A systematic review of cellular therapies for the treatment of limbal stem cell deficiency affecting one or both eyes.

PURPOSE: This systematic review (SR) assessed the efficacy, safety and cost-effectiveness of cell-based therapy to manage limbal stem cell deficiency (LSCD), a sight-threatening orphan condition most frequently associated with severe chemical or thermal burns. LSCD has historically been treated by transplanting limbal tissue. In 1997, a new treatment, cultured limbal epithelial autografts, was described for unilateral LSCD. In cases of bilateral disease cultured autologous oral mucosa stem cells have been used. The relative efficacy of different cultured tissue procedures is unknown. METHODS: A protocol was registered with PROSPERO (CRD42017081117). Searches were conducted in 14 databases and 6 conference websites. Two reviewers independently selected studies, conducted data extraction and assessed risk of bias. One reviewer extracted individual patient data (IPD); a second checked extracted data. Data were assessed to determine the feasibility of statistical analysis, with Bayesian synthesis used to estimate improvement achieved by different treatments. RESULTS: Fifty-two studies were eligible for inclusion (1113 eyes); 41 studies (716 eyes) reported IPD. No evidence was identified on cost-effectiveness. This SR was unable to confirm that any of the types of ex vivo cultured stem cell transplants identified for LSCD treatment were statistically superior when assessed against the outcomes of interest. CONCLUSIONS: We believe this SR is the first to include IPD analysis of LSCD data. There is no evidence for the superiority of any method of limbal stem cell transplant. Confirmation of the safety and efficacy of this treatment modality is challenging due to heterogeneity within and between the studies identified. Therefore, recommendations for future research are proposed.

Cochrane Centralised Search Service showed high sensitivity identifying randomized controlled trials: A retrospective analysis.

BACKGROUND AND OBJECTIVES: The Cochrane Central Register of Controlled Trials (CENTRAL) is compiled from a number of sources, including PubMed and Embase. Since 2017, we have increased the number of sources feeding into CENTRAL and improved the efficiency of our processes through the use of application programming interfaces, machine learning, and crowdsourcing.Our objectives were twofold: (1) Assess the effectiveness of Cochrane's centralized search and screening processes to correctly identify references to published reports which are eligible for inclusion in Cochrane systematic reviews of randomized controlled trials (RCTs). (2) Identify opportunities to improve the performance of Cochrane's centralized search and screening processes to identify references to eligible trials. METHODS: We identified all references to RCTs (either published journal articles or trial registration records) with a publication or registration date between 1st January 2017 and 31st December 2018 that had been included in a Cochrane intervention review. We then viewed an audit trail for each included reference to determine if it had been identified by our centralized search process and subsequently added to CENTRAL. RESULTS: We identified 650 references to included studies with a publication year of 2017 or 2018. Of those, 634 (97.5%) had been captured by Cochrane's Centralised Search Service. Sixteen references had been missed by the Cochrane's Centralised Search Service: six had PubMed-not-MEDLINE status, four were missed by the centralized Embase search, three had been misclassified by Cochrane Crowd, one was from a journal not indexed in MEDLINE or Embase, one had only been added to Embase in 2019, and one reference had been rejected by the automated RCT machine learning classifier. Of the sixteen missed references, eight were the main or only publication to the trial in the review in which it had been included. CONCLUSION: This analysis has shown that Cochrane's centralized search and screening processes are highly sensitive. It has also helped us to understand better why some references to eligible RCTs have been missed. The CSS is playing a critical role in helping to populate CENTRAL and is moving us toward making CENTRAL a comprehensive repository of RCTs.

A systematic review and network meta-analysis of injectable antibiotic options for the control of bovine respiratory disease in the first 45 days post arrival at the feedlot.

