cost-effective. CONCLUSION: Ultrasound treatment was not cost-effective for hard-to-heal leg ulcers and should not be recommended for adoption in the NHS.