We conducted a systematic review and network meta-analysis to determine the comparative efficacy of antibiotics used to control bovine respiratory disease (BRD) in beef cattle on feedlots. The information sources for the review were: MEDLINE®, MEDLINE In-Process and MEDLINE® Daily, AGRICOLA, Epub Ahead of Print, Cambridge Agricultural and Biological Index, Science Citation Index, Conference Proceedings Citation Index - Science, the Proceedings of the American Association of Bovine Practitioners, World Buiatrics Conference, and the United States Food and Drug Administration Freedom of Information New Animal Drug Applications summaries. The eligible population was weaned beef cattle raised in intensive systems. The interventions of interest were injectable antibiotics used at the time the cattle arrived at the feedlot. The outcome of interest was the diagnosis of BRD within 45 days of arrival at the feedlot. The network meta-analysis included data from 46 studies and 167 study arms identified in the review. The results suggest that macrolides are the most effective antibiotics for the reduction of BRD incidence. Injectable oxytetracycline effectively controlled BRD compared with no antibiotics; however, it was less effective than macrolide treatment. Because oxytetracycline is already commonly used to prevent, control, and treat BRD in groups of feedlot cattle, the use of injectable oxytetracycline for BRD control might have advantages from an antibiotic stewardship perspective.

Comparative efficacy of blanket versus selective dry-cow therapy: a systematic review and pairwise meta-analysis.

A systematic review and meta-analysis were conducted to determine the efficacy of selective dry-cow antimicrobial therapy compared to blanket therapy (all quarters/all cows). Controlled trials were eligible if any of the following were assessed: incidence of clinical mastitis during the first 30 DIM, frequency of intramammary infection (IMI) at calving, or frequency of IMI during the first 30 DIM. From 3480 identified records, nine trials were data extracted for IMI at calving. There was an insufficient number of trials to conduct meta-analysis for the other outcomes. Risk of IMI at calving in selectively treated cows was higher than blanket therapy (RR = 1.34, 95% CI = 1.13, 1.16), but substantial heterogeneity was present (I2 = 58%). Subgroup analysis showed that, for trials using internal teat sealants, there was no difference in IMI risk at calving between groups, and no heterogeneity was present. For trials not using internal teat sealants, there was an increased risk in cows assigned to a selective dry-cow therapy protocol, compared to blanket treatment, with substantial heterogeneity in this subgroup. However, the small number of trials and heterogeneity in the subgroup without internal teat sealants suggests that the relative risk between treatments may differ from the determined point estimates based on other unmeasured factors.

Comparative efficacy of antimicrobial treatments in dairy cows at dry-off to prevent new intramammary infections during the dry period or clinical mastitis during early lactation: a systematic review and network meta-analysis.

A systematic review and network meta-analysis were conducted to assess the relative efficacy of antimicrobial therapy given to dairy cows at dry-off. Eligible studies were controlled trials assessing the use of antimicrobials compared to no treatment or an alternative treatment, and assessed one or more of the following outcomes: incidence of intramammary infection (IMI) at calving, incidence of IMI during the first 30 days in milk (DIM), or incidence of clinical mastitis during the first 30 DIM. Databases and conference proceedings were searched for relevant articles. The potential for bias was assessed using the Cochrane Risk of Bias 2.0 algorithm. From 3480 initially identified records, 45 trials had data extracted for one or more outcomes. Network meta-analysis was conducted for IMI at calving. The use of cephalosporins, cloxacillin, or penicillin with aminoglycoside significantly reduced the risk of new IMI at calving compared to non-treated controls (cephalosporins, RR = 0.37, 95% CI 0.23-0.65; cloxacillin, RR = 0.55, 95% CI 0.38-0.79; penicillin with aminoglycoside, RR = 0.42, 95% CI 0.26-0.72). Synthesis revealed challenges with a comparability of outcomes, replication of interventions, definitions of outcomes, and quality of reporting. The use of reporting guidelines, replication among interventions, and standardization of outcome definitions would increase the utility of primary research in this area.

A systematic review and network meta-analysis of bacterial and viral vaccines, administered at or near arrival at the feedlot, for control of bovine respiratory disease in beef cattle.

Vaccination against putative causal organisms is a frequently used and preferred approach to controlling bovine respiratory disease complex (BRD) because it reduces the need for antibiotic use. Because approximately 90% of feedlots use and 90% of beef cattle receive vaccines in the USA, information about their comparative efficacy would be useful for selecting a vaccine. We conducted a systematic review and network meta-analysis of studies assessing the comparative efficacy of vaccines to control BRD when administered to beef cattle at or near their arrival at the feedlot. We searched MEDLINE, MEDLINE In-Process, MEDLINE Daily Epub Ahead of Print, AGRICOLA, Cambridge Agricultural and Biological Index, Science Citation Index, and Conference Proceedings Citation Index - Science and hand-searched the conference proceedings of the American Association of Bovine Practitioners and World Buiatrics Congress. We found 53 studies that reported BRD morbidity within 45 days of feedlot arrival. The largest connected network of studies, which involved 17 vaccine protocols from 14 studies, was included in the meta-analysis. Consistent with previous reviews, we found little compelling evidence that vaccines used at or near arrival at the feedlot reduce the incidence of BRD diagnosis.

Comparative efficacy of teat sealants given prepartum for prevention of intramammary infections and clinical mastitis: a systematic review and network meta-analysis.

A systematic review and network meta-analysis were conducted to assess the relative efficacy of internal or external teat sealants given at dry-off in dairy cattle. Controlled trials were eligible if they assessed the use of internal or external teat sealants, with or without concurrent antimicrobial therapy, compared to no treatment or an alternative treatment, and measured one or more of the following outcomes: incidence of intramammary infection (IMI) at calving, IMI during the first 30 days in milk (DIM), or clinical mastitis during the first 30 DIM. Risk of bias was based on the Cochrane Risk of Bias 2.0 tool with modified signaling questions. From 2280 initially identified records, 32 trials had data extracted for one or more outcomes. Network meta-analysis was conducted for IMI at calving. Use of an internal teat sealant (bismuth subnitrate) significantly reduced the risk of new IMI at calving compared to non-treated controls (RR = 0.36, 95% CI 0.25-0.72). For comparisons between antimicrobial and teat sealant groups, concerns regarding precision were seen. Synthesis of the primary research identified important challenges related to the comparability of outcomes, replication and connection of interventions, and quality of reporting of study conduct.

High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance.

The development of obesity-associated insulin resistance is associated with B-lymphocyte accumulation in visceral adipose tissue (VAT) and is prevented by B-cell ablation. To characterize potentially pathogenic B-cell repertoires in this disorder, we performed high-throughput immunoglobulin (Ig) sequencing from multiple tissues of mice fed high-fat diet (HFD) and regular diet (RD). HFD significantly changed the biochemical properties of Ig heavy-chain complementarity-determining region-3 (CDRH3) sequences, selecting for IgA antibodies with shorter and more hydrophobic CDRH3 in multiple tissues. A set of convergent antibodies of highly similar sequences found in the VAT of HFD mice but not RD mice showed significant somatic mutation, suggesting a response shared between mice to a common antigen or antigens. These findings indicate that a simple high-fat dietary intervention has a major impact on mouse B-cell repertoires, particularly in adipose tissues.

Is consuming yoghurt associated with weight management outcomes? Results from a systematic review.

BACKGROUND: Yoghurt is part of the diet of many people worldwide and is commonly recognised as a 'health food'. Epidemiological studies suggest that yoghurt may be useful as part of weight management programs. In the absence of comprehensive systematic reviews, this systematic review investigated the effect of yoghurt consumption by apparently healthy adults on weight-related outcomes. METHODS: An extensive literature search was undertaken, as part of a wider scoping review, to identify yoghurt studies. A total of 13 631 records were assessed for their relevance to weight-related outcomes. RESULTS: Twenty-two publications were eligible according to the review protocol. Cohort studies (n=6) and cross-sectional studies (n=7) all showed a correlation between yoghurt and lower or improved body weight/composition. Six randomised controlled trials (RCTs) and one controlled trial had various limitations, including small size and short duration. One RCT showed significant effects of yoghurt on weight loss, but was confounded by differences in calcium intake. One trial showed nonsignificant weight gain and the remaining five trials showed nonsignificant weight losses that were greater in yoghurt consumers. CONCLUSIONS: Yoghurt consumption is associated with lower body mass index, lower body weight/weight gain, smaller waist circumference and lower body fat in epidemiological studies. RCTs suggest weight reduction effects, but do not permit determination of a cause-effect relationship. Well-controlled, adequately powered trials in research and community settings appear likely to identify a modest but beneficial effect of yoghurt consumption for prevention of weight gain and management of obesity. The ready availability of yoghurt (a nutrient-dense food) and its ease of introduction to most diets suggests that educating the public to eat yoghurt as part of a balanced and healthy diet may potentially contribute to improved public health. Future carefully designed RCTs could provide proof of principle and large community-based studies could determine the practical impact of yoghurt on body weight/composition.

Deep sequencing in library selection projects: what insight does it bring?

High throughput sequencing is poised to change all aspects of the way antibodies and other binders are discovered and engineered. Millions of available sequence reads provide an unprecedented sampling depth able to guide the design and construction of effective, high quality naïve libraries containing tens of billions of unique molecules. Furthermore, during selections, high throughput sequencing enables quantitative tracing of enriched clones and position-specific guidance to amino acid variation under positive selection during antibody engineering. Successful application of the technologies relies on specific PCR reagent design, correct sequencing platform selection, and effective use of computational tools and statistical measures to remove error, identify antibodies, estimate diversity, and extract signatures of selection from the clone down to individual structural positions. Here we review these considerations and discuss some of the remaining challenges to the widespread adoption of the technology.

Applicability and feasibility of systematic review for performing evidence-based risk assessment in food and feed safety.

Food and feed safety risk assessment uses multi-parameter models to evaluate the likelihood of adverse events associated with exposure to hazards in human health, plant health, animal health, animal welfare, and the environment. Systematic review and meta-analysis are established methods for answering questions in health care, and can be implemented to minimize biases in food and feed safety risk assessment. However, no methodological frameworks exist for refining risk assessment multi-parameter models into questions suitable for systematic review, and use of meta-analysis to estimate all parameters required by a risk model may not be always feasible. This paper describes novel approaches for determining question suitability and for prioritizing questions for systematic review in this area. Risk assessment questions that aim to estimate a parameter are likely to be suitable for systematic review. Such questions can be structured by their "key elements" [e.g., for intervention questions, the population(s), intervention(s), comparator(s), and outcome(s)]. Prioritization of questions to be addressed by systematic review relies on the likely impact and related uncertainty of individual parameters in the risk model. This approach to planning and prioritizing systematic review seems to have useful implications for producing evidence-based food and feed safety risk assessment.

The value of FDG positron emission tomography/computerised tomography (PET/CT) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation.

OBJECTIVES: In the UK, colorectal cancer (CRC) is the third most common malignancy (behind lung and breast cancer) with 37,514 cases registered in 2006: around two-thirds (23,384) in the colon and one-third (14,130) in the rectum. Treatment of cancers of the colon can vary considerably, but surgical resection is the mainstay of treatment for curative intent. Following surgical resection, there is a comprehensive assessment of the tumour, it's invasion characteristics and spread (tumour staging). A number of imaging modalities are used in the pre-operative staging of CRCs including; computerised tomography (CT), magnetic resonance imaging, ultrasound imaging and positron emission tomography (PET). This report examines the role of CT in combination with PET scanning (PET/CT 'hybrid' scan). The research objectives are: to evaluate the diagnostic accuracy and therapeutic impact of fluorine-18-deoxyglucose (FDG) PET/CT for the pre-operative staging of primary, recurrent and metastatic cancer using systematic review methods; undertake probabilistic decision-analytic modelling (using Monte Carlo simulation); and conduct a value of information analysis to help inform whether or not there is potential worth in undertaking further research. DATA SOURCES: For each aspect of the research - the systematic review, the handsearch study and the economic evaluation - a database was assembled from a comprehensive search for published and unpublished studies, which included database searches, reference lists search and contact with experts. In the systematic review prospective and retrospective patient series (diagnostic cohort) and randomised controlled trials (RCTs) were eligible for inclusion. Both consecutive series and series that are not explicitly reported as consecutive were included. REVIEW METHODS: Two reviewers extracted all data and applied the criteria independently and resolved disagreements by discussion. Data to populate 2 × 2 contingency tables consisting of the number of true positives, true negatives, false positives and false negatives using the studies' own definitions were extracted, as were data relating to changes in management. Fourteen items from the Quality Assessment of Diagnostic Accuracy Studies checklist were used to assess the methodological quality of the included studies. Patient-level data were used to calculate sensitivity and specificity with confidence intervals (CIs). Data were plotted graphically in forest plots. For the economic evaluation, economic models were designed for each of the disease states: primary, recurrent and metastatic. These were developed and populated based on a variety of information sources (in particular from published data sources) and literature, and in consultation with clinical experts. RESULTS: The review found 30 studies that met the eligibility criteria. Only two small studies evaluated the use of FDG PET/CT in primary CRC, and there is insufficient evidence to support its routine use at this time. The use of FDG PET/CT for the detection of recurrent disease identified data from five retrospective studies from which a pooled sensitivity of 91% (95% CI 0.87% to 0.95%) and specificity of 91% (95% CI 0.85% to 0.95%) were observed. Pooled accuracy data from patients undergoing staging for suspected metastatic disease showed FDG PET/CT to have a pooled sensitivity of 91% (95% CI 87% to 94%) and a specificity of 76% (95% CI 58% to 88%), but the poor quality of the studies means the validity of the data may be compromised by several biases. The separate handsearch study did not yield any additional unique studies relevant to FDG PET/CT. Models for recurrent disease demonstrated an incremental cost-effectiveness ratio of £ 21,409 per quality-adjusted life-year (QALY) for rectal cancer, £ 6189 per QALY for colon cancer and £ 21,434 per QALY for metastatic disease. The value of handsearching to identify studies of less clearly defined or reported diagnostic tests is still to be investigated. CONCLUSIONS: The systematic review found insufficient evidence to support the routine use of FDG PET/CT in primary CRC and only a small amount of evidence supporting its use in the pre-operative staging of recurrent and metastatic CRC, and, although FDG PET/CT was shown to change patient management, the data are divergent and the quality of research is generally poor. The handsearch to identify studies of less clearly defined or reported diagnostic tests did not find additional studies. The primary limitations in the economic evaluations were due to uncertainty and lack of available evidence from the systematic reviews for key parameters in each of the five models. In order to address this, a conservative approach was adopted in choosing DTA estimates for the model parameters. Probabilistic analyses were undertaken for each of the models, incorporating wide levels of uncertainty particularly for the DTA estimates. None of the economic models reported cost-savings, but the approach adopted was conservative in order to determine more reliable results given the lack of current information. The economic evaluations conclude that FDG PET/CT as an add-on imaging device is cost-effective in the pre-operative staging of recurrent colon, recurrent rectal and metastatic disease but not in primary colon or rectal cancers. There would be value in undertaking an RCT with a concurrent economic evaluation to evaluate the therapeutic impact and cost-effectiveness of FDG PET/CT compared with conventional imaging (without PET) for the pre-operative staging of recurrent and metastatic CRC.

Rimonabant for the treatment of overweight and obese people.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rimonabant for the treatment of obese or overweight patients based upon a review of the manufacturer's submission to the National Centre for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's main evidence came from four randomised controlled trials. Rimonabant resulted in a significantly greater benefit than placebo for all primary weight loss outcomes. At 1 year, rimonabant had a statistically significant beneficial effect on systolic blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting plasma glucose in diabetics and non-diabetics, and glycosylated haemoglobin in diabetics. Improvements were maintained over 2 years with rimonabant; withdrawal of rimonabant at 1 year resulted in a reduction in weight loss until there was no difference from placebo at 2 years. Psychiatric adverse events were experienced by 26% and 14% of rimonabant and placebo patients respectively; figures for symptoms of depression were 9% and 5% respectively. Pairwise comparisons of orlistat, sibutramine and rimonabant showed beneficial effects of rimonabant over orlistat and sibutramine for weight loss outcomes; however, response hurdles imposed on orlistat or sibutramine in clinical practice may not have been applied in the orlistat and sibutramine trials. The manufacturer's Markov cohort model evaluated rimonabant versus orlistat, sibutramine and diet and exercise alone for three base-case populations. The incremental cost-effectiveness ratio (ICER) of rimonabant varied from 10,534 pounds to 13,236 pounds per quality-adjusted life-year (QALY) versus diet and exercise, to 8977 pounds to 12,138 pounds per QALY versus orlistat, to 1463 pounds to 3908 pounds per QALY versus sibutramine. In subgroup analysis there was a wider variation in the ICER estimates although none exceeded 20,000 pounds per QALY. The ICER of rimonabant remained under 20,000 pounds per QALY in reanalyses by the manufacturer and the ERG, with the results sensitive to the source of health-related quality of life (HRQoL) benefits in the model. Four treatment strategies were modelled in comparisons of rimonabant versus diet and exercise alone and orlistat and sibutramine in which rimonabant was continued only in patients achieving 5% weight loss at 3, 6, 9 or 12 months. In pairwise comparisons rimonabant remained below a threshold of 30,000 pounds per QALY in 70% of the comparisons reported. The results were most sensitive to the decrement applied to depression and the costs of screening for depression. In conclusion, areas of uncertainty remain in relation to the clinical effectiveness and cost-effectiveness of rimonabant, for example lack of evidence on long-term outcomes and the effect of rimonabant on cardiovascular events, developing diabetes and mortality, and lack of data on the HRQoL benefits associated with rimonabant. The lack of response hurdles applied to sibutramine and orlistat means that the comparator strategies were not considered by the ERG to reflect their respective product licenses or current NHS use. The NICE guidance issued as a result of the STA states that rimonabant is recommended as an adjunct to diet and exercise for adults who are obese or overweight and who have had an inadequate response to, are intolerant of or are contraindicated to orlistat and sibutramine.

Modern trends in ovulation induction.

Patients with anovulatory infertility, who received treatment at one unit over a four year period, were assessed to determine the pregnancy rate and the incidence of complications while undergoing ovulation induction with gonadotropins. The patients in this group who had further in vitro fertilization (IVF) treatment were followed up, and the outcome in IVF cycles was assessed. Data from a total of 75 patients, who had completed 91 episodes of treatment involving 273 cycles of ovulation induction over a 4-year period in a University-affiliated teaching hospital, was analysed retrospectively. The cumulative pregnancy rate was 34% after three ovulation induction cycles, and was 46% overall. The clinical pregnancy rate per cycle was 15.4%, and per ovulatory cycle was 21%. The multiple pregnancy rate was 12%, and there were no cases of ovarian hyperstimulation syndrome (OHSS). In this group of patients undergoing ovulation induction, the multiple pregnancy rate was 12% and there were no cases of ovarian hyperstimulation syndrome (OHSS). The multiple pregnancy rate was 17%. Our result indicate that anovulatory patients benefit from ovulation induction with gonadotropins prior to IVF treatment.

Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

OBJECTIVES: To determine the diagnostic accuracy of tests for detecting urinary tract infection (UTI) in children under 5 years of age and to evaluate the effectiveness of tests used to investigate further children with confirmed UTI. Also, to evaluate the effectiveness of following up children with UTI and the cost-effectiveness of diagnostic and imaging tests for the diagnosis and follow-up of UTI in children under 5. An additional objective was to develop a preliminary diagnostic algorithm for healthcare professionals. DATA SOURCES: Electronic databases were searched up to the end of 2002/early 2003. Consultation with experts in the field. REVIEW METHODS: A systematic review was undertaken using published guidelines and results were analysed according to test grouping: diagnosis of UTI and further investigation of UTI. The cost-effectiveness results from existing evaluations were synthesised. A separate cost-effectiveness model was developed using the best available evidence, in part derived from the results of the systematic review, to illustrate the potential cost-effectiveness of some alternative management strategies in a UK setting. The results of the systematic review were used to propose diagnostic algorithms for the diagnosis and further investigation of UTI in children. Economic analyses did not contribute directly to the development of these algorithms. RESULTS: The studies included in the review provided very little data on the accuracy of clinical investigations for the diagnosis of UTI, and criteria for clinical suspicion of UTI were not further defined. The majority of studies included in the review found that clean voided midstream urine (CVU) samples had similar accuracy to suprapubic aspiration (SPA) samples when cultured with the advantage of being a non-invasive collection method that can be used in the GP's surgery. Pad, nappy or bag specimens may be appropriate methods for obtaining a urine sample in non-toilet-trained children, although only limited data were available. Although the glucose test was reported to have the highest accuracy in terms of both ruling in and ruling out disease, only a limited number of studies of this test were included and these were conducted over 30 years ago. Dipstick tests are easy to perform in the GP's surgery, give an immediate result and are relatively cheap. The results of the systematic review showed that a dipstick for leucocyte esterase (LE) and nitrite, where both test results are interpreted in combination, was a good test both for ruling in (both positive) and ruling out (both negative) a UTI. A dipstick positive for either LE or nitrite and negative for the other provides inconclusive diagnostic information and further testing is therefore required in these patients. Microscopy is more time consuming and expensive to perform than a dipstick test, but potentially quicker and cheaper than culture. As with dipstick tests, a combination of microscopy for pyuria and bacteriuria can be used accurately to rule in and rule out a UTI. An indeterminate test result is again obtained if microscopy is positive for either pyuria or bacteriuria, and negative for the other. Confirmatory culture is required in these patients. In patients considered to have a UTI, further culture to determine antibiotic sensitivities may be an option to inform treatment decisions. Only one study satisfied the inclusion criteria of the economic review and the review highlighted a number of potential limitations of this study for NHS decision-making. A separate decision-analytic model was therefore developed to provide a more reliable estimate of the optimal strategy regarding the diagnosis and further investigation of children under 5 with suspected UTI from the perspective of the NHS. The economic model found that the optimal diagnostic strategy for children presenting with symptoms suggestive of UTI depends on a number of key factors. These included the relevant subgroup of children concerned, in terms of gender and age, and the health service's maximum willingness to pay for an additional quality-adjusted life-year. CONCLUSIONS: The results of the systematic review were used to derive an algorithm for the diagnosis of UTI in children under 5. This algorithm represents the conclusions of the review in terms of effective practice. There were insufficient data to propose an algorithm for the further investigation of UTI in children under 5. The quality assessment highlighted several areas that could be improved upon in future diagnostic accuracy studies.

Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

OBJECTIVES: To investigate the cost-effectiveness of using prognostic information to identify patients with breast cancer who should receive adjuvant therapy. DATA SOURCES: Electronic databases from 1980 through to February 2002. A survey of clinical practice in UK cancer centres and units. Large retrospective dataset containing data on prognostic factors, treatments and outcomes for women with early breast cancer treated in Oxford. REVIEW METHODS: Between six and nine databases were searched by an information expert. Evidence-based methods were used to review and select those studies and the quality of each included paper was assessed using standard assessment tools reported in the literature or piloted and developed for this study. A survey of clinical practice in UK cancer centres and units was carried out to ensure that conclusions drawn from the report could be implemented. These data, along with the information gathered in the systematic reviews, informed the methodological approach adopted for the health economic modelling. An illustrative framework was developed for incorporating patient-level prediction within a health economic decision model. This framework was applied to a large retrospective dataset containing data on prognostic factors, treatments and outcomes for women with early breast cancer treated in Oxford. The data were used to estimate directly a parametric regression-based risk equation, from which a prognostic index was developed, and prognosis-specific estimates of the baseline breast cancer hazard could be observed. Published estimates of treatment effects, health service treatment costs and utilities were used to construct a decision analytic framework around this risk equation, thus enabling simulation of the effectiveness and cost-effectiveness of adjuvant therapy for all possible combinations of prognostic factors included in the model. RESULTS: The lack of good-quality systematic reviews and well-conducted studies of prognostic factors in breast cancer is a striking finding. There are no registers of studies of prognostic factors or of reviews of prognostic studies. Many of the reviews used weak methods, primary studies are similar with poor methodology and reporting of results. In addition, there is much variation in patient populations, assay methods, analysis of results, definitions used and reporting of results. Most studies appear to be retrospective and some use inappropriate methods likely to inflate outcomes such as optimising cut points and failing to test the results in an independent population. Very few reviews used meta-analysis to conduct a pooled analysis and to provide an estimate of the average size of any association. Instead, most reviews relied on vote counting. Although many prognostic models for breast cancer have been published, remarkably few have been re-examined by independent groups in independent settings. The few validation studies have been carried out on ill-defined samples, sometimes of smaller size and short follow-up, and sometimes using different patient outcomes when validating a model. The evidence from the validation studies shows support for the prognostic value of the Nottingham Prognostic Index (NPI). No new prognostic factors have been shown to add substantially to those identified in the 1980s. Improvement of this index depends on finding factors that are as important as, but independent of, lymph node, stage and pathological grade. The NPI remains a useful clinical tool, although additional factors may enhance its use. We accepted that hormone receptor status (ER) for hormonal therapy such as tamoxifen and prediction of response to trastuzumab by HER2 did not require systematic review, as the mechanism of action of these drugs requires intact receptors. There was no clear evidence that other factors were useful predictors of response and survival. The survey confirmed pathological nodal status, tumour grade, tumour size and ER status as the most clinically important factors for consideration when selecting women with early breast cancer for adjuvant systemic therapy in the UK. The protocols revealed that although UK cancer centres appear to be using the same prognostic and predictive factors when selecting women to receive adjuvant therapy, much variation in clinical practice exists. Some centres use protocols based upon the NPI whereas others do not use a single index score. Within NPI and non-NPI users, between-centre variability exists in guidelines for women for whom the benefits are uncertain. Consensus amongst units appears to be greatest when selecting women for adjuvant hormone therapy with the decision based primarily upon ER or progesterone receptor status rather than combinations of a number of factors. Guidelines as to who should receive adjuvant chemotherapy, however, were found to be much less uniform. Searches of the literature revealed only five published papers that had previously examined the cost-effectiveness of using prognostic information for clinical decision-making. These studies were of varying quality and highlight the fact that economic evaluation in this area appears still to be in its infancy. By combining methodologies used in determining prognosis with those used in health economic evaluation, it was possible to illustrate an approach for simulating the effectiveness (survival and quality-adjusted survival) and the cost-effectiveness associated with the decision to treat individual women or groups of women with different prognostic characteristics. The model showed that effectiveness and cost-effectiveness of adjuvant systemic therapy have the potential to vary substantially depending upon prognosis. For some women therapy may prove very effective and cost-effective, whereas for others it may actually prove detrimental (i.e. the reductions in health-related quality of life outweigh any survival benefit). CONCLUSIONS: Outputs from the framework constructed using the methods described here have the potential to be useful for clinicians, attempting to determine whether net benefits can be obtained from administering adjuvant therapy for any presenting woman; and also for policy makers, who must be able to determine the total costs and outcomes associated with different prognosis based treatment protocols as compared with more conventional treat all or treat none policies. A risk table format enabling clinicians to look up a patient's prognostic factors to determine the likely benefits (survival and quality-adjusted survival) from administering therapy may be helpful. For policy makers, it was demonstrated that the model's output could be used to evaluate the cost-effectiveness of different treatment protocols based upon prognostic information. The framework should also be valuable in evaluating the likely impact and cost-effectiveness of new potential prognostic factors and adjuvant therapies.